Transplant stratification

Abstract

The invention relates to biomarker signatures for stratifying the graft function and / or infection status of a solid organ transplant recipient, methods of using the same and kits for the detection thereof. In particular, the present invention relates to biomarker signatures for stratifying Chronic Lung Allograft Dysfunction (CLAD) and / or infection status of a lung transplant recipient.

Description

[0001] TRANSPLANT STRATIFICATION FIELD OF THE INVENTION The invention relates to biomarker signatures for stratifying the graft function and / or infection status of a solid organ transplant recipient, methods of using the same and kits for the detection thereof. In particular, the present invention relates to biomarker signatures for stratifying Chronic Lung Allograft Dysfunction (CLAD) and / or infection status of a lung transplant recipient. BACKGROUND Recipients of a solid organ transplant are prescribed immunosuppressant drugs to avoid graft rejection. While often effective, the evident reduction in the functioning of the immune system leaves the patient at a higher risk of contracting an infection, which in turn may negatively impact graft function. Clinicians are required to decipher if the symptoms that the patient is experiencing are in fact linked to an infection or are indicative of graft rejection. There is currently no clear diagnostic test that can rapidly and efficiently inform clinicians on the simultaneous infection and / or graft rejection status of their patient, and thereby better inform the route to an effective treatment. In the case of lung transplant, graft rejection initially manifests as acute lung allograft dysfunction (ALAD). ALAD is a reversible form of graft dysfunction and by definition, graft function returns to baseline on recovery. ALAD can be caused by multiple aetiologies and increases the risk / may precipitate the development of chronic or irreversible lung allograft dysfunction. This phenomenon is referred to as Chronic Lung Allograft Dysfunction (CLAD). Lung dysfunction therefore may be indicative of the presence of CLAD but may also be due to an acute injury such as, but not limited to, an infection that could be bacterial, viral, or fungal in origin. The prognosis of patients diagnosed with CLAD is poor, with the two manifestations – Bronchiolitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS) – having average ‘survival after onset’ times of 3-5 years and 1-1.5 years respectively. Among the varied factors implicated in the development of CLAD, an infection can pose a significant risk in the 90-day window post- transplantation and beyond, wherein acute infections from respiratory pathogens are high risk factors for CLAD onset and this includes viral, bacterial, or fungal infections. For example, fungal infections by invasive Aspergillus can significantly reduce 5-yr survival in lung transplant recipients. A variety of immune cells exert critical roles in innate and adaptive immune responses including: T lymphocytes (also referred to as T cells), B lymphocytes (also referred to as B cells), and natural killer (NK) cells, among others. T cells principally differentiate into cytotoxic CD8+ or CD4+ T cells, including CD4+ T-helpers (Th). Other T cellsubsets relevant in the context of transplant engraftment and / or rejection include Mucosal Associated Invariant T (MAIT), Gamma delta ( ), regulatory (Treg), follicular helper(Tfh), and terminally differentiated effector memory (TEMRA). Immune cell populations can migrate into the circulating blood of the transplant recipient and lung grafts can retain donor immunome patterns several months post transplantation. For example, some previous studies have shown that higher levels of CCR2+CD4+ T cells are associated with increased symptoms of lung fibrosis in patients; the expression of PDL1 in donor tissue is associated with graft tolerance; and CD4+CD57+PD1- T cells within a bronchoalveolar lavage (BAL) sample have been linked to a higher risk of CLAD. Some previous studies have also assessed a combination of markers for predicting disease outcomes, for example T-cell antigens were found to be differentially expressed in patients with lung diseases or lung transplant rejection, and were determined to be correlated with the occurrence of a severe adverse event. However, to-date, whilst specific biomarkers or biomarker signatures have been described which are useful in the diagnosis and / or prognosis of a single disease state, e.g. the presence of an infection or CLAD, there is as yet no biomarker signature or protocol which is capable of differentiating between different sub-types of graft rejection, between graft rejection and infection, and between different types of infection in lung transplant patients in a single assay. Therefore, patients presenting with symptoms may be subjected to multiple rounds of testing before the underlying disease state is identified. This can increase the time between clinical presentation, diagnosis and treatment, increasing the risk of poor clinical outcomes, or more aggressive treatment to cause their disease. Accordingly, there is a need in the art to simplify the stratification of graft function and / or infection status of solid organ transplant recipients, enabling early diagnosis and prognosis of graft dysfunction and / or infection, such that treatment can be initiated earlier and clinical outcomes improved. In particular, non-invasive tests for such stratification, using biomarker signatures present in the blood or bronchoalveolar lavage (BAL) would be highly desirable. It is an object of the present invention to address one or more of these address challenges and to provide an effective means for screening solid organ transplant recipients and stratifying their graft function and / or infection status. 1 SUMMARY OF THE INVENTION The present inventors have for the first time identified a single panel of biomarkers which can differentiated between graft function / dysfunction and infection status in a solid organ transplant recipient. Biomarker signatures within this panel from blood or BAL samples are diagnostic of graft function, graft dysfunction and infection. Further, specific biomarker signatures are diagnostic of the grade of graft dysfunction and the type of infection. Thus, the biomarker signatures identified by the inventors can be used to stratifying the graft function and / or infection status of a solid organ transplant recipient. In particular, the present inventors have identified a panel of biomarkers which can be used to differentiate between CLAD and infection status in lung transplant recipients. Thus, the present invention relates to methods comprising detecting biomarkers in immune cells derived from a solid organ (e.g. lung) transplant recipient’s blood and / or BAL samples, and stratifying the subject’s graft function and / or infection status by comparing those biomarker signatures to reference profiles consisting of novel validated immune cell markers. These biomarker signatures can be exploited to predict, diagnose, prognose or characterise risk of graft function loss or rejection and infection. In the context of lung transplant recipients, the biomarker signatures have utility in discriminating CLAD; as well as clinical phenotypes: BOS / RAS, grade of CLAD, or graft rejection; and infection status, including specifically discriminating between different infectious agents (bacterial, viral or fungal (Aspergillus)). Accordingly, the present invention provides a method for stratifying the graft function and / or infection status of a lung transplant recipient, said method comprising determining a biomarker signature which comprises: (a) at least one biomarker in a population of T cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1 and ICOS; (b) at least one biomarker in a population of B cells, wherein said at least one biomarker is selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD; and / or (c) at least one biomarker in a population of Natural Killer (NK) cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1 and CD62L; wherein the population of T cells, B cells and / or NK cells is obtained from a sample from said recipient. Determining said biomarker signature may comprise or consist of determining the level of said at least one said biomarkers in a population of T cells, at least one said biomarkers in a population of B cells and / or at least one said biomarkers in a population of NK cells. The biomarker signature may comprise or consist of: (a) (i) at least one of said biomarkers in a population of T cells, and (ii) at least one of said biomarkers in a population of B cells; (b) (i) at least one of said biomarkers in a population of T cells, and (ii) at least one of said biomarkers in a population of NK cells; (c) (i) at least one of said biomarkers in a population of B cells, and (ii) at least one of said biomarkers in a population of NK cells; and / or (d) (i) at least one of said biomarkers in a population of T cells, (ii) at least one of said biomarkers in a population of B cells and at least one of said biomarkers in a population of NK cells. Determining said biomarker signature may comprise or consist of quantifying a population of: (a) T cells expressing at least one biomarker selected from KLRG1, TIGIT, PD1 and ICOS; (b) B cells expressing at least one biomarker selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD; and / or (c) NK cells expressing at least one at least one biomarker selected from KLRG1, TIGIT, PD1 and CD62L. Alternatively or in addition: (a) the population of T cells may comprise or consist of one or more of: CD4- positive T cells (CD4+), CD8-positive T cells (CD8+), mucosal-associated invariant T cells (MAIT), gamma delta T cells ( ), follicular T helper cells (Tfh), regulatory T cells (Treg), and effector memory RA T cells (TEMRA); and / or (c) the method may comprise or consist of quantifying one or more populations of CD4+T cells, CD8+T cells, MAIT, T cells, Tfhcells, Tregcells, and / or TEMRA. Determining the level of said at least one said biomarkers in a population of T cells, at least one said biomarkers in a population of B cells and / or at least one said biomarkers in a population of NK cells may comprise or consist of determining whether the level of said at least one biomarker exceeds a threshold value. Quantifying said population of T cells expressing at least one biomarker, said population of B cells expressing at least one biomarker and / or said population of NK cells expressing at least one biomarker may comprise or consist of determining whether the number of cells in said population exceeds a threshold value. Optionally said threshold value may be: (a) a fold- change increase of at least 1.5, preferably at least 2; or (b) a fold-change decrease of at least 1.5, preferably at least 2, depending on the biomarker in question. Determining a biomarker signature may comprise or consist of the use of Fluorescent Activated Cell Sorting (FACS) and / or transcriptomics. The sample may be selected from a blood, bronchoalveolar lavage (BAL), a tissue sample, cell sample and / or organ sample, wherein preferably said tissue, cell or organ sample is taken from the transplanted solid organ; wherein preferably the solid organ transplant is a lung transplant and the sample is a blood or BAL sample. 2

[0002] According to methods of the invention, stratifying the graft function and / or infection status can determine whether a lung transplant recipient has: Chronic Lung Allograft Dysfunction (CLAD); an infection; and / or a functional graft. Optionally said stratifying may comprise or consist of differentiating between the category of CLAD and / or infection type. According to methods of the invention, stratifying the graft function and / or infection status may comprise determining if a lung transplant recipient exhibits a biomarker signature associated with a first phenotype or a second phenotype in a comparison of the form: first phenotype versus second phenotype; wherein optionally the comparison comprises the following: CLAD versus a functional lung graft; incipient CLAD versus functional lung graft; active disease (active lung graft dysfunction) versus quiescent disease (i.e. stable lung graft function, whether a functional lung graft or stable lung graft dysfunction); progressive CLAD versus stable CLAD; infection versus no infection (optionally fungal infection versus no infection; viral infection versus no infection; and / or bacterial infection versus no infection); CLAD versus infection; fungal infection versus viral infection; fungal infection versus bacterial infection; and / or viral infection versus bacterial infection. According to methods of the invention, a sample may be a blood sample, wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 in a population of T cells; (b) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (c) (i) an increase in the level of TACI; (ii) a decrease in the level of IgD; and / or a decrease in the level of CD27; in a population of B cells; compared with a functional lung graft. Optionally: said CLAD phenotype may be associated with any one, any two or all three of (a) to (c); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a blood sample and (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT and T cells; (b) the level of PD1 is increased in one or more T cell population selected from CD8+T cells, MAIT, and TfhT cells; (c) the level of PD1 is decreased in a population of Tregcells; (d) the level of TIGIT is increased in one or more T cell population selected from CD8+T cells and T cells; (e) the level of TIGIT is decreased in a population of TEMRA; (f) the level of KLRG1 and / or PD1 is increased in a population of NK cells; (g) the level of TACI is increased in a population of B cells; and / or (h) the level of IgD and / or CD27 is decreased in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any two or more, any five or more or all eight of (a) to (h); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a BAL sample, and wherein a CLAD phenotype is associated with: (a) a decrease in the level of TIGIT, PD1, KLRG1 and / or ICOS in a population of T cells; (b) a decrease in the level of KLRG1 in a population of NK cells; and / or (c) an increase in the level of PD1 in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any one, any two or all three of (a) to (c); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a BAL sample and: (a) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, Tregcells and TEMRA; (b) the level of KLRG1 and / or ICOS is decreased in a population of CD8+T cells; (c) the level of PD1 is decreased in one or more T cell population selected from CD4+T cells and CD8+T cells; (d) the level of KLRG1 is decreased in a population of NK cells; and / or (e) the level of PD1 is increased in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any two or more, or all five of (a) to (e); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a blood sample, and wherein active disease (active lung graft dysfunction) is associated with: (a) an increase in the level of KLRG1, TIGIT and / or ICOS in a population of T cells; and / or (b) an increase in the level of TACI in a population of B cells; compared with quiescent disease (i.e. stable lung graft function, whether a functional lung graft or stable lung graft dysfunction). According to methods of the invention, a sample may be a blood sample, and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (b) the level of PD1 is increased in one or more T cell population selected from CD8+T cells, Tfhcells and Tregcells; (c) the level of PD1 is decreased in a population of MAIT; (d) the level of TIGIT is increased in one or more T cell population selected from CD8+T cells and Tregcells; (e) the level of ICOS is increased in a population of Tfhcells; and / or (f) the level of TACI is increased in a population of B cells; compared with quiescent disease (i.e. stable lung graft function, whether a functional lung graft or stable lung graft dysfunction). Optionally active disease (active lung graft dysfunction) may be associated with any two or more, any four or more or all six of (a) to (f). According to methods of the invention, a sample may be a blood sample, and wherein active CLAD is associated with: (a) an increase in the level of KLRG1, TIGIT and / or ICOS in a population of T cells; and / or (b) an increase in the level of TACI in a population of B cells; compared with stable CLAD. According to methods of the invention, a sample may be a blood sample, and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (b) the level of PD1 is increased in one or more T cell population selected from CD8+T cells, Tfhcells and Tregcells; (c) the level of PD1 is decreased in a population of MAIT; (d) the level of TIGIT is increased in one or more T cell population selected from CD8+T cells and Tregcells; (e) the level of ICOS is increased in a population of Tfhcells; 3 and / or (f) the level of TACI is increased in a population of B cells; compared with stable CLAD. Optionally active CLAD may be associated with any two or more, any four or more or all six of (a) to (f). According to methods of the invention, a sample may be a BAL sample, and wherein active disease (active lung graft dysfunction) is associated with: (a) an increase in the level of KLRG1 in a population of T cells; (b) a decrease in the level of TIGIT, PD1, and / or ICOS in a population of T cells; and / or (c) an increase in the level of TACI in a population of B cells; compared with quiescent disease (i.e. stable lung graft function, whether a functional lung graft or stable lung graft dysfunction). Optionally active disease (active lung graft dysfunction) may be associated with any one, any two or all three of (a) to (c). According to methods of the invention, a sample may be a BAL sample and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, T cells and Tregcells; (b) the level of PD1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells and Tregcells; (c) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (d) the level of ICOS is decreased in one or more T cell population selected from CD8+T cells and MAIT; and / or (e) the level of TACI is increased in a population of B cells; compared with quiescent disease (i.e. stable lung graft function, whether a functional lung graft or stable lung graft dysfunction). Optionally active disease (active lung graft dysfunction) is associated with any two or more, any three or more or all five of (a) to (e). According to methods of the invention, a sample may be a BAL sample, and wherein active CLAD is associated with: (a) an increase in the level of KLRG1 in a population of T cells; (b) a decrease in the level of TIGIT, PD1, and / or ICOS in a population of T cells; and / or (c) an increase in the level of TACI in a population of B cells; compared with stable CLAD. Optionally active CLAD may be associated with any one, any two or all three of (a) to (c). According to methods of the invention, a sample may be a BAL sample and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, T cells and Tregcells; (b) the level of PD1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells and Tregcells; (c) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (d) the level of ICOS is decreased in one or more T cell population selected from CD8+T cells and MAIT; and / or (e) the level of TACI is increased in a population of B cells; compared with stable CLAD. Optionally active CLAD is associated with any two or more, any three or more or all five of (a) to (e). According to methods of the invention, a sample may be a blood sample and wherein progressive CLAD is associated with: (a) an increase in the level of KLRG1 and / or ICOS in a population of T cells; and / or (b) a decrease in the level of PD1 in a population of T cells; compared with stable CLAD. According to methods of the invention, a sample may be a blood sample and (a) the level of KLRG1 is increased in one or more T cell population selected from MAIT and T cells; (b) the level of ICOS is increased in one or more T cell population selected from CD4+T cells, CD8+T cells and MAIT; (c) the level of TIGIT is increased in one or more T cell population selected from CD4+T cells, CD8+T cells and TEMRA; (d) the level of TIGIT is decreased in one or more T cell population selected from MAIT and T cells; and / or (e) the level of PD1 is decreased in a population of MAIT; compared with stable CLAD. Optionally progressive CLAD may be associated with any two or more, any three or more or all five of (a) to (e). According to methods of the invention, a sample may be a BAL sample, and wherein progressive CLAD is associated with: (a) an increase in the level of KLRG1 in a population of T cells; (b) a decrease in the level of TIGIT and / or PD1 in a population of T cells; and / or (c) an increase in the level of TACI in a population of B cells; compared with stable CLAD. Optionally progressive CLAD may be associated with any one, any two or all three of (a) to (c). According to methods of the invention, a sample may be a BAL sample and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells and MAIT; (b) the level of PD1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT and Tfhcells; (c) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; and / or (d) the level of TACI is increased in a population of B cells; compared with stable CLAD. Optionally progressive CLAD may be associated with any two, any three or all four of (a) to (d). According to methods of the invention, a sample may be a blood sample, and wherein incipient CLAD is associated with: (a) an increase in the level of KLRG1, PD1 and / or TIGIT in a population of T cells; and / or (b) a decrease in the level of KLRG1 and / or TIGIT in a population of NK cells; compared with a functional lung graft. According to methods of the invention, a sample may be a blood sample, and: (a) the level of KLRG1 is increased in a population of T cells; (b) the level of PD1 is increased in one or more T cell population selected from CD8+T cells, T cells and TEMRA; (c) the level of TIGIT is increased in one or more T cell population selected from CD8+T cells and T cells; and / or (d) the level of KLRG1 and / or TIGIT is decreased in a population of NK cells; compared with a functional lung graft. Optionally incipient CLAD may be associated with any two, any three or all four of (a) to (d). According to methods of the invention, a sample may be a BAL sample and wherein incipient CLAD is associated with a decrease in the level of KLRG1 in a population of T cells compared with a functional lung graft. According to methods of the invention, a sample may be a BAL sample and the level of KLRG1 is decreased in one or more T cell population selected from CD8+T cells, MAIT and Tregcells compared with a functional lung graft. 4

