Compositions and methods for treating chronic allograft rejection

Abstract

The invention features compositions and methods for treating transplant recipients (e.g., chronic allograft rejection) using a senolytic agent and an angiotensin II receptor antagonist or using a senolytic agent and senomorphic agent. The methods and compositions are useful in a variety of transplant settings including, without limitation, solid organ transplants including kidney, lung, heart, liver, intestine, or pancreas transplantation procedures and cellular transplants including but not limited to bone marrow transplants.

Description

[0001]PATENT Attorney Docket No.: 51834-002WO2 COMPOSITIONS AND METHODS FOR TREATING CHRONIC ALLOGRAFT REJECTION STATEMENT AS TO FEDERALLY SPONSORED RESEARCH This invention was made with government support under award numbers 5R01AG064165- 04 from the National Institutes of Health. The government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATION(S) This application relates to and claims priority from U.S. Patent Application No.63 / 635,552 filed on April 17, 2024, the entire disclosure of which is incorporated herein by reference. BACKGROUND OF THE INVENTION This invention relates to compositions and methods for treating transplant recipients. Solid organ transplantation has become the standard of care for patients with end-stage organ failure. Despite the dramatic advances of modern immunosuppression in reducing acute graft loss, the development of chronic allograft injury remains the major obstacle to long-term allograft survival. Part of the difficulty in improving long-term outcomes has been that multiple factors contribute to a common histologic pattern of injury. Accordingly, methods and compositions for preventing or treating chronic allograft rejection are needed. SUMMARY OF THE INVENTION In an aspect, the invention features a method of treating chronic allograft rejection in a transplant recipient including administering a senolytic agent and an angiotensin II receptor antagonist, each in a therapeutically effective amount, thereby treating chronic allograft rejection. In some embodiments, the senolytic agent is a senolytic combination. In some embodiments, the senolytic combination is dasatinib and quercetin. In some embodiments, the therapeutically effective amount of dasatinib is about 100 mg orally per day. In some embodiments, the therapeutically effective amount of quercetin is about 1,000 mg orally per day. In some embodiments, the angiotensin II receptor antagonist is losartan. In some embodiments, the therapeutically effective amount of losartan is between 10mg to 100mg orally per day. In some embodiments, the senolytic agent and angiotensin II receptor antagonist are administered orally. In some embodiments, the senolytic agent and angiotensin II receptor antagonist are administered intravenously. PATENT Attorney Docket No.: 51834-002WO2 In some embodiments, the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient. In some embodiments, the recipient is a heart transplant recipient. In some embodiments, the senolytic agent and angiotensin II receptor antagonist are administered simultaneously. In some embodiments, the senolytic agent is administered prior to administering an angiotensin II receptor antagonist. In some embodiments, the angiotensin II receptor antagonist is administered prior to the senolytic agent. In another aspect, the invention features a method of treating chronic allograft rejection in a transplant recipient including administering a senolytic agent and an angiotensin II receptor antagonist, each in a therapeutically effective amount, prior to a transplant procedure, thereby treating chronic allograft rejection. In some embodiments, the senolytic agent is a senolytic combination. In some embodiments, the senolytic combination is dasatinib and quercetin. In some embodiments, the therapeutically effective amount of dasatinib is about 100 mg orally per day. In some embodiments, the therapeutically effective amount of quercetin is about 1,000 mg orally per day. In some embodiments, the angiotensin II receptor antagonist is losartan. In some embodiments, the therapeutically effective amount of losartan is between 10mg to 100mg orally per day. In some embodiments, the senolytic agent and angiotensin II receptor antagonist are administered orally. In some embodiments, the senolytic agent and angiotensin II receptor antagonist are administered intravenously. In some embodiments, the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient. In some embodiments, the recipient is a heart transplant recipient. In yet another aspect, the invention features a kit including a senolytic agent and an angiotensin II receptor antagonist. In some embodiments, the kit includes dasatinib and quercetin as senolytic agents. In some embodiments, the kit includes losartan as the angiotensin II receptor antagonist. In some embodiments, the kit includes dasatinib, quercetin, and losartan. In yet another aspect, the invention features a method of treating chronic allograft rejection in a transplant recipient including administering a senolytic agent and senomorphic agent, each in a therapeutically effective amount, thereby treating chronic allograft rejection. In some embodiments, the senolytic agent is a senolytic combination. In some embodiments, the senolytic combination is dasatinib and quercetin. PATENT Attorney Docket No.: 51834-002WO2 In some embodiments, the therapeutically effective amount of dasatinib is about 100 mg orally per day. In some embodiments, the