[0003] According to methods of the invention, a sample may be a blood sample, and wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1, PD1 and / or TIGIT in a population of T cells; (b) a decrease in the level of ICOS in a population of T cells; (c) an increase in the level of TACI in a population of B cells and / or (d) an increase in the level of KLRG1 in a population of NK cells; compared with a lung graft without a CLAD phenotype, wherein said recipient has an infection. Optionally said CLAD phenotype may be associated with any two, any three or all four of (a) to (d); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a blood sample, and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and TEMRA; (b) the level of PD1 is increased in one or more T cell population selected from CD8+T cells and MAIT; (c) the level of TIGIT is increased in a population of CD8+T cells; (d) the level of ICOS is decreased in a population of T cells; (e) the level of KLRG1 is increased in a population of NK cells; and / or (f) the level of TACI is increased in a population of B cells; compared with a lung graft without a CLAD phenotype, wherein said recipient has an infection. Optionally: said CLAD phenotype may be associated with any two or more, any four or more or all six of (a) to (f); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a BAL sample, and wherein a CLAD phenotype is associated with: (a) a decrease in the level of PD1, ICOS and / or TIGIT in a population of T cells; and / or (b) an increase in the level of KLRG1 in a population of NK cells; and / or (c) an increase in the level of TACI in a population of B cells; compared with a lung graft without a CLAD phenotype, wherein said recipient has an infection. Optionally: said CLAD phenotype may be associated with any one, any two or all three of (a) to (c); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a BAL sample, and: (a) the level of PD1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells and MAIT; (b) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and TEMRA; (c) the level of ICOS is decreased in a population of CD8+T cells; (d) the level of KLRG1 is decreased in one or more T cell population selected from CD8+T cells and MAIT; (e) the level of KLRG1 is increased in a population of T cells; (f) the level of KLRG1 is increased in a population of NK cells; and / or (g) the level of TACI is increased in a population of B cells; compared with a lung graft without a CLAD phenotype, wherein said recipient has an infection. Optionally said CLAD phenotype may be associated with any two or more, any four or more, any six or more or all seven of (a) to (g); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, the lung transplant may be without a CLAD phenotype and the sample may be a blood sample, and wherein an infection is associated with a decrease in the level of KLRG1 and / or TIGIT in a population of NK cells compared with a lung transplant without a CLAD phenotype and without an infection; According to some embodiments, the sample is a blood sample, and: (a) the level of KLRG1 is decreased in one or more T cell population selected from CD4+T cells and TEMRA; (b) the level of PD1 is decreased in a population of CD4+T cells; (c) the level of PD1 is increased in one or more T cell population selected from CD8+T cells, T cells, TEMRA and Tfhcells; (d) the level of TIGIT is decreased in a population of CD4+T cells; (e) the level of TIGIT is increased in one or more T cell population selected from CD8+T cells and T cells; and / or (f) the level of KLRG1 and / or TIGIT is decreased in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said infection may be associated with any two or more, any four or more or all six of (a) to (f). Further optionally: (i) said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD; (ii) the infection may be any one or more of a bacterial infection, a fungal infection and / or a viral infection; and / or (iii) the lung transplant without a CLAD phenotype and without an infection may be free of any bacterial, fungal and viral infections. According to methods of the invention, the lung transplant may be without a CLAD phenotype the sample is a BAL sample, and wherein an infection is associated with: (a) a decrease in the level of KLRG1 and / or TIGIT in a population of T cells; and / or (b) an increase in the level of CD43 and / or CD27 in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. According to some embodiments, the sample is a BAL sample and: (a) the level of KLRG1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT and T cells; (b) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells and Tregcells; (c) the level of PD1 is decreased in one or more T cell population selected from CD8+T cells, MAIT, T cells and TEMRA; (d) the level of PD1 is increased in a population of Tfhcells; and / or (e) the level of CD43 and / or CD27 is increased in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said infection may be associated with any two or more, any three or more or all five of (a) to (e). Further optionally: (i) said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD; (ii) the infection may be any one or more of a bacterial infection, a fungal infection and / or a viral infection; and / or (iii) the lung transplant without a CLAD phenotype and without an infection may be free of any bacterial, fungal and viral infections. According to methods of the invention, the lung transplant may be without a CLAD phenotype, the sample may be a blood sample and wherein a viral infection is associated with: (a) an increase in the level of KLRG1, PD1, ICOS and / or TIGIT in a population of T cells; and / or (b) a decrease in the level of CD69 in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. According to some embodiments, the sample is a blood sample, and: (a) the level of KLRG1 5 is increased in one or more T cell population selected from MAIT and T cells; (b) the level of PD1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells, Tfhcells and Tregcells; (c) the level of TIGIT is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (d) the level of ICOS is increased in a population of CD8+T cells; and / or (e) the level of CD69 is decreased in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said viral infection may be associated with any two or more, any three or more or all five of (a) to (e). According to methods of the invention, the lung transplant may be without a CLAD phenotype, the sample may be a BAL sample, and wherein a viral infection is associated with an increase in the level of CD43 and / or CD27 in a population of B cells compared with a lung transplant without a CLAD phenotype and without an infection. According to some embodiments, the sample is a BAL sample, and: (a) the level of KLRG1 is decreased in one or more T cell population selected from CD8+T cells, MAIT and T cells; (b) the level of KLRG1 is increased in a population of CD4+T cells; (c) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells and Tregcells; (d) the level of PD1 is increased in a population of T cells; and / or (e) the level of CD43 and / or CD27 is increased in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said viral infection may be associated with any two or more, any three or more or all five of (a) to (e). According to methods of the invention, the lung transplant may be without a CLAD phenotype, the sample may be a blood sample, and wherein a fungal infection is associated with: (a) a decrease in the level of KLRG1 and / or ICOS in a population of T cells; (b) a decrease in the level of KLRG1 in a population of NK cells; and / or (c) an increase in the level of TIGIT in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said fungal infection may be associated with any one, two or all three of (a) to (c). According to some embodiments, the sample may be a blood sample, and: (a) the level of KLRG1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (b) the level of PD1 is decreased in one or more T cell population selected from CD4+T cells and Tregcells; (c) the level of TIGIT is decreased in a population of MAIT; (d) the level of ICOS is decreased in a population of Tregcells; (e) the level of PD1 is increased in one or more T cell population selected from T cells and Tfhcells; (f) the level of TIGIT is increased in one or more T cell population selected from CD8+T cells and T cells; (g) the level of KLRG1 is decreased in a population of NK cells; and / or (h) the level of TIGIT is increased in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said fungal infection may be associated with any two or more, any five or more or all eight of (a) to (h). According to methods of the invention, the lung transplant may be without a CLAD phenotype, the sample may be a BAL sample, and wherein a fungal infection is associated with: (a) a decrease in the level of KLRG1, PD1, TIGIT and / or ICOS in a population of T cells; and / or (b) a decrease in the level of KLRG1 in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. According to some embodiments, the sample may be a BAL sample, and: (a) the level of KLRG1 is decreased in one or more T cell population selected from CD8+T cells, MAIT and TEMRA; (b) the level of PD1 is decreased in one or more T cell population selected from CD8+T cells, MAIT, T cells and Tregcells; (c) the level of TIGIT is decreased in one or more T cell population selected from CD8+T cells, MAIT, Tregcells and TEMRA; (d) the level of ICOS is decreased in a population of MAIT; and / or (e) the level of KLRG1 is decreased in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said fungal infection may be associated with any two or more, or all five of (a) to (e). According to methods of the invention, the lung transplant may be without a CLAD phenotype, and: the sample may be a blood sample, and wherein a bacterial infection is associated with: (a) an increase in the level of TIGIT and / or ICOS in a population of T cells; and / or (b) a decrease in the level of KLRG1 in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. According to some embodiments, the sample is a blood sample, and: (a) the level of TIGIT is increased in a population of CD4+T cells; (b) the level of ICOS is increased in a population of T cells; and / or (c) the level of KLRG1 is decreased in a population of NK cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said bacterial infection may be associated with any one, two or all three of (a) to (c). According to methods of the invention, the lung transplant may be without a CLAD phenotype, and: the sample may be a BAL sample, and wherein a bacterial infection is associated with: (a) an increase in the level of TIGIT in a population of T cells; (b) a decrease in the level of PD1 in a population of T cells; and / or (c) an increase in the level of CD43 and / or CD27 in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said bacterial infection may be associated with any one, any two or all three of (a) to (c). According to some embodiments, the sample is a BAL sample, and: (a) the level of TIGIT is increased in one or more T cell population selected from CD4+T cells, CD8+T cells and MAIT; (b) the level of PD1 is decreased in a population of MAIT; and / or (c) the level of CD43 and / or CD27 is increased in a population of B cells; compared with a lung transplant without a CLAD phenotype and without an infection. Optionally said bacterial infection is associated with any one, any two or all three of (a) to (c). 6

[0004] Unless otherwise stated (a) said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD; and / or (b) the lung transplant without a CLAD phenotype and without an infection may be free of any bacterial, fungal and viral infections. According to methods of the invention, the lung transplant may be without a CLAD phenotype, and the sample may be a blood sample, and wherein a viral infection is associated with an increase in the level of TIGIT and / or PD1 in a population of T cells compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD. According to some embodiments, the sample may be a blood sample, and: (a) the level of TIGIT and / or PD1 is increased in one or more T cell population selected from CD8+T cells, MAIT and T cells; (b) the level of KLRG1 is increased one or more T cell population selected from MAIT and Tregcells; and / or (c) the level of KLRG1 is decreased in a population of CD8+T cells; compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally: said viral infection may be associated with any one, any two or all three of (a) to (c); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, the lung transplant may be without a CLAD phenotype, and the sample may be a BAL sample, and wherein a viral infection is associated with a decrease in the level of TIGIT and / or KLRG1 in a population of T cells compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to some embodiments, the sample may be a BAL sample and: (a) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, T cells and Tregcells; and / or (b) the level of KLRG1 is decreased in a population of CD8+T cells, MAIT and T cells; compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, the lung transplant may be without a CLAD phenotype, and the sample may be a blood sample, and wherein a fungal infection is associated with an increase in the level of TACI in a population of B cells compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to some embodiments, the sample may be a blood sample and: (a) the level of TIGIT is decreased one or more T cell population selected from CD4+T cells, CD8+T cells and MAIT; (b) the level of TIGIT is increased in a population of T cells; (c) the level of KLRG1 is increased in a population of MAIT; and / or (d) the level of TACI is increased in a population of B cells; compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally: said fungal infection may be associated with any two, any three or all four of (a) to (d); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, the lung transplant may be without a CLAD phenotype, and the sample may be a BAL sample, and wherein a fungal infection is associated with a decrease in the level of KLRG1 and / or TIGIT in a population of T cells compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD. According to some embodiments, the sample may be a BAL sample and: (a) the level of KLRG1 is decreased in one or more T cell population selected from CD8+T cells and T cells; and / or (b) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT and T cells; compared with a lung transplant without a CLAD phenotype and with a bacterial infection. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, the lung transplant may be without a CLAD phenotype, and the sample may be a blood sample, and wherein a fungal infection is associated with: (a) a decrease in the level of KLRG1, TIGIT and / or PD1 in a population of T cells; (b) a decrease in the level of KLRG1 and / or TIGIT in a population of NK cells; and / or (c) an increase in the level of CD69 in a population of B cells; compared with a lung transplant without a CLAD phenotype and with a viral infection. Optionally: said fungal infection may be associated with any one, any two or all three of (a) to (c); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to some embodiments, the sample may be a blood sample, and: (a) the level of KLRG1 and / or TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, T cells and Tregcells; (b) the level of PD1 is decreased in one or more T cell population selected CD4+T cells, CD8+T cells, MAIT and Tregcells; (c) the level of KLRG1 and / or TIGIT is decreased in a population of NK cells; and / or (d) the level of CD69 is increased in a population of B cells; compared with a lung transplant without a CLAD phenotype and with a viral infection. Optionally: said fungal infection may be associated with any two, any three or all four of (a) to (d); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, the lung transplant may be without a CLAD phenotype, and the sample may be a BAL sample, and wherein a fungal infection is associated with a decrease in the level of KLRG1, TIGIT and / or PD1 in a population of T cells compared with a lung transplant without a CLAD phenotype and with a viral infection. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to some embodiments, the sample may be a BAL sample, and: 7 (a) the level of KLRG1 is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells and T cells; (b) the level of TIGIT is decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT and T cells; (c) the level of PD1 is decreased in a population of T cells; compared with a lung transplant without a CLAD phenotype and with a viral infection. Optionally: said fungal infection may be associated with any one, any two or all three of (a) to (c); and / or said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. The invention also provides the use of a biomarker signature for stratifying the transplant function and / or infection status of a lung transplant recipient, said biomarker signature comprising: (a) at least one biomarker in a population of T cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1 and ICOS; (b) at least one biomarker in a population of B cells, wherein said at least one biomarker is selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD; and / or (c) at least one biomarker in a population of Natural Killer (NK) cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1 and CD62L; wherein the population of T cells, B cells and / or NK cells is obtained from a sample from said recipient. The invention also provides a method of stratifying the transplant function and / or infection status of a lung transplant recipient and treating a lung transplant recipient who has CLAD and / or an infection, said method comprising: [A] stratifying the transplant function and / or infection status of said lung transplant recipient using a method as defined herein; and [B] (a) treating the recipient for CLAD if said recipient is determined to have CLAD and / or (b) treating the recipient for an infection if said recipient is determined to have an infection, wherein an antifungal agent is used to treat a fungal infection, an antibiotic is used to treat a bacterial infection and an antiviral agent is used to treat a viral infection; The invention further provides a method of detecting one or more of biomarker selected from KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, PD1, IgM, IgD and CD62L in a lung transplant recipient, said method comprising: (a) obtaining a blood or BAL sample from the lung transplant recipient; and (b) detecting whether one or more of biomarker is expressed on a population of cells present in the blood or BAL sample by contacting the blood or BAL sample with an anti-biomarker antibody and detecting binding between the biomarker and the antibody. Typically (i) at least one biomarker selected from KLRG1, TIGIT, PD1 and ICOS is detected in a population of T cells; (ii) at least one biomarker selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD is detected in a population of B cells; and / or (iii) at least one biomarker selected from KLRG1, TIGIT, PD1 and CD62L is detected in a population of NK cells. The invention also provides a kit of parts comprising a binding member for one or more of KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, PD1, IgM, IgD and CD62L. Optionally: [A] the binding member for each of the one or more of KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, PD1, IgM, IgD and CD62L is: (a) selected from an antibody, and aptamer or, preferably an antibody; (b) labelled, optionally with a fluorescent label; and / or (c) in a separate container. Alternatively or in addition, the kit may optionally further comprise: (a) a buffer, optionally a lyse buffer and / or a staining buffer; (b) an Fc receptor blocking regent; (c) a labelled secondary antibody; (d) isotype control antibodies; and / or (e) instructions for use. In particular, the invention provides a method for stratifying a lung transplant recipient as having CLAD versus having a functional lung graft, said method comprising determining a biomarker signature which comprises at least two biomarkers in a population of T cells, wherein said at least two biomarkers are selected from KLRG1, TIGIT, PD- 1, and ICOS; wherein the population of T cells is obtained from a sample from said recipient. Determining said biomarker signature may comprise or consist of determining the level of said at least two biomarkers in a population of T cells. The biomarker signature may comprise or consist of KLRG1 and one or more of (i) TIGIT, (ii) PD-1, and / or (iii) ICOS. Accordingly, determining said biomarker signature may comprise or consist of quantifying a population of: T cells expressing KLRG1 and one or more of (i) TIGIT, (ii) PD-1, and / or (iii) ICOS. The population of T cells may comprise or consist of one or more of: CD4-positive T cells (CD4+), CD8-positive T cells (CD8+), mucosal-associated invariant T cells (MAIT), gamma delta T cells ( ), follicular T helper cells (Tfh), regulatory T cells (Treg), and effector memory RA T cells (TEMRA). Alternatively or in addition, the method may comprise or consist of quantifying one or more populations of CD4+T cells, CD8+T cells, MAIT, T cells, Tfhcells, Tregcells, and / or TEMRA. Determining the level of said at least two biomarkers in a population of T cells may comprise or consist of determining whether the level of said biomarkers exceeds a threshold value. Quantifying said population of T cells expressing at least two biomarkers may comprise or consist of determining whether the number of cells in said population exceeds a threshold value. Optionally said threshold value may be: (a) a fold-change increase of at least 1.5, preferably at least 2; or (b) a fold-change decrease of at least 1.5, preferably at least 2. Determining a biomarker signature may comprise or consist of the use of Fluorescent Activated Cell Sorting (FACS) and / or transcriptomics. 8

[0005] The sample may be selected from a blood, bronchoalveolar lavage (BAL), a tissue sample, cell sample and / or organ sample, wherein preferably said tissue, cell or organ sample is taken from the transplanted solid organ; wherein preferably the solid organ transplant is a lung transplant and the sample is a blood or BAL sample. According to methods of the invention, a sample may be a blood sample, wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 in a population of T cells; and (b) (i) an increase in the level of TIGIT in a population of T cells; and / or (ii) a decrease in the level of PD1, and / or ICOS in a population of T cells; compared with a functional lung graft. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a blood sample and: (a) the level of KLRG1 may be increased in one or more T cell population selected from CD4+T cells, CD8+T cells, and T cells; (b) the level of TIGIT may be increased in one or more T cell population selected from CD4+T cells, T cells, and Tregcells; (c) the level of PD1 may be decreased in one or more T cell population selected from CD8+T cells and CD4+T cells; and / or (d) the level of ICOS may be decreased in a population of CD8+T cells; compared with a functional lung graft. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. Wherein the sample is a blood sample, a CLAD phenotype may be further associated with: (a) an increase in the level of KLRG1 in a population of MAIT; and / or (b) an increase in the level of TIGIT in a population of CD8+T cells; compared with a functional lung graft. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a BAL sample, wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 in a population of T cells; and (b) a decrease in the level of TIGIT, PD-1, and / or ICOS in a population of T cells; compared with a functional lung graft. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. According to methods of the invention, a sample may be a BAL sample and: (a) the level of KLRG1 may be increased in one or more T cell population selected from CD4+T cells, CD8+T cells, and T cells; and / or (b) the level of ICOS may be decreased in one or more T cell population selected from CD4+T cells, and CD8+T cells; compared with a functional lung graft. Optionally said CLAD phenotype may be active CLAD, progressive CLAD or stable CLAD. Wherein the sample is a BAL sample, a CLAD phenotype may be further associated with: (a) a decrease in the level of TIGIT in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, Tregcells and TEMRA; and / or (b) a decrease in the level of PD1 in one or more T cell population selected from CD4+T cells and CD8+T cells; compared with a functional lung graft. Optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD. In a method of the invention, preferably a biomarker signature for CLAD compared with a functional lung graft comprises or consists of: KLRG1 and TIGIT; KLRG1 and PD-1; KLRG1 and ICOS; KLRG1,TIGIT and PD-1; KLRG1, TIGIT and ICOS; KLRG1, PD-1 and ICOS; or KLRG1, PD-1, ICOS and TIGIT. Wherein the sample is a blood sample, a CLAD phenotype may be further associated with: (a) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (b) (i) an increase in the level of TACI in a population of B cells; (ii) a decrease in the level of IgD in a population of B cells; (iii) a decrease in the level of CD43 in a population of B cells; and / or (iv) a decrease in the level of CD27 in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD. Wherein the sample is a BAL sample, a CLAD phenotype may be further associated with: (a) a decrease in the level of KLRG1 in a population of NK cells; and / or (b) an increase in the level of (i) CD27, (ii) CD43, and / or (ii) PD1 in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD. The invention also provides the use of a biomarker signature for stratifying the transplant function and / or infection status of a lung transplant recipient, said biomarker signature comprising at least two biomarkers in a population of T cells, wherein said at least two biomarker are selected from KLRG1, TIGIT, PD-1, and ICOS; wherein the population of T cells is obtained from a sample from said recipient. The biomarker signature may comprise or consist of KLRG1 and one or more of (i) TIGIT; (ii) PD-1, and / or (iii) ICOS. The invention further provides a method of stratifying a lung transplant recipient as having CLAD versus having a functional lung graft and treating a lung transplant recipient who has CLAD, said method comprising: (a) stratifying said lung transplant recipient as having CLAD versus having a functional lung graft using a method of the invention; and (b) treating the recipient for CLAD if said recipient is determined to have CLAD. A method of detecting two or more biomarkers selected from KLRG1, TIGIT, PD-1, and ICOS in a lung transplant recipient, said method comprising: (a) obtaining a blood or BAL sample from the lung transplant recipient; and (b) detecting whether one or more of biomarker is expressed on a population of cells present in the blood or BAL sample by contacting the blood or BAL sample with an anti-biomarker antibody and detecting binding between the biomarker and the antibody; wherein the at least two biomarkers selected from KLRG1, TIGIT, PD-1, and ICOS are detected in a population of T cells. The biomarker signature may comprise or consist of KLRG1 one or more of (i) TIGIT; (ii) PD-1, and / or (iii) ICOS. 9

[0006] The invention also provides a kit of parts comprising a binding member for two or more of KLRG1, TIGIT, PD-1, and ICOS; wherein optionally: A. the binding member for each of the two or more of KLRG1, TIGIT, PD-1, and ICOS, is: (a) selected from an antibody, and aptamer or, preferably an antibody; (b) labelled, optionally with a fluorescent label; (c) in a separate container; and / or B. the kit further comprises: (a) a buffer, optionally a lyse buffer and / or a staining buffer; (b) an Fc receptor blocking regent; (c) a labelled secondary antibody; (d) isotype control antibodies; and / or (e) instructions for use. BRIEF DESCRIPTON OF THE DRAWINGS Figure 1: Immunome comparison of CLAD vs No CLAD in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 2: Immunome comparison of Incipient CLAD vs No CLAD in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 3: Immunome comparison of Progressive CLAD vs Stable CLAD in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 4: Immunome comparison of Active disease vs Quiescent disease in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 5: Immunome comparison of CLAD vs Infection in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 6: Immunome comparison of Infection vs No Infection in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 7: Immunome comparison of Fungal vs No Infection in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 8: Immunome comparison of Viral vs No Infection in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 9: Immunome comparison of Bacterial vs No Infection in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 10: Immunome comparison of Fungal vs Viral in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. 10

[0007] Figure 11: Immunome comparison of Fungal vs Bacterial in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 12: Immunome comparison of Viral vs Bacterial in blood (A and C) and BAL (B and D). A and B) Volcano plots representing the significantly different populations of cells between CLAD and No CLAD. Mann-Whitney Test, p < 0.05. C and D) PCA analysis using a subset of the significant populations based on the repeated markers. Figure 13: Immunome comparison by spectral flow cytometry of T cells in blood samples from lung transplant recipients with CLAD vs No CLAD using KLRG1 (A), PD1 (B) and ICOS (C). Mann-Whitney Test, * = p<0.05, ** = p<0.01. Figure 14: Immunome comparison by spectral flow cytometry of T cells in BAL samples from lung transplant recipients with CLAD vs No CLAD using KLRG1 (A) and ICOS (B). Mann-Whitney Test, * = p<0.05. Figure 15: Immunome comparison by spectral flow cytometry of: NK cells in blood samples (A and B) and B cells in BAL samples (C) from lung transplant recipients with CLAD vs No CLAD using KLRG1 (A), PD1 (B) and CD27 / CD43 (C). Mann-Whitney Test, * = p<0.05. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure. The meaning and scope of the terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts described herein to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims. The headings provided herein are not limitations of the various aspects or embodiments of this disclosure. As used herein, the term "capable of' when used with a verb, encompasses or means the action of the corresponding verb. For example, "capable of interacting" also means interacting, "capable of cleaving" also means cleaves, "capable of binding" also means binds and "capable of specifically targeting…" also means specifically targets. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure. 11

[0008] As used herein, the articles "a" and “an” may refer to one or to more than one (e.g. to at least one) of the grammatical object of the article. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Preferably, the term “about” shall be understood herein as plus or minus (±) 5%, preferably ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the number with which it is being used. The term "consisting of'' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the invention. As used herein the term "consisting essentially of'' refers to those elements required for a given invention. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that invention (i.e. inactive or non-immunogenic ingredients). Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of” and / or “consisting essentially of” such features. Concentrations, amounts, volumes, percentages and other numerical values may be presented herein in a range format. It is also to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. The terms “decrease” "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition (i.e. abrogation) as compared to a reference level. The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1.5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10-fold or greater as compared to a reference level. In the context of a yield or titre, an "increase" is an observable or statistically significant increase in such level. As used herein, the terms "protein" and "polypeptide" are used interchangeably herein to designate a series of amino acid residues, connected to each other by peptide bonds between the alpha-amino and carboxyl groups of adjacent residues. The terms "protein", and "polypeptide" refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogues, regardless of its size or function. "Protein" and "polypeptide" are often used in reference to relatively large polypeptides, whereas the term "peptide" is often used in reference to small polypeptides, but usage of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein when referring to a gene product and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogues of the foregoing. Minor variations in the amino acid sequences of proteins of the invention are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence(s) maintain at least 60%, at least 70%, more preferably at least 80%, at least 85%, at least 90%, at least 95%, and most preferably at least 97% or at least 99% sequence identity to the proteins of the invention or an immunogenic fragment thereof as defined anywhere herein. The term homology is used herein to mean identity. As such, the sequence of a variant or analogue sequence of a protein of the invention may differ on the basis of substitution (typically conservative substitution) deletion or insertion. Proteins of the invention may include variants in which amino acid residues from one species are substituted for the corresponding residue in another species, either at the conserved or non-conserved positions. Variants of protein molecules disclosed herein may be produced and used in the present invention. Following the lead of 12

[0009] computational chemistry in applying multivariate data analysis techniques to the structure / property-activity relationships [see for example, Wold, et al. Multivariate data analysis in chemistry. Chemometrics-Mathematics and Statistics in Chemistry (Ed.: B. Kowalski); D. Reidel Publishing Company, Dordrecht, Holland, 1984 (ISBN 90-277-1846-6] quantitative activity-property relationships of proteins can be derived using well-known mathematical techniques, such as statistical regression, pattern recognition and classification [see for example Norman et al. Applied Regression Analysis. Wiley-lnterscience; 3rd edition (April 1998) ISBN: 0471170828; Kandel, Abraham et al. Computer- Assisted Reasoning in Cluster Analysis. Prentice Hall PTR, (May 11, 1995), ISBN: 0133418847; Krzanowski, Wojtek. Principles of Multivariate Analysis: A User's Perspective (Oxford Statistical Science Series, No 22 (Paper)). Oxford University Press; (December 2000), ISBN: 0198507089; Witten, Ian H. et al Data Mining: Practical Machine Learning Tools and Techniques with Java Implementations. Morgan Kaufmann; (October 11, 1999), ISBN:1558605525; Denison David G. T. (Editor) et al Bayesian Methods for Nonlinear Classification and Regression (Wiley Series in Probability and Statistics). John Wiley & Sons; (July 2002), ISBN: 0471490369; Ghose, Arup K. et al. Combinatorial Library Design and Evaluation Principles, Software, Tools, and Applications in Drug Discovery. ISBN: 0-8247-0487-8]. The properties of proteins can be derived from empirical and theoretical models (for example, analysis of likely contact residues or calculated physicochemical property) of proteins sequence, functional and three-dimensional structures and these properties can be considered individually and in combination. Amino acids are referred to herein using the name of the amino acid, the three-letter abbreviation or the single letter abbreviation. The term “protein", as used herein, includes proteins, polypeptides, and peptides. As used herein, the term “amino acid sequence” is synonymous with the term “polypeptide” and / or the term “protein”. In some instances, the term “amino acid sequence” is synonymous with the term “peptide”. The terms "protein" and "polypeptide" are used interchangeably herein. In the present disclosure and claims, the conventional one-letter and three-letter codes for amino acid residues may be used. The 3-letter code for amino acids as defined in conformity with the IUPACIUB Joint Commission on Biochemical Nomenclature (JCBN). It is also understood that a polypeptide may be coded for by more than one nucleotide sequence due to the degeneracy of the genetic code. Amino acid residues at non-conserved positions may be substituted with conservative or non-conservative residues. In particular, conservative amino acid replacements are contemplated. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, or histidine), acidic side chains (e.g., aspartic acid or glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, or cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, or tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, or histidine). Thus, if an amino acid in a polypeptide is replaced with another amino acid from the same side chain family, the amino acid substitution is considered to be conservative. The inclusion of conservatively modified variants in a protein of the invention does not exclude other forms of variant, for example polymorphic variants, interspecies homologs, and alleles. “Non-conservative amino acid substitutions” include those in which (i) a residue having an electropositive side chain (e.g., Arg, His or Lys) is substituted for, or by, an electronegative residue (e.g., Glu or Asp), (ii) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by, a hydrophobic residue (e.g., Ala, Leu, Ile, Phe or Val), (iii) a cysteine or proline is substituted for, or by, any other residue, or (iv) a residue having a bulky hydrophobic or aromatic side chain (e.g., Val, His, Ile or Trp) is substituted for, or by, one having a smaller side chain (e.g., Ala or Ser) or no side chain (e.g., Gly). “Insertions” or “deletions” are typically in the range of about 1, 2, or 3 amino acids. The variation allowed may be experimentally determined by systematically introducing insertions or deletions of amino acids in a protein using recombinant DNA techniques and assaying the resulting recombinant variants for activity. This does not require more than routine experiments for a skilled person. A “fragment” of a polypeptide comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% or more of the original polypeptide. As used herein, the terms “polynucleotides”, "nucleic acid" and "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid or an analogue thereof. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other suitable nucleic acid molecules are RNA, including siRNA, shRNA, and antisense oligonucleotides. 13

[0010] The terms "individual”, "subject”, and "patient”, “recipient” and “transplant recipient” are used interchangeably herein to refer to a mammalian subject for whom diagnosis, prognosis, disease monitoring, treatment, therapy, and / or therapy optimisation is desired. The mammal can be (without limitation) a human, non-human primate, mouse, rat, dog, cat, horse, or cow. In a preferred embodiment, the individual, subject, or patient is a human. An “individual” may be an adult, juvenile or infant. An “individual” may be male or female. A "subject in need" of treatment for a particular condition can be an individual having that condition, diagnosed as having that condition, or at risk of developing that condition. Typically said subject is a transplant recipient who is diagnosed as having or at risk of developing graft dysfunction and / or an infection using a method of the invention, and who can then be treated for said graft dysfunction and / or an infection. A transplant recipient can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications or symptoms related to such a condition, and optionally, have already undergone treatment for a condition as defined herein or the one or more complications or symptoms related to said condition. Alternatively, a transplant recipient can also be one who has not been previously diagnosed as having a condition as defined herein or one or more or symptoms or complications related to said condition. For example, a transplant recipient can be one who exhibits one or more risk factors for a condition, or one or more or symptoms or complications related to said condition or a subject who does not exhibit risk factors. As used herein, the term “healthy individual” refers to an individual or group of individuals who are in a healthy state, e.g. individuals who have not shown any symptoms of the disease, have not been diagnosed with the disease and / or are not likely to develop the disease e.g. a bacterial infection. Preferably said healthy individual(s) has not received a solid organ transplant (typically at least has not received a solid organ transplant of the same type as the transplant recipient who is the subject of the method of the invention, and preferably has not received any solid organ transplant), is not on anti-infective medication (e.g. antivirals, antibiotics and / or antifungals) and has not been diagnosed with any other disease. The one or more healthy individuals may have a similar sex, age, and / or body mass index (BMI) as compared with the test individual. Application of standard statistical methods used in medicine permits determination of normal levels of expression in healthy individuals, and significant deviations from such normal levels. Herein the terms “control” and “reference population” are used interchangeably. The term “pharmaceutically acceptable” as used herein means approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized pharmacopeia. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. As used herein, “patient stratification” or “transplant recipient stratification” refers to the categorisation of a transplant recipient into one or more distinct subgroups in a population of transplant recipients based on the presence or absence of particular disease characteristics. Transplant recipient stratification can be used to account for the underlying pathology of a disease, it can help physicians to tailor therapeutic interventions to individuals and optimise their care management and treatment regime. As used herein, the term “transplant recipient” refers to a patient receiving a transplanted organ or tissue. Said transplant material may be autologous (from the same donor) or allogenic (from a different individual from the same species). In the case of an allogenic transplant, the term “transplant recipient” refers to a patient receiving the donor organ or tissue. As used herein, the term “stratifying graft function and / or infection status” refers to the categorisation of a transplant recipient into one or more distinct subgroup based on the functional status of their graft and / or the presence or absence of an infection. Thus, stratifying graft function and / or infection status of a transplant recipient can be used to determine (diagnose) whether a patient has: (a) a graft dysfunction; (b) an infection; and / or (c) a functional graft. In other words, stratifying graft function and / or infection status of a transplant recipient can be used to categorise the recipient as having: (a) a graft dysfunction; (b) an infection; and / or (c) a functional graft. Stratifying the infection status of a patient can comprise differentiating the type of infection the patient has, as described herein. As used herein, the term “graft function” refers to the degree of functioning of a graft. This encompasses the range from a fully-integrated healthy graft through to a graft rejection. As used herein, the term “functional graft” refers to a graft which is able to carry out the normal physiological function of the transplanted cell, tissue or organ following transplantation. By way of non-limiting example, a functional lung transplantation is capable of gas exchange above a therapeutically defined threshold. Lung function after transplant may be defined by measurement of a recipient’s spirometry, specifically the forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). The recipients post-transplant baseline lung function is computed as the mean of the best two post-operative FEV1measurements (taken >3 weeks apart). After transplantation, graft 14

[0011] function (as measured by spirometry) improves progressively over time to a post-transplant baseline. This baseline is used to monitor ongoing health of the lung, alongside respiratory symptoms such as breathlessness. As used herein, the term “graft dysfunction”, “clinical graft dysfunction” and a “dysfunctional graft” are used interchangeably to refer to a graft which is not able to carry out the normal physiological function of the transplanted cell, tissue or organ following transplantation. For example, for a lung transplant, once a stable post-transplant baseline is reached (see above), any drop in FEV1(and FVC in the RAS phenotype) is used to describe graft dysfunction. Accordingly, for lung transplants, graft dysfunction may be defined as a decrease in FEV1from post-transplant baseline. By way of non-limiting example, a dysfunctional lung graft may be defined as a lung graft with a measured decrease in FEV1below a threshold of 10% of the post-transplant baseline (e.g. a decrease of at least 10%, at least 15%, at least 20%, at least 25% or more) in FEV1. By way of a further non-limiting example, a dysfunctional lung graft may be defined as a lung graft with a measured decrease in FVC below a threshold of 10% of the post-transplant baseline (e.g. a decrease of at least 10%, at least 15%, at least 20%, at least 25% or more) in FVC. By way of further non-limiting example, CLAD may be defined as a lung graft with a measured decrease in FEV1below a threshold of 20% of the post-transplant baseline (e.g. a decrease of at least 20%, at least 25%, at least 30% or more) in FEV1. By way of a further non-limiting example, CLAD may be defined as a lung graft with a measured drop in FVC below a threshold of 20% of the post-transplant baseline (e.g. a decrease of at least 20%, at least 25%, at least 30% or more) in FVC. Typically in CLAD the decrease in lung function (e.g. as measured by FEV1or FVC) is irreversible. “Graft dysfunction” encompasses different stages and categories of graft dysfunction, including incipient graft dysfunction, active graft dysfunction, stable graft dysfunction, progressive graft dysfunction and graft rejection. In the context of lung transplants, the term “graft dysfunction” encompasses hyperacute transplant rejection, acute transplant rejection, chronic lung allograft dysfunction (CLAD) and the clinical phenotypes of bronchioloitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). There are two types of lung graft dysfunction defined in the literature: acute lung allograft dysfunction (ALAD), which is defined as a reversible decline of at least 10% in post-transplant baseline FEV1; chronic lung allograft dysfunction (CLAD), which is defined as an irreversible decline of at least 20% in post-transplant baseline FEV1.Within CLAD, the clinical subtypes are bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), mixed and undefined. These subtypes are defined on the basis of presence / absence of obstructive spirometry (FEV1 / FVC < 0.7), Restriction TLC >10% decline from baseline and opacities on chest x-ray or high-resolution CT scan consistent with RAS. As used herein, the term “graft rejection” refers to immune-mediated rejection of the donor cells by residual host cells because of genetic disparity between the recipient and the donor. This term encompasses both acute cellular rejection AND antibody mediated rejection. Therefore, this term is only relevant to allogeneic transplants. As used herein the term “incipient graft dysfunction” defines a patient who does not meet the diagnostic criteria for graft dysfunction at the time of testing, but who develops clinical graft dysfunction that meets the diagnostic criteria for that solid organ transplant within six months of testing. Incipient graft dysfunction is interchangeably referred to as “subclinical graft dysfunction” and “pre-graft dysfunction”. The biomarkers signatures of the invention are useful as they can be used to differentiate solid organ transplant recipients without clinical symptoms into those without graft dysfunction and those who are likely to progress to clinical (symptomatic) graft dysfunction. As used herein the terms “active disease” and “active graft dysfunction” are used interchangeably to refer to a patient with an ongoing decline in one or more diagnostic criteria for graft dysfunction regardless of previous graft function status (presence / absence of graft dysfunction) at the onset of the decline in said one or more diagnostic criteria. Associated markers for loss of graft function (e.g. histology, radiological and / or functional parameters for measuring graft function may additionally demonstrate a decrease in graft function). Typically “active graft dysfunction” refers to an ongoing decline of at least 10% in any appropriate diagnostic criteria for graft dysfunction (e.g. any histological, radiological and / or functional parameter). Active graft dysfunction can encompass incipient, and / or progressive graft dysfunction. Active disease may refer to dysfunction that is reversible or irreversible. As used herein the term “stable graft dysfunction” defines a patient who meets the diagnostic criteria for graft dysfunction, and which diagnostic criteria has remained stable (i.e. has not increased in severity) for a period of time, typically where the level of dysfunction has remained unchanged for at least six months. In other words, the grade of dysfunction remains constant for a period of time, typically at least six months or more. As used herein the terms “quiescent graft dysfunction” and “quiescent disease” are used interchangeably to refer to solid organ transplant recipients with stable graft function. These solid organ transplant recipients can either have stable graft dysfunction (as defined herein, typically less than a 10% decline compared with the recipient’s baseline graft function) or no graft dysfunction (i.e. a functional graft). In other words, “quiescent disease” refers to a solid organ transplant who has stable graft function, irrespective of whether they have graft dysfunction or a functional graft. 15 As used herein the term “progressive graft dysfunction” defines a patient who meets the diagnostic criteria for graft dysfunction of a particular solid organ transplant and has a new and ongoing decline in said diagnostic criteria from a previously stable baseline. Typically where the level of dysfunction increases over a period of at least one month, at least six months, at least 1 year or more. In other words, the grade of dysfunction increases over a period of time, typically at least one month, at least six months, at least 1 year or more. As used herein, the term “stratifying graft function and / or infection status” in the context of a lung transplant typically refers to the categorisation of a lung transplant recipient into one or more distinct subgroups based on the functional status of their graft and / or the presence or absence of an infection. Thus, stratifying graft function and / or infection status of a lung transplant recipient can be used to determine (diagnose) whether a patient has: (a) chronic lung allograft dysfunction (CLAD); (b) an infection; and / or (c) a functional graft. In other words, stratifying graft function and / or infection status of a lung transplant recipient can be used to categorise the recipient as having: (a) CLAD; (b) an infection; and / or (c) a functional graft. Stratifying may comprise differentiating between the category of CLAD i.e. does the patient have BOS / RAS / mixed / undefined CLAD (meaning that the CLAD has not been defined as BOS / RAS / mixed), the severity or grade of CLAD (0 = FEV1> 80% baseline, 1 = FEV166 – 80% baseline, 2 = 51 – 65% baseline and 3 = FEV1 , 50% baseline), as described herein. Stratifying the infection status of a patient can comprise differentiating the type of infection the patient has, as described herein. As used herein the term “Chronic Lung Allograft Dysfunction (CLAD) refers to a decline in lung function from post-transplant baseline and persisting for more than 3 weeks. Based on the physiology of pulmonary function impairment and the microscopic pathology, it has 2 distinct phenotypes: bronchiolitis obliterans syndrome (BOS), which is predominantly an obstructive disease; and restrictive allograft syndrome (RAS), which is predominantly a restrictive disease. As used herein the term “incipient CLAD” refers to a patient who does not meet the diagnostic criteria for CLAD at the time of testing, but who develops clinical graft dysfunction that meets the diagnostic criteria for CLAD within six months of testing. Incipient CLAD is interchangeably referred to as “subclinical CLAD” and “pre-CLAD”. The biomarkers signatures of the invention are useful as they can be used to differentiate lung transplant recipients without clinical symptoms into those without CLAD and those who are likely to progress to CLAD. In the context of lung transplants, the terms “active disease” and “active lung graft dysfunction” are used interchangeably to refer to a lung transplant recipient with an ongoing decline in one or more diagnostic criteria for lung graft dysfunction regardless of previous graft function status (presence / absence of graft dysfunction) at the onset of the decline in said one or more diagnostic criteria. Associated markers for loss of graft function (e.g. histology, radiological and / or functional parameters for measuring graft function may additionally demonstrate a decrease in graft function). Typically “active disease” in the context of a lung transplant refers to an ongoing decline of at least 10% in any appropriate diagnostic criteria for lung graft dysfunction (e.g. any histological, radiological and / or functional parameter, particularly FEV1and / or FVC). Thus, active disease in the context of lung transplants may encompass CLAD, but also other lung graft dysfunction, such as ALAD. Active graft dysfunction can encompass incipient, and / or progressive graft dysfunction. Active disease may refer to dysfunction that is reversible or irreversible. As used herein the term “active CLAD” refers to defines a patient with an ongoing decline in FEV1(as defined herein) regardless of previous graft function status (presence / absence of CLAD) at onset of this episode of FEV1decline. Additional markers for loss of graft function (e.g. histology, and / or radiological parameters for may additionally demonstrate graft dysfunction). Active CLAD can include incipient CLAD and / or progressive CLAD. As used herein the term “stable CLAD” defines a patient who meets the diagnostic criteria for CLAD, but wherein the FEV1has not decreased further for a period of time, typically where the level dysfunction has remained unchanged for at least six months, at least 1 year or more. In other words, the grade of CLAD remains constant for a period of time, typically at least six months or more. As used herein the term “progressive CLAD” defines a patient who meets diagnostic criteria for CLAD, wherein FEV1continues to decline over a period of at least one month, at least six months, at least 1 year or more. In other words, the FEV1continues to decline below the CLAD diagnostic threshold (greater than / equal to 20% post- transplant baseline) over a period of time, typically at least one month, at least six months, at least 1 year or more. In the context of lung transplants, the terms “quiescent lung graft dysfunction” and “quiescent disease” are used interchangeably to refer to lung transplant recipients with stable lung graft function. These lung transplant recipients can either have stable lung graft dysfunction (as defined herein, typically less than a 10% decline compared with the recipient’s baseline lung graft function measured using any appropriate diagnostic criteria (e.g. any histological, radiological and / or functional parameter, particularly FEV1and / or FVC particularly FEV1and / or FVC)) or no lung graft dysfunction (i.e. a functional lung graft). In other words, in the context of lung transplants, “quiescent disease” refers to a lung transplant recipient who has stable lung graft function, irrespective of whether they have lung graft dysfunction or a functional lung graft. 16

[0012] An “infection” refers to the presence of a pathogen, which may be a bacteria, virus, fungus, parasite (e.g. protozoa or helminth) or combination thereof which gives rise to a disease in the infected individual. As used herein, the term “infection status” refers to a description of the health of a patient with regards to the presence or absence of an infection, and optionally with the further ability to (i) define the severity of the infection and / or (ii) classify the type of infection as fungal, viral, bacterial, or a combination of two or more different infection types. A fungal infection means an infection by any fungus, whether a yeast, mold or filamentous fungus. Non-limiting example of fungal infections common in lung transplant recipients include aspergillus. A viral infection means an infection by any virus. Non-limiting example of viruses common in lung transplant recipients include community acquired respiratory virus (CARV), influenza and coronaviruses. A bacterial infection means an infection by any bacteria (Gram-positive, Gram-negative, mycobacteria, etc.). Non-limiting example of bacterial infections common in lung transplant recipients include Pseudomonas aeruginosa and Staphylococcus aureus. As used herein, the term “differentiating infection type” refers to the categorisation of a transplant recipient into one or more distinct subgroup based on the presence or absence of a particular type of infection. Thus, differentiating the infection type of a transplant recipient can be used to determine (diagnose) whether a patient has: (a) bacterial infection; (b) a viral infection; and / or (c) a fungal infection; or a combination thereof. In other words, stratifying comprises differentiating infection type of a transplant recipient can be used to categorise the recipient as having: (a) bacterial infection; (b) a viral infection; and / or (c) a fungal infection; or a combination thereof. As used herein, the term “stratifying graft function and / or infection status” refers to the categorisation of a transplant recipient into one or more distinct subgroup based on the functional status of their graft and / or the presence or absence of an infection, and optionally the type of infection (if an infection is present). Thus, stratifying graft function and / or infection status of a transplant recipient can be used to determine (diagnose) whether a patient has: (a) a graft dysfunction; (b) an infection (and optionally the type of infection); and / or (c) a functional graft. In other words, stratifying graft function and / or infection status of a transplant recipient can be used to categorise the recipient as having: (a) a graft dysfunction; (b) an infection (and optionally the type of infection); and / or (c) a functional graft. Stratifying graft function and / or infection status according to the invention may comprise determining if a solid organ transplant recipient exhibits a biomarker signature associated with a first phenotype or a second phenotype. As used herein, the term “phenotype” particularly refers to a set of observable characteristics from a graft function or graft dysfunction (including a specific stage or category of graft dysfunction), infection status or an infection type. According to the invention said phenotypes have been shown to be associated with specific biomarker signatures. The first and second phenotypes may be independently selected from a graft function or graft dysfunction (including a specific stage or category of graft dysfunction), infection status or an infection type. Thus, a first phenotype may be a functional graft, clinical graft dysfunction (including incipient, active, stable or progressive graft dysfunction), incipient graft dysfunction, active graft dysfunction, stable graft dysfunction, progressive graft dysfunction, presence of an infection (i.e. infection), absence of an infection (i.e. no infection), a fungal infection, a viral infection, or a bacterial infection. A second phenotype may be a functional graft, clinical graft dysfunction, incipient graft dysfunction, active graft dysfunction, stable graft dysfunction, progressive graft dysfunction, presence of an infection (i.e. infection), absence of an infection (i.e. no infection), a fungal infection, a viral infection, or a bacterial infection. When the solid organ transplant is a lung transplant, the first and second phenotypes may be independently selected from lung graft function or CLAD (including a specific stage or category of graft dysfunction), infection status or an infection type. Thus, a first phenotype may be a functional lung graft, CLAD (including incipient, active, stable or progressive CLAD), incipient CLAD, active CLAD, stable CLAD, progressive CLAD, presence of an infection (i.e. infection), absence of an infection (i.e. no infection), fungal infection, viral infection, bacterial infection. A second phenotype may be a functional lung graft, CLAD (including incipient, active, stable or progressive CLAD), incipient CLAD, active CLAD, stable CLAD, progressive CLAD, presence of an infection (i.e. infection), absence of an infection (i.e. no infection), fungal infection, viral infection, bacterial infection. As used herein, the term “solid organ transplant” refers to the transfer of a solid organ, or a part, tissue or cells thereof to a recipient. Transplants may be autologous or allogenic. Typically, solid organ transplants are allogenic. A solid organ transplant may either refer to the material (organ, part, tissue or cells) that are transplanted, or to the procedure by which said material is taken from a donor and transferred to a recipient. Solid organs which can be transplanted typically include the lung, liver, kidney, pancreas, 17

[0013] intestines, heart, and uterus. Part of an organ (e.g. a lobe of the liver or lung) may be transplanted. Cells or tissues of solid organs (e.g. pancreatic islet cells) are also encompassed. One or both of the lungs or kidneys may be transplanted. Heart and lung transplants are also encompassed by the term solid organ transplant. As used herein, the term "biomarker" refers to virtually any biological compound, such as a protein and a fragment thereof, a peptide, a polypeptide, a proteoglycan, a glycoprotein, a lipoprotein, a carbohydrate, a lipid, a nucleic acid, an organic on inorganic chemical, a natural polymer, and a small molecule, that is present in the biological sample and that may be isolated from, or measured in, the biological sample. Furthermore, a biomarker can be the entire intact molecule, or it can be a portion thereof that may be partially functional or recognised, for example, by an antibody or other specific binding protein. A biomarker is considered to be informative if a measurable aspect or characteristic of the biomarker is associated with a given state of an individual, such as a bacterial infection or graft dysfunction. Such a measurable aspect or characteristic may include, for example, the presence, absence, or concentration of the biomarker in the biological sample from the individual and / or its presence as part of a biomarker signature. Such a measurable aspect of a biomarker is defined herein as a ''feature." For example, the presence of a biomarker may be a feature. As another example, the amount of a biomarker in a sample, or the amount of a biomarker in a sample compared with a control or reference sample may be a feature. A feature may also be a ratio of two or more measurable aspects of biomarkers, which biomarkers may or may not be of known identity, for example. The terms “biomarker signature” or "biomarker profile" are used interchangeably to refer to a combination of at least two such features, where the features can correspond to the same or different classes of biomarkers such as, for example, two nucleic acids or a nucleic acid and a carbohydrate. A biomarker signature may comprise at least two, three, four, five, 10, or more features. A biomarker signature may also comprise at least one measurable aspect of at least one internal standard. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) plays an inhibitory role on natural killer (NK) cells and T-cell functions upon binding to their non-MHC ligands. A non-limiting example of a human KLRG1 amino acid sequence is given by UniProt Accession No Q96E93 (version 1, accessed 08 July 2024). A non-limiting example of a human KLRG1 mRNA sequence is given by GenBank Accession No. NM_005810 (version 4, accessed 08 July 2024). T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint inhibitory receptor expressed on immune cells including cytotoxic T cells, regulatory T cells and NK cells. A non-limiting example of a human TIGIT amino acid sequence is given by UniProt Accession No. C9J0B0 (version 1, accessed 08 July 2024). A non-limiting example of a human TIGIT mRNA sequence is given by GenBank Accession No. NM_173799 (version 4, accessed 08 July 2024). Programmed cell death protein 1 (PD1) is an inhibitory receptor on antigen activated T-cells that plays a critical role in induction and maintenance of immune tolerance to self. A non-limiting example of a human PD1 amino acid sequence is given by UniProt Accession No. Q15116 (version 3, accessed 08 July 2024). A non-limiting example of a human PD1 mRNA sequence is given by GenBank Accession No. NM_005018 (version 3, accessed 08 July 2024). Inducible T-cell costimulator (ICOS) enhances all basic T-cell responses to a foreign antigen (proliferation, secretion of lymphokines, up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B-cells) ICOS is essential both for efficient interaction between T and B-cells and for normal antibody responses to T-cell dependent antigens. A non-limiting example of a human ICOS amino acid sequence is given by UniProt Accession No. Q9Y6W8 (version 1, accessed 08 July 2024). A non-limiting example of a human ICOS mRNA sequence is given by GenBank Accession No. NM_012092 (version 4, accessed 08 July 2024). CD27 antigen; (CD27) is a receptor specifically expressed at the surface of T cells which binds and is activated by its ligand CD70 / CD27L expressed by B cells. A non-limiting example of a human CD27 amino acid sequence is given by UniProt Accession No. P26842 (version 2, accessed 08 July 2024). A non-limiting example of a human CD27 mRNA sequence is given by GenBank Accession No. NM_001242 (version 4, accessed 08 July 2024). Tumor necrosis factor receptor superfamily, member 13B, also referred to as transmembrane activator and CAML interactor protein (TACI) is a tumor necrosis factor receptor superfamily member found expressed on peripheral B-lymphocytes. It has specificity for B-cell maturation antigen and TNF ligand superfamily member 13. A non- limiting example of a human TACI amino acid sequence is given by UniProt Accession No. O14836 (version 1, accessed 08 July 2024). A non-limiting example of a human TACI mRNA sequence is given by GenBank Accession No. NM_012452. (version 3, accessed 08 July 2024).Primary accession Q4ACX1 CD43 (also known as leukosialin and sialophorin) is a protein encoded by the SPN gene in humans. It is a sialic acid-rich protein and an integral cell membrane mucin that plays an important role in activation of T-lymphocytes. A non-limiting example of a human CD43 amino acid sequence is given by UniProt Accession No. P16150 (version 1, accessed 08 July 2024). A non-limiting example of a human CD43 mRNA sequence is given by GenBank Accession No. NM_001030288. (version 4, accessed 08 July 2024). 18 CD69 antigen (CD69) is involved in lymphocyte proliferation and functions as a signal transmitting receptor in lymphocytes, NK cells and platelets. A non-limiting example of a human CD69 amino acid sequence is given by UniProt Accession No. Q07108 (version 1, accessed 08 July 2024). A non-limiting example of a human CD69 mRNA sequence is given by GenBank Accession No. NM_001781. (version 2, accessed 08 July 2024). CD62 antigen-like family member L (also known as L-selectin) is a cell adhesion molecule and CD antigen that serves as a homing receptor for lymphocytes to lymph node high endothelial venules. A non-limiting example of a human CD62 amino acid sequence is given by UniProt Accession No. P14151 (version 2, accessed 08 July 2024). A non-limiting example of a human CD62 mRNA sequence is given by GenBank Accession No. NM_000655 (version 5, accessed 08 July 2024). Immunoglobulin M (IgM) refers to a class of immunoglobulins bearing mu chains Immunoglobulin D refers to an immunoglobulin which accounts for less than 1% of plasma immunoglobulin. It is found on the membrane of many circulating B lymphocytes. T lymphocytes or T cells are immune cells that are responsible for cell-mediated immunity. They release immune response mediators and drive cell / tissue destruction and cell-mediated immune responses. T cells express T cell receptors (TCRs) on their cell surface. There are numerous T cell subtypes, including CD4-positive T cells (CD4+),CD8-positive Tcells (CD8+), mucosal-associated invariant T cells (MAIT), gamma delta T cells ( ), follicular T helper cells (Tfh), regulatory T cells (Treg), and effector memory RA T cells (TEMRA). The term “CD4-positive T cell” or “CD4+T cell” is a common term of art that describes T lymphocytes (T cells) that express the T-cell surface glycoprotein CD4. CD4+T cells are also known as T helper cells or Thcells. CD4+T cells co-ordinate activation of various immune responses and form T memory cells for durable immunity. A non- limiting example of a human CD4 amino acid sequence is given by UniProt Accession No. P01730 (version 1, accessed 08 July 2024). A non-limiting example of a human CD4 mRNA sequence is given by GenBank Accession No. NM_000616 (version 5, accessed 08 July 2024). Other common markers for CD4+ T cells include IFN and T-bet (for T helper type1 (Th1) cells); IL4 (for T helper type 2 (Th2) cells), IL9 (for T helper type 9 (Th9) cells), IL17 (for T helper type 17 (Th17) cells), and IL22 (for T helper type 22 (Th22) cells). The term “CD8 positive T cell” or “CD8+T cell” is a common term of art that describes T lymphocytes (T cells) that express the T-cell surface glycoprotein CD8 alpha and / or beta chain. CD8+T cells are also known as cytotoxic T cells, TC or killer T cells. A non-limiting example of a human CD8 alpha amino acid sequence is given by UniProt Accession No. P01732 (version 1, accessed 08 July 2024). A non-limiting example of a human CD8 alpha mRNA sequence is given by GenBank Accession No. NM_001768 (version 7, accessed 08 July 2024). A non-limiting example of a human CD8 beta amino acid sequence is given by UniProt Accession No. P10966 (version 1, accessed 08 July 2024). A non-limiting example of a human CD8 beta mRNA sequence is given by GenBank Accession No. NM_172213 (version 5, accessed 08 July 2024). Other common markers for CD8+T cells include IFN , perforin, and granzyme B. Mucosal-associated invariant T cells (MAITs) are T lymphocytes, most typically found in mucosa tissues that form a covering over organs and cavities that make contact with external substances, such as molecules or particles in the air for example. MAITs are characterised by the expression of an invariant T cell receptor (TCR) alpha chain that joins with a restricted TCR beta chain, and are able to trigger augmented immune responses by connecting the innate and adaptive immune systems together, and are involved in microbial ligand recognition. Specifically, the MAIT are presented with vitamin B2 by MHC Class I-related protein (MR1). In humans, MAIT cells may be characterised by surface expression of high levels of CD161, interleukin-18 (IL-18) receptor, and chemokine receptors CCR5, CXCR6, and CCR6. Gamma delta T cells ( T cells) are a subset of T cells known for their significant cytokine production that are known to be localised in peripheral tissues such aslungs, intestines, and skin. Gamma delta T cells are involved in tissue homeostasis, responses to pathogens or tumours – directly attacking targets via cytotoxic activity or indirectly by activating other immune cells. Gamma delta T cells express a TCR comprising a heterodimer of and chains, which normally do not express the co-receptors CD4 and CD8, and account for, on average, 4% of human peripheral blood T cells. Asides from the gamma delta TCR, additional markers for gamma delta T cells include Fc gamma RIII / CD16, Toll-like receptors and E-cadherin. Follicular T helper cells (Tfh cells) a population of CD4+ T cells that are primarily found in secondary lymphoid organs, e.g. tonsils, spleen, lymph nodes, or in circulation, and aid B cells in the production of antibodies. Markers for follicular helper T cells include CXCR5, ICOS and PD1. Regulatory T cells (Treg cells) are responsible for managing immune responses to prevent autoimmune disease; this is achieved by eliciting a suppressive effect that keeps cells from reacting to their own antigens (self-antigen tolerance). FoxP3 expression a common marker for Treg cells in humans. Human Treg cells are further differentiated by low expression levels of CD127 (CD127lo). 19

[0014] Terminally differentiated effector memory T cells, also known as terminal effector memory T cells (TEMRA cells) are a class of CD8+T-cells which are positive for CD45RA expression and negative for CD27 and / or CCR7 expression, i.e. they are CD27- CD45RA+and CD27- and / or CCR7-. TEMRA are polyfunctional cells with cytotoxic and proinflammatory properties. Natural Killer cells (NK cells) are non-antigen specific bone marrow-derived lymphocytes that possess cytotoxic properties, classically directed against transformed and virus-infected cells, inducing apoptosis of targeted cells. Common markers for NK cells include CD56 and CD16. B lymphocytes or B cells are immune cells that are responsible for antibody-mediated (humoral) immunity. B cells express B cell receptors (BCRs) on their surface, which bind to antigens in a specific manner. On activation, B cells initiate an antibody response against the specific activating antigen. Once activated, B cells participate in a two-step differentiation process that yields both short-lived plasmablasts for immediate protection and long-lived plasma cells and memory B cells for persistent protection. As used herein, the term “sample” refers to any suitable biological material, typically biological matter that has been extracted from or produced by the human body. Non-limiting examples pf suitable biological materials include blood, plasma, saliva, serum, bronchoalveolar lavage (BAL), sputum, urine, cerebral spinal fluid, cells, a cellular extract, a tissue sample, a tissue biopsy, a stool sample and the like. A tissue biopsy or cell sample may be obtained by brush cytology, The nature of the sample may depend on the solid organ which has been transplanted. For example, for the recipient of a lung transplant, the sample may be blood, BAL, sputum or a lung biopsy; for the recipient of a liver transplant, the sample may be a liver biopsy, such as cells from the bile ducts of the liver; for the recipient of a kidney transplant, the sample may be urine; for the recipient of a pancreas transplant, the sample may be a blood sample, stool sample or biopsy from the pancreas; for the recipient of an intestinal transplant, the sample may be a stool sample, or tissue biopsy. The nature of the sample may be independent from the solid organ which has been transplanted. For example, a blood sample may be used for the recipient of a lung, liver, kidney, pancreatic, heart or other solid organ transplant. Determining the level of a biomarker typically comprises or consists of determining the presence and / or level of the at least one biomarker of the invention in an patient. The level of a biomarker in a patient may be measured relative to a control or reference population, for example relative to the level of said biomarker in a reference population. Similarly, the biomarker profile of a patient may be measured relative to a biomarker profile from a control or reference population. Herein the terms "control" and "reference population" are used interchangeably. The level of a biomarker may refer to the absolute amount of the biomarker, such as the mass, molar amount, concentration or molarity of the one or more biomarker of the invention may be assessed and compared with the corresponding value from the control or reference population. Alternatively, the amount of a biomarker may be compared with that of the control or reference population without quantifying the mass, molar amount, concentration or molarity of the biomarker. The level of a biomarker may be determined as the number or proportion of cells within a given cell population which are positive for said biomarker, i.e. by quantifying a population of cells expressing said biomarker. A control or reference can be one individual or a population of two or more individuals. The control or reference population, for example, may comprise three, four, five, ten, 15, 20, 30, 40, 50 or more individuals. Furthermore, the level of a biomarker in a control or reference biomarker and the level of the biomarker in a patient sample (test) that are compared in the methods of the present invention may be generated from the same individual, provided that the test and reference are generated from biological samples taken at different time points and compared to one another. For example, a sample may be obtained from an individual at the start of a study period. The level of a control or reference biomarker taken from that sample may then be compared to the level of that biomarker in subsequent samples from the same individual. Such a comparison may be used, for example, to determine the progression of graft function and / or infection status in the patient by repeated classifications over time. The control or reference may be obtained, for example, from a healthy individual (or population thereof) who has not had a solid organ transplant, from a solid organ transplant recipient (or population thereof) who have had a solid organ transplant and which transplant is functional. Typically wherein the control or reference is obtained from a solid organ transplant recipient (or population thereof) who have had a solid organ transplant, the solid organ transplant is of the same type as that of the patient. For example, individuals with functional lung transplants may be used as controls when stratifying the graft function and / or infection status of a lung transplant recipient. As used herein, a “threshold value” defines a value beyond which the level of a biomarker is useful in the stratification of the graft function and / or infection status of a solid organ transplant recipient. In other words, when the level of a biomarker exceeds a threshold value, this may be useful in the stratification of the graft function and / or infection status of a solid organ transplant recipient. When a decrease in a biomarker is associated with graft dysfunction and / or infection, then when the level of said biomarker is determined to be below said threshold value, this may be useful in the stratification of the graft function and / or infection status of a solid organ transplant recipient. When an increase in a biomarker is associated with graft dysfunction and / or infection, then when the level of said biomarker is determined to be above said threshold value, this may be useful in the stratification of the graft function and / or infection status of a solid organ transplant recipient. 20

[0015] As used herein, the term “a population of cells” refers to a plurality of cells, typically wherein the majority of said cells are of the same cell type. For example, a population of immune cells may comprise a majority of immune cells (e.g. T cells, B cells, etc.), with a minority or no non-immune cells. By way of further example, the majority of cells in a population of T cells are T cells (which may be of one or more subtype of T cells), with a minority or no B cells and / or NK cells. By way of further example, the majority of cells in a population of Treg cells are Treg cells, with a minority or no MAIT, B cells and / or NK cells. In a population of a cell type of interest, the number of cells of a different cell type is typically low relative to the number of the cells of the cell type of interest present in the population. Typically, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more, up to 100% of the cells of a cell population of the invention may be the cell type of interest. Preferably, at least 80%, preferably at least 90%, more preferably at least 95% of the cells of an cell population are the cell type of interest. By way of non-limiting example, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more, up to 100% of the cells of an NK cell population of the invention are NK cells. Preferably at least 80%, more preferably at least 90%, and even more preferably at least 95%, even more preferably at least 98% or more of the cells of an NK cell population of the invention are NK cells. The number of other cell types may be less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% of the cells of a cell population. Typically the number of other cell types is less than 20%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% or less of the cells of the cell population. By way of example, the number of B cells may be less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% of the cells of a T cell population. Typically the number of B cells is less than 20%, preferably less than 10%, more preferably less than 5%, even more preferably less than 2% or less of the cells of a T cell population. The number of other immune and / or non-immune cells may be less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11 %, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1% of the cells of a cell population. Typically the number of other immune and / or non-immune cells is less than 20%, preferably less than 10%, more preferably less than 5% of the cells, even more preferably less than 2%, or less of a cell population. As used herein, the term “quantifying a population of cells” refers to determining the proportion or absolute number of cells expressing at least one biomarker of interest within a cell population. Thus, quantifying a population of cells may comprise determining the percentage of said cells expressing said biomarker. By way of non-limiting example, quantifying a population of T cells according to the invention may comprise determining the percentage of T cells that express at least one biomarker as described herein. As used herein, the term “graft dysfunction progression” means a change in the way a graft dysfunction affects a subject over time. For chronic and / or incurable diseases, “progression” typically describes the worsening of a disease or symptoms of said disease over time. For example, in the context of CLAD, progression may be defined as a worsening of CLAD or the symptoms thereof. Progression may be defined by any established clinical measure, such as those described herein. Symptoms of CLAD include breathlessness, cough and sputum production, as well as decreases in spirometry parameters such as FEV and FVC (both as defined here). Classification of a subject by a method of the invention does not require perfect classification. Classification may be characterised by its "sensitivity." Stratification may be characterized by its "sensitivity". "Sensitivity" relates to the percentage of individuals with graft dysfunction (e.g. CLAD) and / or an infection who were correctly identified as having graft dysfunction (e.g. CLAD) and / or an infection. "Sensitivity" is defined in the art as the number of true positives divided by the sum of true positives and false negatives. The "specificity" of stratification is defined as the percentage of patients who were correctly identified as not having graft dysfunction (e.g. CLAD) and / or an infection, compared with a healthy control(s). That is, "specificity" relates to the number of true negatives divided by the sum of true negatives and false positives. “Accuracy” is defined as the rate or frequency by which subjects can be allocated to the correct group, and is defined mathematically as: Accuracy = (true negatives + true positives) / ( true negatives + true positives + false positives + false negatives). 21

[0016] Stratifying graft function and / or infection status The present invention provides a method for stratifying the graft function and / or infection status of a transplant recipient. Typically the transplant recipient is a solid organ transplant recipient. In other words, the invention allows a patient to be classified post-transplant on the basis of their graft function / dysfunction and / or the presence or absence of an infection. References herein to stratifying graft function and graft dysfunction are used interchangeably. The present inventors have demonstrated for the first time that immunophenotyping, can successfully be used as a diagnostic tool. The inventors have shown that by quantifying one or more population of immune cells and typically by comparing these with a control or reference group, it is possible to diagnose a disease or disorder of interest. The one or more populations of immune cells may depend on the disease or disorder to be diagnosed. In particular, the present inventors have demonstrated that one or more population of T cells, B cells and / or NK cells may be useful in such a method. Thus, the invention provides a method of diagnosing a disease or disorder of interest, said method comprising quantifying one or more population of T cells, B cells and / or NK cells in a sample obtained from a patient. A disease or disorder of interest may be any disease which is mediated by the immune system (innate and / or adaptive), or otherwise has an immune component. By way of non-limiting example, a disease or disorder of interest may be graft dysfunction of a solid organ transplant, an infection (e.g. a viral, bacterial or fungal infection), an autoimmune disease (e.g. rheumatoid arthritis or systemic lupus erythematosus (SLE)), sepsis, cancer or an inflammatory disease (e.g. asthma, psoriasis or interstitial lung disease). As exemplified herein, the inventors have shown that graft dysfunction and / or infection status in a solid organ transplant recipient can be stratified using immunophenotyping. Thus, the invention provides a method of stratifying graft dysfunction and / or infection status in a solid organ transplant recipient, said method comprising quantifying one or more population of T cells, B cells and / or NK cells in a sample obtained from the solid organ transplant recipient. Said solid organ transplant may be any type as described herein, particularly a lung transplant. Said one or more population may be (i) one or more population of T cells; (ii) one or more population of B cells; (iii) one or more population of NK cells; (iv) one or more population of T cells and one or more population of B cells; (v) one or more population of T cells and one or more population of NK cells; (vi) one or more population of B cells and one or more population of NK cells; or (vii) one or more population of T cells, one or more population of B cells and one or more population of NK cells. A population of T cells may comprise or consist of one or more (i.e. any 1, 2, 3, 4, 5, 6 or 7) of CD4-positive T cells (CD4+), CD8-positive T cells (CD8+), mucosal- associated invariant T cells (MAIT), gamma delta T cells ( ), follicular T helper cells (Tfh), regulatory T cells (Treg), and effector memory RA T cells (TEMRA). These different subtypes of T cells are known in the art and are described herein. The one or more population of immune cells (i.e. the one or more population of T cells, B cells and / or NK cells) may be identified by a biomarker signature. Determining a biomarker signature according to the invention may comprise quantifying the level of the one or more biomarkers at the cellular or population level. The level of a biomarker at a cellular level may be defined as determining the expression of said biomarker in at least one individual cell. Thus, there is granularity of expression at the level of individual cells. Any appropriate technique can be used for such quantification. The biomarker signature may depend on the cell population and / or the disease or disorder to be diagnosed. Thus, when a method of the invention relates to stratifying graft dysfunction and / or infection status in a solid organ transplant recipient comprising quantifying one or more population of T cells, B cells and / or NK cells in a sample obtained from a solid organ transplant recipient, the biomarker signature may be any as described herein. In particular, such methods of the invention are advantageous, as they allow for a single panel of biomarkers which can differentiated between graft function / dysfunction and infection status in a solid transplant recipient. Further, the biomarkers of the present invention can be detected in blood or BAL samples, allowing for a single, non-invasive (liquid biopsy) sample to be used in the stratification of graft function / dysfunction and infection status. As described and exemplified herein, the present inventors have identified biomarker signatures, i.e. combinations of biomarkers that are useful in the stratification of graft function and / or infection status in solid organ transplant recipients. Therefore, whilst the specific biomarkers may be described in the art, the inventors are the first to devise the biomarker signatures described herein, and to identify that these signatures have clinical utility in the stratification of graft function and / or infection status of solid organ 22

[0017] transplant recipients. Further, the biomarker signatures identified by the present invention are all derived from a single panel of biomarkers. Thus, by quantifying these biomarkers or biomarker signatures, the inventors have developed a method which is capable of stratifying graft function / dysfunction and infection status in a single assay. The biomarkers of the present invention are selected from KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, IgM, IgD and CD62L, as described herein. Any combination of these 11 biomarkers as may be used according to the present invention. Thus, a method for stratifying the graft function and / or infection status of a solid organ transplant recipient may comprise determining a biomarker signature which comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10 or all 11 of KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, IgM, IgD and CD62L. In other words, the invention relates to a method for stratifying the graft function and / or infection status of a solid organ transplant recipient, said method comprising determining a biomarker signature which comprises any one, two, three, four, five, six, seven, eight, nine, 10 or all 11 of KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, IgM, IgD and CD62L. Any one or more of these biomarkers may be detected in the same or different cell types, typically the same or different immune cell types, as described herein. The cell type in which any given biomarker is detected may be selected independently of the cell type in which any other biomarker is detected. Typically, a method of the invention comprises detecting at least one (i.e. any 1, 2, 3 or all 4) of KLRG1, TIGIT, PD1 and ICOS in a population of T cells. Any combination of KLRG1, TIGIT, PD1 and ICOS may be detected in a population of T cells according to the invention. Thus, KLRG1 may be detected in a population of T cells according to the invention. TIGIT may be detected in a population of T cells according to the invention. PD1 may be detected in a population of T cells according to the invention. ICOS may be detected in a population of T cells according to the invention. Preferably, the biomarker signature may comprise at least two biomarkers selected from KLRG1, TIGIT, PD1, and ICOS. In other words, at least two of KLRG1, TIGIT, PD1 and ICOS may be detected in a population of T cells according to the invention. More preferably, the biomarker signature may comprise or consist of KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS. In other words KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS may be detected in a population of T cells according to the invention. By way of non-limiting example, the biomarker signature may comprise or consist of: KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT. In said examples, KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT may be detected in a population of T cells according to the invention. Alternatively or in addition, a method of the invention comprises detecting at least one (i.e. any 1, 2, 3, 4, 5, 6 or all 7) of CD27, TACI, CD43, CD69, PD1, IgM and IgD in a population of B cells. Thus, CD27 may be detected in a population of B cells according to the invention. TACI may be detected in a population of B cells according to the invention. CD43 may be detected in a population of B cells according to the invention. PD1 may be detected in a population of B cells according to the invention. IgD may be detected in a population of B cells according to the invention. CD69 may be detected in a population of B cells according to the invention. IgM may be detected in a population of B cells according to the invention. Any combination of CD27, TACI, CD43, CD69, PD1, IgM and IgD may be detected in a population of B cells according to the invention. For example, CD27 and CD43 may be detected in a population of B cells according to the invention. Further alternatively or in addition, at least one (i.e. any 1, 2, 3 or all 4) of KLRG1, TIGIT, PD1 and CD62L in a population of NK cells. Thus, KLRG1 may be detected in a population of NK cells according to the invention. TIGIT may be detected in a population of NK cells according to the invention. PD1 may be detected in a population of NK cells according to the invention. CD62L may be detected in a population of NK cells according to the invention. Any combination of KLRG1, TIGIT, PD1 and CD62L may be detected in a population of NK cells according to the invention. Determining a biomarker signature according to the invention may comprise quantifying the level of the one or more biomarkers at the cellular or population level. The level of a biomarker at a cellular level may be defined as determining the expression of said biomarker in at least one individual cell. Thus, there is granularity of expression at the level of individual cells. Any appropriate technique can be used for such quantification. By way of non-limiting example, flow cytometry can be used to quantify the level of biomarker expression on individual cells. The level of a biomarker at a population level may be defined as determining the expression of said biomarker in a population of multiple cells. Thus, there is no granularity of expression at the level of individual cells. Any appropriate technique can be used for such quantification. By way of non-limiting example, flow cytometry can be used to quantify the level of biomarker expression in a population cells (combining the results for individual cells that are analysed within a sample will quantify said marker at the level of the population). By way of further non-limiting example, an ELISA may be used to quantify the level of biomarker expression in a population cells (here no readout for individual cells may be obtained, a single data-point is generated for each population). 23

[0018] Determining a biomarker signature according to the invention may comprise or consist of determining the level of said at least one said biomarkers in a population of T cells, at least one said biomarkers in a population of B cells and / or at least one said biomarkers in a population of NK cells. Determining a biomarker signature according to the invention may comprise or consist of determining the level of at least one of said biomarkers in a population of T cells, and at least one of said biomarkers in a population of B cells. Determining a biomarker signature according to the invention may comprise or consist of determining the level of at least one of said biomarkers in a population of T cells, and at least one of said biomarkers in a population of NK cells. Determining a biomarker signature according to the invention may comprise or consist of determining the level of at least one of said biomarkers in a population of B cells, and at least one of said biomarkers in a population of NK cells. Determining a biomarker signature according to the invention may comprise or consist of determining the level of at least one of said biomarkers in a population of T cells, at least one of said biomarkers in a population of B cells and at least one of said biomarkers in a population of NK cells. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and ICOS. Thus, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing KLRG1. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing TIGIT. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing PD1. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing ICOS. Preferably, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing at least two biomarkers selected from KLRG1, TIGIT, PD1, and ICOS. More preferably, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS. By way of non-limiting example, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of T cells expressing: KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT. In said examples, KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT. Alternatively or in addition, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing at least one biomarker (i.e. any 1, 2, 3, 4, 5, 6 or 7 biomarkers) selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD. Thus, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing CD27. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing TACI. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing CD43. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing PD1. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing IgD. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing CD69. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing IgM. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing any combination of CD27, TACI, CD43, CD69, PD1, IgM and IgD. For example, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of B cells expressing CD27 and CD43. Alternatively or in addition, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of NK cells expressing at least one at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and CD62L. Thus, determining a biomarker signature according to the invention may comprise or consist of quantifying a population of NK cells expressing KLRG1. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of NK cells expressing TIGIT. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of NK cells expressing PD1. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of NK cells expressing CD62L. Determining a biomarker signature according to the invention may comprise or consist of quantifying a population of NK cells expressing any combination of KLRG1, TIGIT, PD1 and CD62L. Determining a biomarker signature according to the invention may comprise or consist of quantifying (a) a population of T cells expressing at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and ICOS; and (b) a population of B cells expressing at least one biomarker (i.e. any 1, 2, 3, 4, 5, 6 or 7 biomarkers) selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD. 24 Determining a biomarker signature according to the invention may comprise or consist of quantifying (a) a population of T cells expressing at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and ICOS; and (b) a population of NK cells expressing at least one at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and CD62L. Determining a biomarker signature according to the invention may comprise or consist of quantifying (a) a population of B cells expressing at least one biomarker (i.e. any 1, 2, 3, 4, 5, 6 or 7 biomarkers) selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD; and (b) a population of NK cells expressing at least one at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and CD62L. Determining a biomarker signature according to the invention may comprise or consist of quantifying (a) a population of T cells expressing at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and ICOS; (b) a population of B cells expressing at least one biomarker (i.e. any 1, 2, 3, 4, 5, 6 or 7 biomarkers) selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD; and (c) a population of NK cells expressing at least one at least one biomarker (i.e. any 1, 2, 3 or 4 biomarkers) selected from KLRG1, TIGIT, PD1 and CD62L. In any embodiment of the invention, a population of T cells may comprise or consist of one or more (i.e. any 1, 2, 3, 4, 5, 6 or 7) of CD4-positive T cells (CD4+), CD8-positive T cells (CD8+), mucosal-associated invariant T cells (MAIT), gamma delta T cells ( ), follicular T helper cells (Tfh), regulatory T cells (Treg), and effector memory RA T cells (TEMRA). These different subtypes of T cells are known in the art and are described herein. A method of the invention may comprise or consist of quantifying one or more (i.e. any 1, 2, 3, 4, 5, 6 or 7) population of T cells selected from CD4+T cells, CD8+T cells, MAIT, T cells, Tfhcells, Tregcells, and / or TEMRA. Any combination of said populations of T cells may be quantified in a method of the invention. As exemplified herein, as well as enabling the stratification of in the stratification of graft function / dysfunction and infection status at a high level, the inventors have further identified specific biomarker signatures which are able to stratify different grades of graft dysfunction and / or different types of infection. In particular, as described in more detail and exemplified below, as well as a general biomarker signature for CLAD, the inventors have identified biomarker signatures for specific grades of graft dysfunction (particularly CLAD), including active, stable, incipient, progressive graft dysfunction, and quiescent graft dysfunction (particularly active, stable, incipient, and progressive CLAD, as well as active and quiescent disease in the context of lung transplants) as defined herein. Further, also as described in more detail and exemplified below, as well as a general biomarker signature for infection, the inventors have identified biomarker signatures for specific types of infection, including bacterial, viral and fungal infections. The methods of the invention may be useful in the diagnosis or stratification of CLAD as BOS or RAS. This is important because these distinct clinical syndromes have different prognoses. Earlier detection of graft dysfunction (e.g. CLAD) and / or diagnosis of an infection, with an improved ability to distinguish between graft dysfunction (e.g. CLAD) subsets or infection type has the potential to prolong survival and improve patient outcomes. Typically a method of the invention comprises determining the level of said one or more biomarker or a combination thereof as described above. Said quantification may be at the cellular or population level, as described herein. As used herein, the phrase “determining the level of a biomarker” means determining the amount of the biomarker that are present in a sample obtained from a test subject, i.e. transplant recipient. As used herein, the phrase “quantifying a population of cells” means determining the number of cells expressing a biomarker or biomarker signature of interest that are present in a sample obtained from a test subject, i.e. transplant recipient. When determining the level of one or more biomarkers or a cell population present in a sample this means quantifying each biomarker or cell by determining, for example, the relative or absolute amount of the biomarker or cell. It will be appreciated that the assay methods do not necessarily require measurement of absolute values of biomarker or cell number, unless it is desired, because relative values are sufficient for many applications of the invention. Accordingly, the "amount" of a biomarker can be the (absolute) total amount of the biomarker (e.g. mass, molar amount, concentration or molarity) that is detected in a sample, or it can be a "relative" amount, e.g., the difference between the biomarker detected in a sample and e.g. another constituent of the sample. The amount of the biomarker may be expressed by its concentration in a sample, or by the concentration of a reagent that detects the marker. Similarly, the "number" of a cell population can be the (absolute) total number of cells detected in a sample, or it can be a "relative" amount, e.g., the difference between the biomarker detected in a sample and e.g. another cell type of the sample. The cell population may be expressed in terms of the total cell number, or by the concentration of a reagent that detects the cell type of interest. The level of a biomarker of the invention may be determined by quantitative and / or qualitative analysis. The level of the biomarker may be given in any appropriate units. For example, the concentration of the one or more biomarker may be given in pg / ml, ng / ml or g / ml. 25

[0019] The population of a cell type of interest according to the invention may be determined by quantitative and / or qualitative analysis. The population of a cell type of interest may be given in any appropriate units. For example, the number of cells of said cell type, or the percentage of said cell type in a sample. Measurement of the biomarkers of the invention and / or quantification of a population of a cell type of interest can be performed by any method that provides satisfactory analytical specificity, sensitivity and precision. The invention thus encompasses the use of those methods known to a person skilled in the art to measure the amount of biomarker(s) and / or quantify a population of a cell type of interest for the purposes of stratifying graft dysfunction and / or infection status according to the invention. A biomarker of the invention may be detected at the nucleic acid or protein level. Thus, a biomarker of the invention may be DNA, RNA or protein and may be quantified using any appropriate technique. Typically biomarkers of the invention are detected at the protein level. The amount of a biomarker of the invention may be measured directly or indirectly. The relative amount of a biomarker of the invention may be determined using any appropriate technique. Suitable standard techniques are known in the art, for example aptamer-based assays or antibody-based assays such as Western blotting and enzyme-linked immunosorbent assays (ELISAs). Other non-limiting examples of standard techniques that may be used include microarray analysis, transcriptomics analysis, quantitative real-time PCR (qPCR), high Performance Liquid Chromatography (HPLC) and mass spectrometry (e.g. matrix-assisted laser desorption / ionization mass spectrometry (MALDI MS), surface-enhanced laser desorption / ionization mass spectrometry (SELDI MS), time of flight mass spectrometry (TOF MS) and liquid chromatography mass spectrometry (LC MS)). When populations of one or more cell type of interest are quantified, methods include flow cytometry, particularly Fluorescent Activated Cell Sorting (FACS). Preferred methods include flow cytometry (as used in the Examples). Quantification means may be in multiplex form. Multiplexed assays advantageously allow for quantification of biomarker combinations at minimal additional cost and uses instrumentation that is now widely available with increasing extent of automation and availability for non-specialist use. Different biomarkers or cell populations may be quantified using different detection methods according to the present invention. For example one or more biomarker of the invention may be quantified using a nucleic acid-based assay, and a different one or more biomarker of the invention may be quantified using an antibody-based assay (e.g. an ELISA). Preferably, different biomarkers or cell populations may be quantified using the same detection method according to the present invention. For example, each cell population quantified in a method of the invention may be quantified using FACS. When the levels of two or more biomarker or cell populations are determined, the methods of the present invention typically determine the level of each biomarker or cell population. Alternatively, the methods of the invention may determine the cumulative amount of all the markers or cell populations. Alternatively, the amount of the biomarkers or cell populations can be combined with each other in a formula to form an index value. A method of the present invention may comprise determining the level of (i) at least one biomarker as defined herein in a population of T cells, (ii) at least one biomarker as defined herein in a population of B cells; and / or (iii) at least one biomarker as defined herein in a population of NK cells; or any combination of (i), (ii) and (iii), i.e. (i) and (ii), (i) and (iii) or (i), (ii) and (iii). Determining the level of each at least one biomarker may comprise determining whether the level of said at least one biomarker exceeds a threshold value. Alternatively or in addition, a method of the present invention may comprise quantifying (i) a population of T cells expressing at least one biomarker as defined herein, (ii) a population of B cells expressing at least one biomarker as defined herein; and / or (iii) a population of NK cells expressing at least one biomarker as defined herein; or any combination of (i), (ii) and (iii), i.e. (i) and (ii), (i) and (iii) or (i), (ii) and (iii). Quantifying each population may comprise determining whether the number of cells in said population exceeds a threshold value. It is within the routine skill of one of ordinary skill in the art to determine an appropriate threshold level for any biomarker and / or cell population as described herein. Wherein a biomarker of the invention is increased in a phenotype of interest, said threshold value may be an increase as defined herein, such as an increase can be, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140% or at least 150% of the reference value. The increase in the amount of the markers may be statistically significant. Wherein a biomarker of the invention is decreased in a phenotype of interest, said threshold value may be a decrease as defined herein, such as a decrease can be, for example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the reference value. The decrease in the amount of the markers may be statistically significant. Wherein a biomarker of the invention is increased in a phenotype of interest, said threshold value may be an increase as defined herein, such as a fold-change increase of at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.2, at least 2.5, at least 3 or more relative to a 26

[0020] suitable reference value. Typically, wherein a biomarker of the invention is increased in a phenotype of interest, said threshold value may be a fold-change increase of at least 1.5, preferably at least 2. Wherein a biomarker of the invention is decreased in a phenotype of interest, said threshold value may be a decrease as defined herein, such as a fold-change decrease of at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 2.2, at least 2.5, at least 3 or more relative to a suitable reference value. Typically, wherein a biomarker of the invention is decreased in a phenotype of interest, said threshold value may be a fold-change decrease of at least 1.5, preferably at least 2. The methods of the invention typically comprise a step of “comparing the level” of one or more biomarkers and / or one or more cell population with the amount of the same biomarker(s) and / or cell population(s) in a reference standard. The “reference standard” typically refers to a value obtained from a population of individual(s) whose disease status is known. A reference standard can be determined for any particular population, subpopulation, or group of individuals according to standard methods well known to those of skill in the art. The reference standard can be generated from one individual or a population of two or more individuals. The control or reference population, for example, may comprise three, four, five, ten, 15, 20, 30, 40, 50 or more individuals, preferably at least ten individuals. The reference standard may be the amount of a biomarker and / or cell population in a sample or samples derived from one individual. Alternatively, the reference standard may be derived by pooling data obtained from multiple individuals, and calculating an average (for example, mean or median) amount for a biomarker and / or cell population. Thus, the reference standard may reflect the average amount of a biomarker and / or cell population in multiple individuals. Said amounts may be expressed in absolute or relative terms, in the manner as described above in relation to the sample that is to be tested using the method of the invention. The reference standard is typically obtained from a reference sample, i.e. a sample of the same sample type (e.g. biofluid, tissue or cells, particularly blood or BAL) as the sample(s) obtained from the subject, wherein the reference sample is obtained from a reference population. By way of non-limiting example, if the sample obtained from a subject is a blood sample (e.g. a whole blood sample), the reference standard is also obtained from a blood sample (e.g. a whole blood). The amount of a biomarker and / or cell population of the invention may be assessed and compared with the corresponding value for the same biomarker and / or cell population from the reference standard. Alternatively, the amount of a biomarker and / or cell population of the invention may be compared with that of the reference standard without quantifying the mass, molar amount, concentration or molarity of the one or more biomarker and / or the cell number of the cell population. When comparing between the sample and the reference standard, the way in which the amounts are expressed is matched between the sample and the reference standard. Thus, an absolute amount is compared with an absolute amount, and a relative amount is compared with a relative amount. When the amounts of two or more biomarkers and / or cell populations are determined, the method may comprise comparing the amount of each biomarker and / or cell population to its corresponding reference standard. When the cumulative amount of all the biomarkers and / or cell population is determined, the method may comprise comparing the cumulative amount to a corresponding reference standard. The reference standard may be obtained either within (i.e. constituting a step of) or separately to (i.e. not constituting a step of) the methods of the invention. The methods of the invention may comprise a step of establishing a reference standard for the quantity of the biomarkers. Alternatively, the reference standard may be obtained separately to the method of the invention and accessed during a comparison step of the invention. The reference standard and the subject’s (test) sample that are compared in the methods of the present invention may be generated from the same individual (transplant recipient), provided that the sample and reference standard are generated from biological samples taken at different time points and compared to one another. For example, a sample may be obtained from a transplant recipient prior to the transplant, or immediately following surgical recovery and serve as a reference standard. This reference standard may then be compared to the amount of the biomarkers and / or cell populations of the invention generated from subsequent samples from the same subject post-transplant. Such a comparison may be used, for example, to determine the progression of graft dysfunction in the subject by repeating the method over time, to monitor a subject for infection, or for optimising therapy, such as treatment of graft dysfunction and / or infection, as described herein. The reference standard may be obtained, for example, from a population of solid organ transplant recipient(s), i.e. individual(s) who have not undergone the same type of solid organ transplant as the subject (e.g. a lung transplant), or how have not undergone any solid organ transplant. Typically the reference standard may be obtained from a population of healthy individual(s), as defined herein. Healthy and non-solid organ transplant recipient reference standards may be interchangeably referred to herein as “non-solid organ transplant reference standards”. 27

[0021] Alternatively, the reference standard may be obtained, for example, from a population of individual(s) who have undergone a solid organ transplant, typically the same type of solid organ transplant as the subject (e.g. a lung transplant), i.e. solid organ transplant recipients. Such reference standards may be interchangeably referred to herein as “solid organ transplant recipient reference standards”. These solid organ transplant recipient(s) may be different to the subject, or may be the subject at a different time point (as described above). If the solid organ transplant recipient(s) are different to the subject, such solid organ transplant recipient(s) preferably have similar sex, age, and body mass index (BMI) as compared with the test subject, and are typically matched for the same type of solid organ transplant. Multiple separate reference standards may be used in the methods of the invention for each marker. For example, reference standards obtained from a population of solid organ transplant recipients and reference standards obtained from a population of healthy individuals may be used according to the present invention. By comparing the amount of biomarkers and / or cell populations quantified in a sample obtained from a solid organ transplant recipient to the amount of markers and / or cell populations quantified for a reference standard (such as that obtained from a population of healthy individuals, or from a population of solid organ transplant recipients, it is possible to stratify a solid organ transplant recipient’s graft dysfunction and / or infection status. The methods of the invention permit classification of the subject as belonging to or not belonging to the reference population (i.e. by determining whether the levels of biomarker(s) and / or cell populations quantified in the solid organ transplant recipient are statistically similar to the reference standard or statistically deviate from the reference standard). Hence, classification of the solid organ transplant recipient’s biomarker signature as corresponding to a particular reference standard is predictive that the solid organ transplant recipient falls (or does not fall) within the reference population from which the reference standard was derived. A solid organ transplant recipient may be diagnosed as having or being at risk of graft dysfunction (e.g. CLAD) and / or an infection when the amount of biomarker(s) and / or cell populations quantified is statistically similar to the amount determined for the corresponding values obtained in a graft dysfunction (e.g. CLAD) and / or infection reference standard. Alternatively, a solid organ transplant recipient may be diagnosed as not having or not being at risk of having of graft dysfunction (e.g. CLAD) and / or an infection when the amount of biomarker(s) and / or cell population(s) quantified is statistically similar to the amount determined for the corresponding values obtained in a non- solid organ transplant reference standard. A solid organ transplant recipient may be diagnosed as having or being at risk of graft dysfunction (e.g. CLAD) and / or an infection when the amount of biomarker(s) and / or cell population(s) quantified statistically deviates from the amount determined for the corresponding values obtained in a non-solid organ transplant reference standard. Alternatively, a solid organ transplant recipient may be diagnosed as not having or not being at risk of having of graft dysfunction (e.g. CLAD) and / or an infection when the amount of biomarker(s) and / or cell population(s) quantified statistically deviates from the amount determined for the corresponding values obtained in a solid organ transplant reference standard. By comparing the amount of biomarkers and / or cell population(s) quantified in a sample obtained from a solid organ transplant recipient to the amount of markers quantified for a reference standard (such as that obtained from a population of healthy individuals, or from a population of individuals known to have a solid organ transplant, graft dysfunction and / or an infection), it is possible to determine a stratify the graft dysfunction and / or infection status of a solid organ transplant recipient. The methods of the invention permit stratification of the solid organ transplant recipient as having a functional graft, graft dysfunction and / or an infection, and to further stratify the grade of graft dysfunction and / or type of infection by determining whether the amounts of biomarker quantified in the subject are statistically similar to the reference standard or statistically deviate from the reference standard. As used herein, the term “statistically similar” means that the amounts of biomarker and / or cell population quantified for the solid organ transplant recipient are similar to those quantified for the reference standard to a statistically significant level. The term “statistically significant” means that the alteration is greater than what might be expected to happen by chance alone (p = < 0.05). Statistical significance can be determined by any method known in the art. As used herein, the term “statistically deviates” means that the amounts of biomarker quantified for the solid organ transplant recipient differs from those quantified for the reference standard to a statistically significant level. The term “statistically significant” means that the alteration is greater than what might be expected to happen by chance alone (p = < 0.05). Statistical significance can be determined by any method known in the art. The deviation in marker abundance may be an increase or decrease. The increase or decrease may be statistically significant. For the avoidance of doubt, the methods of the present invention are in vitro methods. Thus, the invention can be carried out in vitro on an isolated sample that has previously been obtained from a test subject (solid organ transplant recipient). 28

[0022] A method of the invention may be useful in stratifying the graft dysfunction and / or infection status of a recipient of any type of solid organ transplant. Solid organ transplants are defined herein. Non-limiting examples of solid organ transplants wherein the stratification methods of the invention may be used include lung transplants, kidney transplants, liver transplants, heart transplants, small bowel transplants and pancreatic transplants. Preferably, the invention relates to stratifying the graft dysfunction and / or infection status of a recipient of a lung transplant. A method of the invention may be carried out using any appropriate sample, as defined herein. The sample obtained from a subject may be any suitable biological material, for example blood, saliva, sputum, urine, cerebral spinal fluid (CSF), cells, a cellular extract, a tissue sample, a tissue biopsy, a stool sample and the like. The precise biological sample that is taken from the subject may vary, but the sampling preferably is minimally invasive and is easily performed by conventional techniques. By way of non-limiting example, a sample may be selected from a biofluid sample, such as a blood sample, a bronchoalveolar lavage (BAL) sample, a CSF sample, a synovial fluid sample, or a urine sample; a tissue sample (biopsy); a cell sample; and / or an organ sample (biopsy). Typically wherein a tissue, cell or organ sample is used, it is taken from the transplanted solid organ. Preferably, the methods of the invention relate to the use of biofluid samples, particularly blood and / or BAL. Particularly preferred, wherein the solid organ transplant is a lung transplant, the sample is a blood or BAL sample. When a blood sample is used, it may be taken with / without the subject fasting beforehand. The methods of the invention may use samples that have undergone minimal or zero processing before testing. This provides a significant advantage over prior art methods in terms of time, cost and practicality. By way of example, a blood sample obtained from a test subject may be tested directly using the method of the present invention, without further processing. The methods may use samples that have been manipulated, in any way, after procurement, such as by treatment with reagents, solubilisation, or enrichment for certain components. A biological sample may be taken from a solid organ transplant recipient before the solid organ transplant recipient shows any symptoms of graft dysfunction and / or infection, e.g. to establish a base line for said solid organ transplant recipient. A biological sample may be taken from the solid organ transplant recipient before the solid organ transplant recipient shows or after the onset of symptoms of graft dysfunction and / or infection, e.g. for the purpose of stratifying graft dysfunction and / or infection status in said solid organ transplant recipient. A biological sample may be taking, during, and / or after treatment for graft dysfunction and / or infection, for example after a change in treatment. In this way, the methods of the invention can be used to assess a subject’s response to treatment, as described herein. The level of a biomarker and / or cell population of the invention may be quantified once, or multiple times (e.g. at least twice, at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, at least nine times, at least ten times, or more). In other words, the method of the invention may be conducted once or multiple times. When the level of a biomarker and / or cell population in the subject is determined multiple times, typically a separate sample taken each time the level of the biomarker and / or cell population is quantified. Typically multiple quantifications are used for monitoring or optimising therapy, as described herein. A sample may be obtained from a solid organ transplant recipient before treatment initiation, after treatment initiation; or separate samples may be taken before and after treatment initiation. Although the invention does not require a monitoring period for stratification of graft dysfunction and / or infection status, it will be understood that repeated samples may be taken from a solid organ transplant recipient may be taken and assessed according to the invention over time until the solid organ transplant recipient is no longer at risk. A biomarker and / or cell population may be quantified in a sample obtained from the solid organ transplant recipient at one time point and may be compared to the amount of the biomarker and / or cell population in one or more sample obtained from the same solid organ transplant recipient at different points in time. As used herein, the terms “stratify”, “stratifying”, “stratification” may refer to the process or act of recognising, deciding on or concluding on a disease or condition in a solid organ transplant recipient on the basis of symptoms and signs and / or from results of various diagnostic procedures (such as for example, from knowing the presence, absence or quantity of biomarkers and / or cell population or other clinical measures characteristic of the diagnosed disease or condition). Thus, “stratifying graft dysfunction and / or infection status” may refer to “diagnosing whether a solid organ transplant recipient has or is at risk of having graft dysfunction and / or infection”, meaning determining whether the solid organ transplant recipient has or is at risk of having graft dysfunction and / or infection. “Stratifying graft dysfunction and / or infection status” or “determining whether the solid organ transplant recipient has or is at risk of having graft dysfunction and / or infection” may mean confirming the presence (or absence) of graft dysfunction and / or infection in a solid organ transplant recipient suspected of having or being at risk of graft dysfunction and / or infection. 29

[0023] “Stratifying graft dysfunction and / or infection status” may also refer to the process or act of recognising, deciding on or concluding on a the likely course or progression of disease or condition, or predicting the outcome of said disease or condition in a subject on the basis of symptoms and signs and / or from results of various prognostic procedures (such as for example, from knowing the presence, absence or quantity of biomarkers or other clinical measures characteristic of the diagnosed disease or condition). Thus, “stratifying graft dysfunction and / or infection status” may refer to “determining a prognosis for graft dysfunction and / or infection”, meaning determining the likely course or progression of graft dysfunction and / or infection in a solid organ transplant with graft dysfunction and / or infection. “Stratifying graft dysfunction and / or infection status” or “determining a prognosis for graft dysfunction and / or infection status” may mean determining whether a solid organ transplant with graft dysfunction and / or infection is at low-risk or high-risk of the graft dysfunction and / or infection progressing. As defined herein, progression of graft dysfunction may be defined as a worsening of graft dysfunction or the symptoms thereof. Progression may be defined by any established clinical measure, such as those described herein. In particular, as exemplified herein, the invention is particularly useful in determining whether a solid organ transplant recipient has active graft dysfunction, as defined and exemplified herein in with reference to active lung graft dysfunction, or progressive graft dysfunction, as defined here and exemplified with reference to progressive CLAD. The methods of the invention may be useful in identifying solid organ transplant recipients with graft dysfunction and / or infection who have not previously been diagnosed with graft dysfunction and / or infection, or a symptom thereof or disease associated therewith. Solid organ transplant recipients may have one or more symptom of graft dysfunction and / or infection, or may be asymptomatic for graft dysfunction and / or infection (or symptom thereof or disease associated therewith). Solid organ transplant recipients may have been identified as being at risk of developing graft dysfunction and / or infection, for example due to a solid organ transplant recipient exhibiting one or more risk factor for graft dysfunction and / or infection. The subject may therefore be one who is suffering from or is at risk of developing graft dysfunction and / or infection (or symptom thereof or disease associated therewith). In particular, as exemplified herein, the invention is particularly useful in determining whether a solid organ transplant recipient has incipient graft dysfunction, as defined here and exemplified with reference to incipient CLAD. The sensitivity of the methods of the invention (as defined herein) may be at least about 90%, at least about 89%, at least about 88%, at least about 87%, at least about 86%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, or at least about 65%. The specificity of the methods of the invention (as defined herein) may be at least about 90%, at least about 89%, at least about 88%, at least about 87%, at least about 86%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, or at least about 65%. The method of the invention for stratifying graft dysfunction and / or infection status can be used in combination with other methods to stratify graft dysfunction and / or infection status. Established clinical measures for stratifying graft dysfunction and / or infection status are known in the art, and non-limiting examples are described herein. As described and exemplified herein, the invention relates to a method for stratifying the graft function and / or infection status of a solid organ transplant recipient. The term “stratifying” is defined here. Said methods can determine whether a solid organ transplant recipient has: (a) a graft dysfunction; (b) an infection; and / or (c) a functional graft. Said stratification can differentiate between the category or grade of graft dysfunction and / or infection type. Thus, the invention provides methods of determining whether a solid organ transplant recipient has: (a) a graft dysfunction; (b) an infection; and / or (c) a functional graft. Said methods may be used to differentiate between the category of graft dysfunction and / or infection type. Typically, stratification via a method of the present invention comprises determining if a solid organ transplant recipient exhibits a biomarker signature associated with a first phenotype or a second phenotype. In terms of notation, such comparisons may be described herein in the form: first phenotype versus second phenotype. A phenotype may be any as described herein. A method of the invention may be used to differentiate between clinical graft dysfunction versus a functional graft. Alternatively or in addition, a method of the invention may be used to differentiate between incipient graft dysfunction versus a functional graft. Further alternatively or in addition, a method of the invention may be used to differentiate between active graft dysfunction versus quiescent graft dysfunction or stable graft dysfunction. Further alternatively or in addition, a method of the invention may be used to differentiate between progressive graft dysfunction versus stable graft dysfunction. Further alternatively or in addition, a method of the invention may be used to differentiate between infection versus no infection (in patients with / without graft dysfunction). In particular a method of the invention may be used to differentiate between (i) fungal infection versus no infection; (ii) viral infection versus no infection; and / or (iii) bacterial infection versus no infection; or any combination of (i), (ii), and (iii), e.g. (i) and (ii), (i) and (iii), (ii) and (iii) or (i), (ii) and (iii). Further alternatively or in addition, a method of the invention may be used to differentiate between clinical graft dysfunction versus infection. 30

[0024] Further alternatively or in addition, a method of the invention may be used to differentiate between fungal infection versus viral infection. Further alternatively or in addition, a method of the invention may be used to differentiate between fungal infection versus bacterial infection. Further alternatively or in addition, a method of the invention may be used to differentiate between viral infection versus bacterial infection. Whilst stratification is exemplified herein in the context of lung transplants and CLAD, and biomarker signatures for stratification are described in detail in this same context, it will be appreciated by one of ordinary skill in the art that the biomarkers for the various comparisons would be equally applicable in the broader context of solid organ transplants and graft dysfunction, rather than being limited to lung transplants and CLAD. Thus, where the present application identified biomarker signatures for CLAD (including incipient, active, stable and progressive CLAD) and infection (including bacterial, viral and fungal infection), these apply equally and without reservation as biomarker signatures for graft dysfunction (including incipient, active, stable and progressive graft dysfunction) and infection (including bacterial, viral and fungal infection) for other solid organ transplants. No matter the organ transplanted, solid organ allograft rejection is mediated by the cellular lymphocyte response, mainly T cells, and the humoral antibody response, B cells. As CLAD is a form of solid organ transplant rejection, the markers that have been identified herein on lymphocytes (T, B and NK cells) for the classification of CLAD and CLAD subtypes will, in view of the unifying mechanisms of solid organ allograft rejection, play a role in other forms of solid organ rejection as well. Thus, the biomarker signatures described are not limited to the exemplified context of lung transplants and CLAD, but are generally applicable to the diagnosis and stratification of the recipients of other solid organ transplants. In particular, as described in more detail below and as exemplified herein, the present invention preferably relates to the stratification of graft dysfunction (CLAD) and / or infection status in lung transplant recipients. Said methods can determine whether a lung transplant recipient has: (a) CLAD; (b) an infection; and / or (c) a functional graft. Said stratification can differentiate between the category or grade of CLAD and / or infection type. Thus, the invention provides methods of determining whether a lung transplant recipient has: (a) CLAD; (b) an infection; and / or (c) a functional graft. Said methods may be used to differentiate between the category of CLAD and / or infection type. A method of the invention may be used to differentiate between CLAD versus a functional lung graft. In some preferred embodiments, a method of the invention may be used to differentiate between CLAD versus a functional lung graft. Alternatively or in addition, a method of the invention may be used to differentiate between incipient CLAD versus functional lung graft. Further alternatively or in addition, a method of the invention may be used to differentiate between active disease (i.e. active lung graft dysfunction) versus quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD). Further alternatively or in addition, a method of the invention may be used to differentiate between active CLAD versus stable CLAD. Further alternatively or in addition, a method of the invention may be used to differentiate between progressive CLAD versus stable CLAD. Further alternatively or in addition, a method of the invention may be used to differentiate between infection versus no infection (in patients with / without CLAD). In particular a method of the invention may be used to differentiate between (i) fungal infection versus no infection; (ii) viral infection versus no infection; and / or (iii) bacterial infection versus no infection; or any combination of (i), (ii), and (iii), e.g. (i) and (ii), (i) and (iii), (ii) and (iii) or (i), (ii) and (iii). Further alternatively or in addition, a method of the invention may be used to differentiate between CLAD versus infection. Further alternatively or in addition, a method of the invention may be used to differentiate between fungal infection versus viral infection. Further alternatively or in addition, a method of the invention may be used to differentiate between fungal infection versus bacterial infection. Further alternatively or in addition, a method of the invention may be used to differentiate between viral infection versus bacterial infection. A method of the invention may be used as a standalone method, or in combination with any other diagnostic or prognostic method, tool or measure for graft dysfunction (e.g. CLAD) and / or infection. Established clinical measures for the diagnosis and / or prognosis of graft dysfunction (e.g. CLAD) and / or infection are known in the art, and non-limiting examples are described herein. Thus, using the methods of the invention in combination with established clinical diagnostic / prognostic measures for graft dysfunction (e.g. CLAD) and / or infection may provide improved granularity of risk of progression, allowing solid organ transplant recipients to be identified for monitoring and / or treatment who may otherwise not be identified. As described herein, the biomarkers of the invention are useful in stratifying the transplant function and / or infection status of a solid organ transplant recipient. Thus, as well as the invention providing methods for stratifying the transplant function and / or infection status of a solid organ transplant recipient using said biomarkers, the invention relates to the use of said biomarkers in stratifying the transplant function and / or infection status of a solid organ transplant recipient. Accordingly, the invention provides the use 31

[0025] of a biomarker signature for stratifying the transplant function and / or infection status of a solid organ transplant recipient, said biomarker signature comprising: (a) at least one biomarker in a population of T cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1 and ICOS; (b) at least one biomarker in a population of B cells, wherein said at least one biomarker is selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD; and / or (c) at least one biomarker in a population of Natural Killer (NK) cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1 and CD62L; wherein the population of T cells, B cells and / or NK cells is obtained from a sample from said recipient. For the avoidance of doubt, any and all disclosure herein in relation to methods of stratifying the transplant function and / or infection status of a solid organ transplant recipient using biomarkers of the invention applies equally and unreservedly to the use of said biomarkers in stratifying the transplant function and / or infection status of a solid organ transplant recipient. This includes, by way of non-limiting example, the specific comparison of phenotypes (clinical graft dysfunction versus functional graft; incipient graft dysfunction versus functional graft; active graft dysfunction versus quiescent disease (e.g. stable graft dysfunction); progressive graft dysfunction versus stable graft dysfunction; infection versus no infection, optionally: (i) fungal infection versus no infection; (ii) viral infection versus no infection; and / or (iii) bacterial infection versus no infection; clinical graft dysfunction versus infection; fungal infection versus viral infection; fungal infection versus bacterial infection; and / or viral infection versus bacterial infection), particularly in the context of lung transplant recipients and CLAD (i.e. CLAD versus a functional lung graft; incipient CLAD versus functional lung graft; active disease (i.e. active lung graft dysfunction) versus quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD); active CLAD versus stable CLAD; progressive CLAD versus stable CLAD; infection versus no infection, optionally: (i) fungal infection versus no infection; (ii) viral infection versus no infection; and / or (iii) bacterial infection versus no infection; CLAD versus infection; fungal infection versus viral infection; fungal infection versus bacterial infection; and / or viral infection versus bacterial infection). By way of further non-limiting example, this also includes specific sample types, biomarker signatures and / or cell populations. The invention also provides a method of detecting one or more of biomarker or biomarker signatures as described herein. In particular, the invention provides a method of detecting one or more of biomarker selected from KLRG1, TIGIT, PD1, ICOS, CD27, TACI, CD43, CD69, PD1, IgM, IgD and CD62L in a patient (i.e. a solid organ transplant recipient), said method comprising: (a) obtaining a blood or BAL sample from the patient (i.e. the solid organ transplant recipient); and (b) detecting whether one or more of biomarker is expressed on a population of cells present in the blood or BAL sample by contacting the blood or BAL sample with an means for detecting said one or more biomarker; wherein: (i) at least one biomarker selected from KLRG1, TIGIT, PD1 and ICOS is detected in a population of T cells; (ii) at least one biomarker selected from CD27, TACI, CD43, CD69, PD1, IgM and IgD is detected in a population of B cells; and / or (iii) at least one biomarker selected from KLRG1, TIGIT, PD1 and CD62L is detected in a population of NK cells. Optionally said means for detecting said one or more biomarker is an anti-biomarker antibody and detecting said one or more biomarker comprises or consists of detecting binding between the biomarker and the antibody. Detection can by carried out using any suitable means. By way of example, wherein antibodies are used, detection may be via FACS or ELISA. Selection of suitable assays is within the routine practice of one of ordinary skill in the art. For the avoidance of doubt, any and all disclosure herein in relation to methods of stratifying the transplant function and / or infection status of a solid organ transplant recipient using biomarkers of the invention applies equally and unreservedly to the use of said biomarkers in stratifying the transplant function and / or infection status of a solid organ transplant recipient. This includes, by way of non-limiting example, the disclosure of biomarker signatures and / or cell populations. CLAD vs functional lung graft Preferably, the solid organ transplant is a lung transplant. Any sample type as described herein may be used in a method of stratifying the graft function and / or infection status of a lung transplant recipient according to the invention. Typically when the solid organ transplant is a lung transplant, the sample is a blood sample and / or a bronchoalveolar lavage (BAL). A first phenotype according to the invention may be CLAD (including incipient, active, stable or progressive CLAD), i.e. a CLAD phenotype. Thus, a first biomarker signature may be associated with CLAD (including incipient, active, stable or progressive CLAD). A second phenotype according to the invention may be a functional lung graft. In embodiments where the first phenotype is a CLAD phenotype and the second phenotype is a functional lung graft, the invention may be used to determine whether a patient has CLAD or a functional lung graft. In other words, preferably the invention provides a method for stratifying the graft function of a lung transplant recipient, by determining whether the patient has CLAD or a functional lung graft, i.e. to determine the success of a lung transplant. 32

[0026] The invention provides a method for stratifying a lung transplant recipient as having CLAD versus having a functional lung graft, said method comprising determining a biomarker signature which comprises at least one biomarkers in a population of T cells, wherein said at least one biomarker is selected from KLRG1, TIGIT, PD1, and ICOS; wherein the population of T cells is obtained from a sample from said recipient. In said a method, a biomarker signature may be determined comprising KLRG1 in a population of T cells obtained from a sample from the lung transplant recipient. A biomarker signature may be determined comprising TIGIT in a population of T cells obtained from a sample from the lung transplant recipient. A biomarker signature may be determined comprising PD1 in a population of T cells obtained from a sample from the lung transplant recipient. A biomarker signature may be determined comprising ICOS in a population of T cells obtained from a sample from the lung transplant recipient. Preferably, the invention provides a method for stratifying a lung transplant recipient as having CLAD versus having a functional lung graft, said method comprising determining a biomarker signature which comprises at least two biomarkers in a population of T cells, wherein said at least two biomarkers are selected from KLRG1, TIGIT, PD1, and ICOS; wherein the population of T cells is obtained from a sample from said recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1 and TIGIT in a population of T cells obtained from a sample from the lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1 and PD1 in a population of T cells obtained from a sample from the lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1 and ICOS in a population of T cells obtained from a sample from the lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising TIGIT and PD1 in a population of T cells obtained from a sample from the lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising TIGIT and ICOS in a population of T cells obtained from a sample from the lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising PD1 and ICOS in a population of T cells obtained from a sample from the lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1, TIGIT, and PD1 in a population of T cells obtained from the sample from a lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1, TIGIT, and ICOS in a population of T cells obtained from the sample from a lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1, PD1, and ICOS in a population of T cells obtained from the sample from a lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising TIGIT, PD1, and ICOS in a population of T cells obtained from the sample from a lung transplant recipient. In a method of the invention, a biomarker signature may be determined comprising KLRG1, TIGIT, PD1, and ICOS in a population of T cells obtained from the sample from a lung transplant recipient. CLAD vs functional lung graft biomarker signature in blood The invention provides a method of stratifying the graft function of a lung transplant recipient, by determining whether the patient has CLAD or a functional lung graft by determining a biomarker signature from a blood sample from the lung transplant recipient. The biomarker signature may comprise at least one biomarker selected from KLRG1, TIGIT, PD1, and ICOS. In other words, at least one of KLRG1, TIGIT, PD1 and ICOS may be detected in a population of T cells from a blood sample from the lung transplant recipient. Preferably, the biomarker signature may comprise at least two biomarkers selected from KLRG1, TIGIT, PD1, and ICOS. In other words, at least two of KLRG1, TIGIT, PD1 and ICOS may be detected in a population of T cells from a blood sample from the lung transplant recipient. More preferably, the biomarker signature may comprise or consist of KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS. In other words KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS may be detected in a population of T cells from a blood sample from the lung transplant recipient. By way of non-limiting example, the biomarker signature may comprise or consist of: KLRG1 and 33

[0027] TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT. In said examples, KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT may be detected in a population of T cells from a blood sample from the lung transplant recipient. Thus, the invention provides a method of stratifying the graft function of a lung transplant recipient, wherein the sample is a blood sample, and wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 in a population of T cells; (b) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (c) (i) an increase in the level of TACI; (ii) a decrease in the level of IgD; and / or a decrease in the level of CD27; in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any one, any two or all three of (a) to (c). Preferably, the invention provides a method of stratifying the graft function of a lung transplant recipient, wherein the sample is a blood sample, and wherein a CLAD phenotype is associated with an increase in the level of KLRG1 in a population of T cells compared with a functional lung graft. In other words, the invention provides a method of stratifying a lung transplant recipient as having a CLAD phenotype (a first phenotype) versus a functional lung graft (a second phenotype). Said method typically involves analysing a sample from the recipient. When said sample is a blood sample, a CLAD phenotype may be associated with: (a) an increase in the level of KLRG1 in a population of T cells; (b) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (c) (i) an increase in the level of TACI; (ii) a decrease in the level of IgD; and / or a decrease in the level of CD27; in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any one, any two or all three of (a) to (c). Preferably, the invention provides a method of stratifying a lung transplant recipient as having a CLAD phenotype (a first phenotype) versus a functional lung graft (a second phenotype) by analysing a blood sample from the recipient, wherein a CLAD phenotype is associated with an increase in the level of KLRG1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of CD43 in a population of B cells. An increase or decrease in the level of any of KRLG1 in a population of T cells, TIGT in a population of T cells, PD1 in a population of T cells, ICOS in a population of T cells, KLRG1 in a population of NK cells, PD1 in a population of NK cells, TACI in a population of B cells, IgD in a population of cells, CD43 in a population of B cells, and CD27 in a population of B cells may be combined to arrive at a biosignature for CLAD vs a functional lung graft in a blood sample according to the invention. Examples of such combinations are set out below. A complete list of biomarker combinations providing biosignatures for CLAD vs a functional lung graft in a blood sample according to the invention is set out in Table A below. 34

[0028] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells and an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells and an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TACI, and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TACI, and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of CD27 and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and an increase in the level of TIGIT in a population of T cells. 35

[0029] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and a decrease in the level of PD1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and a decrease in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT and a decrease in the level of PD1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT and a decrease in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and a decrease in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of PD1 in a population of NK cells; and an increase in the level of TACI in a population of B cells. 36

[0030] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; increase in the level of TACI in a population of B cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TACI in a population of B cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TACI in a population of B cells; a decrease in the level of IgD in a population of B cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells; and a decrease in the level of PD1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells; and a decrease in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of ICOS in a population of T cells, and a decrease in the level of PD1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells; a decrease in the level of ICOS in a population of T cells, and a decrease in the level of PD1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. 37

[0031] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of PD1 in a population of T cells; and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of PD1 in a population of T cells; and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of ICOS in a population of T cells; and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of ICOS in a population of T cells; and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TACI, and a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TACI, and a decrease in the level of IgD and CD43 in a population of B cells. 38

[0032] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and a decrease in the level of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and a decrease in the level of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; an increase in the level of TACI, and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the level of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the level of IgD and CD43 in a population of B cells. 39

[0033] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and a decrease in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of PD1 in a population of T cells; and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of ICOS in a population of T cells; and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells; a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells; a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD43 in a population of B cells. 40

[0034] In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the levels of IgD and CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and a decrease in the levels of IgD and CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the level of CD27 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the level of CD43 in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the level of IgD in a population of B cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of KLRG1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. 41 In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of TIGIT in a population of T cells; a decrease in the level of PD1 and ICOS in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of TIGIT in a population of T cells, a decrease in the level of PD1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of KLRG1 and PD1 in a population of NK cells. In a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; an increase in the level of KLRG1 and PD1 in a population of NK cells; and an increase in the level of TACI and a decrease in the levels of IgD and CD27 in a population of B cells. T ll NK ll B ll

[0035] = marker is increased in CLAD compared with a functional lung graft; = marker is decreased in CLAD compared with a functional lung graft 52

[0036] In particular, in a blood sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated any combination of an increase in KLRG1 and / or TIGIT, and / or a decrease in PD1 and / or ICOS as biomarkers in a population of T cells; optionally in combination with one or more of KLRG1 and / or PD1 as a biomarker in NK cells; and further optionally in combination with one or more of TACI, IgD, CD43 and / or CD27 as a biomarker in B cells. Such combinations are set out in Table A herein. In any of the above embodiments, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of T cells selected from one or more of CD4+T cells, CD8+T cells, MAIT and / or T cells. Thus, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of (i) CD4+T cells; (ii) CD8+T cells; (iii) MAIT; (iv) T cells; (v) CD4+ T cells and CD8+ T cells; (vi) CD4+ T cells and MAIT; (vii) CD4+ T cells and T cells; (viii) CD8+ T cells and MAIT; (ix) CD8+ T cells and T cells; (x) MAIT and T cells; (xi) CD4+ T cells, CD8+ T cells and MAIT; (xii) CD4+ T cells, CD8+ T cells and T cells; (xiii) CD4+ T cells, MAIT and T cells; (xiv) CD8+ T cells, MAIT and T cells; or (xv) CD4+ T cells, CD8+ T cells, MAIT and / or T cells. Preferably the level of KLGR1 may be increased in any one of these populations of T cells. In any of the above embodiments, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of T cells selected from one or more of CD4+T cells, CD8+T cells, and / or T cells. Thus, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of (i) CD4+T cells; (ii) CD8+T cells; (iii) T cells; (iv) CD4+ T cells and CD8+ T cells; (v) CD4+ T cells and T cells; (vi) CD8+ T cells and T cells; or (vii) CD4+ T cells, CD8+ T cells and T cells. Preferably the level of KLGR1 may be increased in any one of these populations of T cells. In addition, a CLAD phenotype may also be associated with an increase in the level of KLRG1 in a population of MAIT. Alternatively or in addition, the level of PD1 in a population of T cells may be the level of PD1 in a population of T cells selected from CD8+ T cells, MAIT, and / or Tfh T cells. Thus, the level of PD1 in a population of T cells may be the level of PD1 in a population of (i) CD8+ T cells; (ii) MAIT; (iii) Tfh T cells; (iv) CD8+ T cells and MAIT; (v) CD8+ T cells and Tfh T cells; (vi) MAIT and Tfh T cells; or (vii) CD8+ T cells, MAIT, and Tfh T cells. Preferably the level of PD1 may be increased in any one of these populations of T cells. Alternatively or in addition, the level of PD1 in a population of T cells may be the level of PD1 in a population of Tregcells. Preferably the level of PD1 may be decreased in this population of T cells. Preferably alternatively or in addition, the level of PD1 in a population of T cells may be the level of PD1 in a population of T cells selected from CD8+ T cells and / or CD4+T cells. Thus, the level of PD1 in a population of T cells may be the level of PD1 in a population of (i) CD8+ T cells; (ii) CD4+ T cells; or (iii) CD8+ T cells and CD4+T cells. Preferably the level of PD1 may be decreased in any one of these populations of T cells. Alternatively or in addition, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of T cells selected from CD8+T cells and T cells. Thus, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of: (i) CD8+T cells; (ii) T cells; or (iii) CD8+T cells and T cells. Preferably the level of TIGIT may be increased in any one of these populations of T cells. Alternatively or in addition, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of TEMRA. Preferably the level of TIGIT may be decreased in this population of T cells. Preferably alternatively or in addition, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of T cells selected from CD4+, T cells, and / or Tregcells. Thus, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of: (i) CD4+T cells; (ii) T cells; (iii) Tregcells; (iv) CD4+ T cells and Tregcells; (v) CD4+ T cells and T cells; (vi) Tregcells and T cells; or (vii) CD4+ T cells, Tregcells and T cells. Preferably the level of TIGIT may be increased in any one of these populations of T cells. In addition, a CLAD phenotype may also be associated with an increase in the level of TIGIT in a population of CD8+ T cells. Alternatively or in addition, the level of ICOS in a population of T cells may be the level of ICOS in a population of CD8+ T cells. Preferably the level of ICOS may be decreased in this population of T cells. The cell population in which a change in level of a first biomarker is associated with a CLAD phenotype may be independent of the cell population in which a change in level of a different biomarker is associated with a CLAD phenotype. Thus, the population of cells may be different for each biomarker. By way of non-limiting example, the level of PD1 may be increased in a population of CD8+ T cells and the level of KLRG1 may be increased in a population of MAIT. Alternatively, the cell population in which a change in level of a first biomarker is associated with a CLAD phenotype may be related to the cell population in which a change in level of a different biomarker is associated 53

[0037] with a CLAD phenotype. Thus, the population of cells may be the same for each biomarker. By way of non-limiting example, the level of PD1 and KLRG1 may both be increased in a population of CD8+ T cells. In methods of stratifying a lung transplant recipient as having a CLAD versus a functional lung graft using a blood sample: (a) the level of KLRG1 may be increased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT and T cells; (b) the level of PD1 may be increased in one or more T cell population selected from CD8+T cells, MAIT, and TfhT cells; (c) the level of PD1 may be decreased in a population of Tregcells; (d) the level of TIGIT may be increased in one or more T cell population selected from CD8+T cells and T cells; (e) the level of TIGIT may be decreased in a population of TEMRA; (f) the level of KLRG1 and / or PD1 may be increased in a population of NK cells; (g) the level of TACI may be increased in a population of B cells; and / or (h) the level of IgD and / or CD27 may be decreased in a population of B cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is associated with any two or more, any five or more or all eight of (a) to (h). In methods of stratifying a lung transplant recipient as having a CLAD versus a functional lung graft using a blood sample: (a) the level of KLRG1 may be increased in a population of T cells; and (b) (i) the level of TIGIT may be increased in a population of T cells; and / or (ii) the level of PD1, and / or ICOS may be decreased in a population of T cells; compared with a functional lung graft. In addition to (a) and (b), a CLAD phenotype may be further associated with: (c) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (d) (i) an increase in the level of TACI in a population of B cells; (ii) a decrease in the level of IgD in a population of B cells; (iii) a decrease in the level of CD43 in a population of B cells; and / or (iv) a decrease in the level of CD27 in a population of B cells; compared with a functional lung graft. In particular, in methods of stratifying a lung transplant recipient as having a CLAD versus a functional lung graft using a blood sample: (a) the level of KLRG1 may be increased in one or more T cell population selected from CD4+T cells, CD8+T cells, and T cells; (b) the level of TIGIT may be increased in one or more T cell population selected from CD4+T cells, T cells, and Tregcells; (c) the level of PD1 may be decreased in one or more T cell population selected from CD8+T cells and CD4+T cells; and / or (d) the level of ICOS may be decreased in a population of CD8+T cells; compared with a functional lung graft. In addition to any one or more of (a) - (d), a CLAD phenotype may be further associated with: (e) an increase in the level of KLRG1 in a population of MAIT; 54

[0038] (f) an increase in the level of TIGIT in a population of CD8+ T cells; (g) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (h) (i) an increase in the level of TACI in a population of B cells; (ii) a decrease in the level of IgD in a population of B cells; (iii) a decrease in the level of CD43 in a population of B cells; and / or (iv) a decrease in the level of CD27 in a population of B cells; compared with a functional lung graft. For the avoidance of doubt, whilst the above biomarker signatures are described in the context of stratifying CLAD vs a functional lung graft in a blood sample, these biomarker signatures apply equally and without reservation to the stratification of graft dysfunction vs a functional graft in a blood sample for other solid organ transplants. CLAD vs functional lung graft biomarker signature in BAL The invention provides a method of stratifying the graft function of a lung transplant recipient, by determining whether the patient has CLAD or a functional lung graft by determining a biomarker signature from a BAL sample from the lung transplant recipient. The biomarker signature may comprise at least one biomarker selected from KLRG1, TIGIT, PD1, and ICOS. In other words, at least one of KLRG1, TIGIT, PD1 and ICOS may be detected in a population of T cells from a BAL sample from the lung transplant recipient. Preferably, the biomarker signature may comprise at least two biomarkers selected from KLRG1, TIGIT, PD1, and ICOS. In other words, at least two of KLRG1, TIGIT, PD1 and ICOS may be detected in a population of T cells from a BAL sample from the lung transplant recipient. More preferably, the biomarker signature may comprise or consist of KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS. In other words KLRG1 and one or more of (i) TIGIT, (ii) PD1, and / or (iii) ICOS may be detected in a population of T cells from a BAL sample from the lung transplant recipient. By way of non-limiting example, the biomarker signature may comprise or consist of: KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT. In said examples, KLRG1 and TIGIT; KLRG1 and PD1; KLRG1 and ICOS; KLRG1,TIGIT and PD1; KLRG1, TIGIT and ICOS; KLRG1, PD1 and ICOS; or KLRG1, PD1, ICOS and TIGIT may be detected in a population of T cells from a BAL sample from the lung transplant recipient. The invention provides a method of stratifying the graft function of a lung transplant recipient, wherein the sample is a BAL sample, and wherein a CLAD phenotype is associated with: (a) a decrease in the level of TIGIT, PD1, KLRG1 and / or ICOS in a population of T cells; (b) a decrease in the level of KLRG1 in a population of NK cells; and / or (c) an increase in the level of PD1 in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any one, any two or all three of (a) to (c). Preferably, the invention provides a method of stratifying the graft function of a lung transplant recipient, wherein the sample is a BAL sample, and wherein a CLAD phenotype is associated with an increase in the level of KLRG1 in a population of T cells compared with a functional lung graft. In other words, the invention provides a method of stratifying a lung transplant recipient as having a CLAD phenotype (a first phenotype) versus a functional lung graft (a second phenotype). Said method typically involves analysing a sample from the recipient. When said sample is a BAL sample, a CLAD phenotype may be associated with: (a) a decrease in the level of TIGIT, PD1, KLRG1 and / or ICOS in a population of T cells; (b) a decrease in the level of KLRG1 in a population of NK cells; and / or (c) an increase in the level of PD1 in a population of B cells; compared with a functional lung graft. Optionally said CLAD phenotype may be associated with any one, any two or all three of (a) to (c). Preferably, the invention provides a method of stratifying a lung transplant recipient as having a CLAD phenotype (a first phenotype) versus a functional lung graft (a second phenotype) by analysing a BAL sample from the recipient, wherein a CLAD phenotype is associated with an increase in the level of KLRG1 in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells. 55

[0039] In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an decrease in the level of ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of CD27 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of CD43 in a population of B cells. An increase or decrease in the level of any of KRLG1 in a population of T cells, TIGT in a population of T cells, PD1 in a population of T cells, ICOS in a population of T cells, KLRG1 in a population of NK cells, PD1 in a population of cells, CD43 in a population of B cells, and CD27 in a population of B cells may be combined to arrive at a biosignature for CLAD vs a functional lung graft in a BAL sample according to the invention. Examples of such combinations are set out below. A complete list of biomarker combinations providing biosignatures for CLAD vs a functional lung graft in a BAL sample according to the invention is set out in Table B below. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and PD1 in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and KLRG1 in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and ICOS in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells and a decrease in the level of TIGIT in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells and a decrease in the level of PD1 in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells and a decrease in the level of ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and KLRG1 in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 and ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 in a population of T cells and a population of NK cells. 56

[0040] In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and KLRG1 in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; and a decrease in the level of TIGIT and PD1 in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; and a decrease in the level of TIGIT and ICOS in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells; and a decrease in the level of PD1 and ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and PD1 in a population of T cells, and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and PD1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, KLRG1 and ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and KLRG1 in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT in a population of T cells, and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and KLRG1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT in a population of T cells, and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. 57

[0041] In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1, KLRG1 and ICOS in a population of T cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and KLRG1 in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1 in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and KLRG1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of ICOS in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. 58

[0042] In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1, KLRG1 and ICOS in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, and a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1 in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and PD1 in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and ICOS in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of ICOS and PD1 in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and KLRG1 in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and PD1 in a population of T cells, and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1, KLRG1 in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and PD1 in a population of T cells, and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and PD1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, KLRG1 and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and ICOS in a population of T cells, and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, KLRG1 and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and ICOS in a population of T cells, and an increase in the level of PD1 in a population of B cells. 59

[0043] In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and KLRG1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1, KLRG1 and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1, and ICOS in a population of T cells, and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1, KLRG1 and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1, and ICOS in a population of T cells, and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and KLRG1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1 and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of KLRG1 and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1, KLRG1 and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. Preferably, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells and a decrease in the level of KLRG1 in a population of NK cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and KLRG1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and PD1 in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. 60

[0044] In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1 and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, KLRG1 and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of PD1, KLRG1 and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells, and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1, and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells, and an increase in the level of PD1 in a population of B cells. Preferably in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT and PD1 in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, and ICOS in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of PD1, and ICOS in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. Preferably in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells, and an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated with a decrease in the level of TIGIT, PD1, KLRG1 and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of TIGIT in a population of T cells, a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells and an increase in the level of PD1 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells, an increase in the level of CD27 and CD43 in a population of B cells. In a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype preferably may be associated with an increase in the level of KLRG1 in a population of T cells, a decrease in the level of TIGIT, PD1, and ICOS in a population of T cells, a decrease in the level of KLRG1 in a population of NK cells, an increase in the level of PD1 in a population of B cells, an increase in the level of CD27 in a population of B cells, and an increase in the level of CD43 in a population of B cells. In particular, in a BAL sample from a lung transplant recipient, the biomarker signature for the CLAD phenotype may be associated any combination of an increase in KLRG1, and / or a decrease in TIGIT, PD1 and / or ICOS as biomarkers in a population of T cells; optionally in combination with KLRG1 as a biomarker in NK cells; and further optionally in combination with one or more of PD1, CD43 and / or CD27 as a biomarker in B cells. Such combinations are set out in Table B below. 61KLRG1

[0045] Table B: = marker is increased in CLAD compared with a functional lung graft; = marker is decreased in CLAD compared with a functional lung graft In any of the above embodiments, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of T cells selected from one or more of CD4+T cells, CD8+T cells, MAIT, Tregcells and / or TEMRA. Thus, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of (i) CD4+T cells; (ii) CD8+T cells; (iii) MAIT; (iv) Tregcells; (v) TEMRA; (vi) CD4+ T cells and CD8+ T cells; (vii) CD4+ T cells and MAIT; (viii) CD4+ T cells and Treg cells; (ix) CD4+ T cells and TEMRA; (x) CD8+ T cells and MAIT; (xi) CD8+ T cells and Treg cells; (xii) CD8+ T cells and TEMRA; (xiii) MAIT and Treg cells; (xiv) MAIT and TEMRA; (xv) Treg cells and TEMRA; (xvi) CD4+ T cells, CD8+ T cells and MAIT; (xvii) CD4+ T cells, CD8+ T cells and Treg cells; (xviii) CD4+ T cells, CD8+ T cells and TEMRA; (xix) CD4+ T cells, MAIT and Treg cells; 64

[0046] (xx) CD4+ T cells, MAIT and TEMRA; (xxi) CD4+ T cells, Treg cells and TEMRA; (xxii) CD8+ T cells, MAIT and Treg cells; (xxiii) CD8+ T cells, MAIT and TEMRA; (xxiv) CD8+ T cells, Treg cells and TEMRA; (xxv) MAIT, Treg cells and TEMRA; (xxvi) CD4+ T cells, CD8+ T cells, MAIT and Treg cells; (xxvii) CD4+ T cells, CD8+ T cells, MAIT and TEMRA; (xxviii) CD4+ T cells, CD8+ T cells, Treg cells and TEMRA; (xxix) CD4+ T cells, MAIT, Treg cells and TEMRA; (xxx) CD8+ T cells, MAIT, Treg cells and TEMRA; or (xxxi) CD4+T cells, CD8+T cells, MAIT, Tregcells and TEMRA. Preferably the level of TIGIT may be decreased in any one of these populations of T cells. Alternatively or in addition, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of CD8+ T cells. Preferably the level of KLRG1 may be decreased in this population of T cells. In any of the above embodiments, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of CD4+ T cells, CD8+ T cells, and / or T cells. Thus, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of T cells selected from CD4+, CD8+T cells, and / or T cells. Thus, the level of KLRG1 in a population of T cells may be the level of KLRG1 in a population of: (i) CD4+T cells; (ii) CD8+T cells; (iii) T cells; (iv) CD4+ T cells and CD8+ T cells; (v) CD4+ T cells and T cells; (vi) CD8+ T cells and T cells; or (vii) CD4+ T cells, CD8+ T cells and T cells. Preferably the level of KLRG1 may be increased in this population of T cells. Alternatively or in addition, the level of ICOS in a population of T cells may be the level of ICOS in a population of CD8+ T cells. Preferably the level of ICOS may be decreased in this population of T cells. Preferably alternatively or in addition, the level of ICOS in a population of T cells may be the level of ICOS in a population of CD8+ T cells, and / or CD4+ cells. Thus, the level of ICOS in a population of T cells may be the level of ICOS in a population of T cells selected from (i) CD8+ T cells; (ii) CD4+ cells; or (iii) CD8+ T cells and CD4+ cells. Preferably the level of ICOS may be decreased in this population of T cells. Alternatively or in addition, the level of PD1 in a population of T cells may be the level of PD1 in a population of T cells selected from CD4+ T cells and / or CD8+ T cells. Thus, the level of PD1 in a population of T cells may be the level of PD1 in a population of (i) CD4+ T cells; (ii) CD8+ T cells; or (iii) CD4+ T cells and CD8+ T cells. Preferably the level of PD1 may be decreased in any one of these populations of T cells. Alternatively or in addition, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of T cells selected from CD4+ T cells, CD8+ T cells, MAIT, Tregcells and / or TEMRA. Thus, the level of TIGIT in a population of T cells may be the level of TIGIT in a population of (i) CD4+ T cells; (ii) CD8+ T cells; (iii) MAIT; (iv) Tregcells; (v) TEMRA; (vi) CD4+ T cells, and CD8+ T cells; (vii) CD4+ T cells, and MAIT; (viii) CD4+ T cells, and Tregcells; (ix) CD4+ T cells, and TEMRA; (x) CD8+ T cells, and MAIT; (xi) CD8+ T cells, and Tregcells; (xii) CD8+ T cells, and TEMRA; (xiii) MAIT, and Tregcells; (xiv) MAIT, and TEMRA; (xv) Tregcells, and TEMRA; (xvi) CD4+ T cells, CD8+ T cells, and MAIT; (xvii) CD4+ T cells, CD8+ T cells, and Tregcells; (xviii) CD4+ T cells, CD8+ T cells, and TEMRA; (xix) CD4+ T cells, MAIT, and Tregcells; (xx) CD4+ T cells, MAIT, and TEMRA; (xxi) CD4+ T cells, Tregcells, and TEMRA; (xxii) CD8+ T cells, MAIT, and Tregcells; (xxiii) CD8+ T cells, MAIT, and TEMRA; (xxiv) CD8+ T cells, Tregcells, and TEMRA; (xxv) MAIT, Tregcells, and TEMRA; (xxvi) CD4+ T cells, CD8+ T cells, MAIT, and Tregcells; (xxvii) CD4+ T cells, CD8+ T cells, MAIT, and TEMRA; (xxviii) CD4+ T cells, CD8+ T cells, Tregcells, and TEMRA; (xxix) CD4+ T cells, MAIT, Tregcells, and TEMRA; (xxx) CD8+ T cells, MAIT, Tregcells, and TEMRA; or (xxxi) CD4+ T cells, CD8+ T cells, MAIT, Tregcells, and TEMRA. Preferably the level of TIGIT may be decreased in any one of these populations of T cells. The cell population in which a change in level of a first biomarker is associated with a CLAD phenotype may be independent of the cell population in which a change in level of a different biomarker is associated with a CLAD phenotype. Thus, the population of cells may be different for each biomarker. By way of non-limiting example, the level of PD1 may be decreased in a population of CD4+ T cells and the level of KLRG1 may be decreased in a population of CD8+ T cells. Alternatively, the cell population in which a change in level of a first biomarker is associated with a CLAD phenotype may be related to the cell population in which a change in level of a different biomarker is associated with a CLAD phenotype. Thus, the population of cells may be the same for each biomarker. By way of non-limiting example, the level of PD1 and KLRG1 may both be decreased in a population of CD8+ T cells. In methods of stratifying a lung transplant recipient as having a CLAD versus a functional lung graft using a BAL sample: (a) the level of TIGIT may be decreased in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, Tregcells and TEMRA; (b) the level of KLRG1 and / or ICOS may be decreased in a population of CD8+T cells; (c) the level of PD1 may be decreased in one or more T cell population selected from CD4+T cells and CD8+T cells; (d) the level of KLRG1 may be decreased in a population of NK cells; and / or (e) the level of PD1 may be increased in a population of B cells; 65

[0047] compared with a functional lung graft; wherein optionally said CLAD phenotype is associated with any two or more, or all five of (a) to (e). In methods of stratifying a lung transplant recipient as having a CLAD versus a functional lung graft using a BAL sample: (a) the level of KLRG1 may be increased in a population of T cells; and (b) the level of ICOS may be decreased in a population of T cells; compared with a functional lung graft. In addition to (a) and (b), a CLAD phenotype may be further associated with: (c) a decrease in the level of TIGIT in a population of T cells; and / or (d) a decrease in the level of PD1 in a population of T cells. compared with a functional lung graft. In addition to (a) and (b) (and optionally (c) and / or (d)), a CLAD phenotype may be yet further associated with: (e) a decrease in the level of KLRG1 in a population of NK cells; and / or (f) (i) an increase in the level of (i) CD27, (ii) CD43 and / or (iii) PD1 in a population of B cells; compared with a functional lung graft. In particular, in methods of stratifying a lung transplant recipient as having a CLAD versus a functional lung graft using a BAL sample: (a) the level of KLRG1 may be increased in one or more T cell population selected from CD4+T cells, CD8+T cells, and T cells; and / or (b) the level of ICOS may be decreased in one or more T cell population selected from CD8+T cells and CD4+T cells; and / or compared with a functional lung graft. In addition to any one or more of (a) and (b), a CLAD phenotype may be further associated with: (c) a decrease in the level of TIGIT in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, Tregcells and TEMRA; and / or (d) a decrease in the level of PD1 in one or more T cell population selected from CD4+T cells and CD8+T cells; compared with a functional lung graft. In addition to (a) and (b) (and optionally (c) and / or (d)), a CLAD phenotype may be yet further associated with: (e) a decrease in the level of KLRG1 in a population of NK cells; and / or (f) an increase in the level of (i) CD27, (ii) CD43 and / or (iii) PD1 in a population of B cells; compared with a functional lung graft. For the avoidance of doubt, whilst the above biomarker signatures are described in the context of stratifying CLAD vs a functional lung graft in a BAL sample, these biomarker signatures apply equally and without reservation to the stratification of graft dysfunction vs a functional graft in a BAL sample for other solid organ transplants. 66

[0048] Active disease vs quiescent disease Preferably, the solid organ transplant is a lung transplant. Any sample type as described herein may be used in a method of stratifying the graft function status of a lung transplant recipient according to the invention. Typically when the solid organ transplant is a lung transplant, the sample is a blood sample and / or a bronchoalveolar lavage (BAL). A first phenotype according to the invention may be active disease, i.e. active lung graft dysfunction (including CLAD). Thus, a first phenotype according to the invention may be active disease, i.e. active lung graft dysfunction phenotype. Thus, a first biomarker signature may be associated with active disease (i.e. active lung graft dysfunction, including CLAD or a CLAD phenotype). A second phenotype according to the invention may be quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD). In embodiments where the first phenotype is an active disease phenotype and the second phenotype is quiescent disease, the invention may be used to determine whether a patient has active lung graft dysfunction or stable lung graft function. In other words, the invention provides a method for stratifying the graft function of a lung transplant recipient, by determining whether the patient has active lung graft dysfunction or stable lung graft function. This may be useful in prognosing the risk of rejection of a lung transplant. A first phenotype according to the invention may be active CLAD, i.e. an active CLAD phenotype (including incipient, or progressive CLAD). Thus, a first biomarker signature may be associated with active CLAD (including incipient or progressive CLAD). A second phenotype according to the invention may be stable CLAD. In embodiments where the first phenotype is an active CLAD phenotype and the second phenotype is stable CLAD, the invention may be used to determine whether a patient has active CLAD or stable CLAD. In other words, the invention provides a method for stratifying the graft function of a lung transplant recipient, by determining whether the patient has active CLAD or stable CLAD. This may be useful in prognosing the risk of rejection of a lung transplant. Active disease vs quiescent disease biomarker signature in blood The invention provides a method of stratifying the graft function of a lung transplant recipient, by determining whether the patient has active disease (i.e. active lung graft dysfunction) versus quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD) by determining a biomarker signature from a blood sample from the lung transplant recipient. The invention provides a method of stratifying the graft function of a lung transplant recipient, by determining whether the patient has active CLAD or stable CLAD by determining a biomarker signature from a blood sample from the lung transplant recipient. Thus, the invention provides a method of stratifying the graft function of a lung transplant recipient, wherein the sample is a blood sample, and wherein an active disease (i.e. active lung graft dysfunction) phenotype is associated with: (a) an increase in the level of KLRG1, TIGIT and / or ICOS in a population of T cells; and / or (b) an increase in the level of TACI in a population of B cells; compared with quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD). Optionally said active disease (i.e. active lung graft dysfunction) phenotype may be associated with either or both of (a) and (b). In other words, the invention provides a method of stratifying a lung transplant recipient as having an active disease (i.e. active lung graft dysfunction) phenotype (a first phenotype) versus a quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD) phenotype (a second phenotype). Said method typically involves analysing a sample from the recipient. When said sample is a blood sample, an active disease (i.e. active lung graft dysfunction) phenotype may be associated with: (a) an increase in the level of KLRG1, TIGIT and / or ICOS in a population of T cells; and / or (b) an increase in the level of TACI in a population of B cells; compared with quiescent disease (i.e. stable graft function, whether a functional lung graft or stable CLAD). Optionally said active disease (i.e. active lung graft dysfunction) phenotype may be associated with either or both of (a) and (b). Thus, the invention provides a method of stratifying the graft function of a lung transplant recipient, wherein the sample is a blood sample, and wherein an active CLAD phenotype is associated with: (a) an increase in the level of KLRG1, TIGIT and / or ICOS in a population of T cells; and / or (b) an increase in the level of TACI in a population of B cells; compared with stable CLAD. Optionally said active CLAD phenotype may be associated with either or both of (a) and (b). In other words, the invention provides a method of stratifying a lung transplant recipient as having an active CLAD phenotype (a first phenotype) versus a stable CLAD phenotype (a second phenotype). Said method typically involves analysing a sample from the recipient. When said sample is a blood sample, an active CLAD phenotype 67

[0049] may be associated with: (a) an increase in the level of KLRG1, TIGIT and / or ICOS in a population of T cells; and / or (b) an increase in the level of TACI in a population of B cells; compared with stable CLAD. Optionally said active CLAD phenotype may be associated with either or both of (a) and (b). In a blood sample from a lung transplant recipient, the biomarker signature for the active disease (i.e. active lung graft dysfunction), e.g. active CLAD, phenotype may be associated with an increase in the level of KLRG1 in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the active disease (i.e. active lung graft dysfunction), e.g. active CLAD, phenotype may be associated with an increase in the level of TIGIT in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the active disease (i.e. active lung graft dysfunction), e.g. active CLAD, phenotype may be associated with an increase in the level of ICOS in a population of T cells. In a blood sample from a lung transplant recipient, the biomarker signature for the active disease (i.e. active lung graft dysfunction), e.g. active CLAD, phenotype may be associated with an increase in the level of TACI in a population of B ce...

Claims

CLAIMS 1. A method for stratifying a lung transplant recipient as having CLAD versus having a functional lung graft, said method comprising determining a biomarker signature which comprises at least two biomarkers in a population of T cells, wherein said at least two biomarkers are selected from KLRG1, TIGIT, PD-1, and ICOS; wherein the population of T cells is obtained from a sample from said recipient.

2. A method according to claim 1, wherein: A. determining said biomarker signature comprises determining the level of said at least two biomarkers in a population of T cells. and / or B. the biomarker signature comprises KLRG1 and one or more of (i) TIGIT, (ii) PD-1, and / or (iii) ICOS.

3. A method according to claim 1 or 2, wherein: A. determining said biomarker signature comprises quantifying a population of T cells expressing KLRG1 and one or more of (i) TIGIT, (ii) PD-1, and / or (iii) ICOS; and / or B. (a) the population of T cells comprises one or more of: CD4-positive T cells (CD4+), CD8-positive T cells (CD8+), mucosal-associated invariant T cells (MAIT), gamma delta T cells ( ), follicular T helper cells (Tfh), regulatory T cells (Treg), and effector memory RA T cells (TEMRA); and / or (b) the method comprises quantifying one or more populations of CD4+T cells, CD8+T cells, MAIT, T cells, Tfhcells, Tregcells, and / or TEMRA.

4. A method according to any one of the preceding claims, wherein: A. determining the level of said at least two biomarkers in a population of T cells comprises determining whether the level of said biomarkers exceeds a threshold value; and / or B. quantifying said population of T cells expressing at least two biomarkers comprises determining whether the number of cells in said population exceeds a threshold value; wherein optionally said threshold value is: (a) a fold-change increase of at least 1.5, preferably at least 2; or (b) a fold-change decrease of at least 1.5, preferably at least 2. 1965. A method according to any one of the preceding claims, wherein: A. determining a biomarker signature comprises the use of Fluorescent Activated Cell Sorting (FACS) and / or transcriptomics; and / or B. the sample is selected from a blood, bronchoalveolar lavage (BAL), a tissue sample, cell sample and / or organ sample, wherein preferably said tissue, cell or organ sample is taken from the transplanted solid organ; wherein preferably the solid organ transplant is a lung transplant and the sample is a blood or BAL sample.

6. A method according to any one of the preceding claims, wherein A. the sample is a blood sample, and wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 in a population of T cells; and (b) (i) an increase in the level of TIGIT in a population of T cells; and / or (ii) a decrease in the level of PD1, and / or ICOS in a population of T cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD; and / or B. the sample is a BAL sample, and wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 in a population of T cells; and (b) a decrease in the level of TIGIT, PD-1, and / or ICOS in a population of T cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD.

7. A method according to claim 6, wherein: A. the sample is a blood sample and (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, and T cells; (b) the level of TIGIT is increased in one or more T cell population selected from CD4+T cells, T cells, and Tregcells; (c) the level of PD1 is decreased in one or more T cell population selected from CD8+T cells and CD4+T cells; and / or (d) the level of ICOS is decreased in a population of CD8+T cells; 197compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD; and / or B. the sample is a BAL sample and: (a) the level of KLRG1 is increased in one or more T cell population selected from CD4+T cells, CD8+T cells, and T cells; and / or (b) the level of ICOS is decreased in one or more T cell population selected from CD4+T cells, and CD8+T cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD.

8. A method according to any one of the preceding claims, wherein: A. the sample is a blood sample, and wherein a CLAD phenotype is further associated with: (a) an increase in the level of KLRG1 in a population of MAIT; and / or (b) an increase in the level of TIGIT in a population of CD8+T cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD; and / or B. the sample is a BAL sample, and wherein a CLAD phenotype is further associated with: (a) a decrease in the level of TIGIT in one or more T cell population selected from CD4+T cells, CD8+T cells, MAIT, Tregcells and TEMRA; and / or (b) a decrease in the level of PD1 in one or more T cell population selected from CD4+T cells and CD8+T cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD.

9. A method according to any one of the preceding claims, wherein the biomarker signature comprises: 198KLRG1 and TIGIT; KLRG1 and PD-1; KLRG1 and ICOS; KLRG1,TIGIT and PD-1; KLRG1, TIGIT and ICOS; KLRG1, PD-1 and ICOS; or KLRG1, PD-1, ICOS and TIGIT.

10. A method according to any one of the preceding claims, wherein: A. the sample is a blood sample, and wherein a CLAD phenotype is associated with: (a) an increase in the level of KLRG1 and / or PD1 in a population of NK cells; and / or (b) (i) an increase in the level of TACI in a population of B cells; (ii) a decrease in the level of IgD in a population of B cells; (iii) a decrease in the level of CD43 in a population of B cells; and / or (iv) a decrease in the level of CD27 in a population of B cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD; and / or B. the sample is a BAL sample, and wherein a CLAD phenotype is associated with: (a) a decrease in the level of KLRG1 in a population of NK cells; and / or (b) an increase in the level of (i) CD27, (ii) CD43, and / or (ii) PD1 in a population of B cells; compared with a functional lung graft; wherein optionally said CLAD phenotype is active CLAD, progressive CLAD or stable CLAD.

11. Use of a biomarker signature for stratifying the transplant function and / or infection status of a lung transplant recipient, said biomarker signature comprising at least two biomarkers in a population of T cells, wherein said at least two biomarker are selected from KLRG1, TIGIT, PD-1, and ICOS; wherein the population of T cells is obtained from a sample from said recipient.

12. A use according to claim 11, wherein the biomarker signature comprises KLRG1 and one or more of (i) TIGIT; (ii) PD-1, and / or (iii) ICOS.

13. A method of stratifying a lung transplant recipient as having CLAD versus having a functional lung graft and treating a lung transplant recipient who has CLAD, said method comprising: 199A. stratifying said lung transplant recipient as having CLAD versus having a functional lung graft using a method as defined in any one of claims 1 to 10; and B. treating the recipient for CLAD if said recipient is determined to have CLAD.

14. A method of detecting two or more biomarkers selected from KLRG1, TIGIT, PD-1, and ICOS in a lung transplant recipient, said method comprising: A. obtaining a blood or BAL sample from the lung transplant recipient; and B. detecting whether one or more of biomarker is expressed on a population of cells present in the blood or BAL sample by contacting the blood or BAL sample with an anti-biomarker antibody and detecting binding between the biomarker and the antibody; wherein the at least two biomarkers selected from KLRG1, TIGIT, PD-1, and ICOS are detected in a population of T cells.

15. A method according to claim 14, wherein the biomarker signature comprises KLRG1 one or more of (i) TIGIT; (ii) PD-1, and / or (iii) ICOS.

16. A kit of parts comprising a binding member for two or more of KLRG1, TIGIT, PD-1, and ICOS; wherein optionally: A. the binding member for each of the two or more of KLRG1, TIGIT, PD-1, and ICOS, is: (a) selected from an antibody, and aptamer or, preferably an antibody; (b) labelled, optionally with a fluorescent label; (c) in a separate container; and / or B. the kit further comprises: (a) a buffer, optionally a lyse buffer and / or a staining buffer; (b) an Fc receptor blocking regent; (c) a labelled secondary antibody; (d) isotype control antibodies; and / or (e) instructions for use. 200

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