therapeutically effective amount of quercetin is about 1,000 mg orally per day. In some embodiments, the senomorphic agent includes rapamycin, metformin, quercetin, resveratrol, aspirin, or a statin. In some embodiments, the senolytic agent senomorphic agent are administered orally. In some embodiments, the senolytic agent and senomorphic agent are administered intravenously. In some embodiments, the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient. In some embodiments, the recipient is a heart transplant recipient. In some embodiments, the senolytic agent and senomorphic agent are administered simultaneously. In some embodiments, the senolytic agent is administered prior to administering a senomorphic agent. In some embodiments, the senomorphic agent is administered prior to the senolytic agent. In yet another aspect, the invention features a method of treating chronic allograft rejection in a transplant recipient including administering a senolytic agent and a senomorphic agent, each in a therapeutically effective amount, prior to a transplant procedure, thereby treating chronic allograft rejection. In some embodiments, the senolytic agent is a senolytic combination. In some embodiments, the senolytic combination is dasatinib and quercetin. In some embodiments, the therapeutically effective amount of dasatinib is about 100 mg orally per day. In some embodiments, the therapeutically effective amount of quercetin is about 1,000 mg orally per day. In some embodiments, the senomorphic agent includes rapamycin, metformin, quercetin, resveratrol, aspirin, or a statin. In some embodiments, the senolytic agent and the senomorphic agent are administered orally. In some embodiments, the senolytic agent and the senomorphic agent are administered intravenously. In some embodiments, the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient. In some embodiments, the recipient is a heart transplant recipient. In yet another aspect, the invention features a kit including a senolytic agent and a senomorphic agent. In some embodiments, the kit includes dasatinib and quercetin as senolytic agents. In some embodiments, the kit includes rapamycin, metformin, quercetin, resveratrol, aspirin, and a statin or a combination thereof as a senomorphic agent. In some embodiments, the kit includes (i) dasatinib and quercetin and (ii) rapamycin, metformin, quercetin, resveratrol, aspirin, or a statin. PATENT Attorney Docket No.: 51834-002WO2 BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG.1 shows chronic cardiac rejection accelerates senescence. FIG.2 shows reduction of senescence cells and SASP by dasatinib and quercetin. FIG.3 shows senolytics treatment improved graft survival and fibrosis modestly. FIG.4 shows combinatorial treatment of senolytics and losartan. FIG.5 shows DQ and losartan treatment extensively prolonged cardiac allograft survival and fibrosis. FIG.6 shows DQ and losartan have broad effects on immune cell populations. FIG.7 shows DQ and losartan treatment significantly reduced donor-specific antibody. FIG.8 shows DQ and losartan dampened alloantigen specific T cell proliferation ex vivo. FIG.9 shows DQ and losartan increased IL-10, enhanced VEGF and TGF-β1 secretion of allogeneic T cells. DETAILED DESCRIPTION Embodiments of the disclosed methods may use agents that target and deplete senescent cells in combination with agents targeting products of the Senescent Associated Secretory Phenotype (SASP). Senolytics, a class of small molecules, have been used in combination with losartan, an angiotensin II receptor antagonists, to prevent chronic graft deterioration. We have demonstrated that chronic allograft rejection represents a process of accelerated aging. Targeting senescent cells (with senolytics) and key factors of SASP (with losartan) resulted in graft survival beyond 100 days (end of observation period) in the majority of transplants while untreated grafts stopped functioning after 34.5 days (MST, p< 0.001). Transplantation The methods and compositions are useful in a variety of transplant settings including, without limitation, solid organ transplants including kidney, lung, heart, liver, intestine, or pancreas transplantation procedures and cellular transplants including but not limited to bone marrow transplants. Senolytics Exemplary senolytics useful in combination therapy include dasatinib and quercetin, used in combination (D+Q). Other senolytics include, without limitation, navitoclax, fisetin, and oleandrin. Angiotensin II Receptor Antagonists An exemplary angiotensin II receptor antagonist useful in combination therapy as disclosed herein includes losartan. Additional examples include, without limitation, candesartan, eprosartan, PATENT Attorney Docket No.: 51834-002WO2 irbesartan, olmesartan, telmisartan, and valsartan. In some embodiments, senomorphic agents may be used as an alternative to losartan targeting SASP / fibrotic pathways. Exemplary senomorphic agents include, without limitation, rapamycin, metformin, quercetin, resveratrol, aspirin, and statins. Administration Administration of the combination therapy can be accomplished using methods generally known in the art for the above compositions, for example, oral or intravenous routes. Pharmaceutical compositions for oral or intravenous use are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, or injections. A therapeutically effective amount of a senolytic can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. For example, when administering senolytics D+Q, a therapeutically effective dose of dasatinib is given orally at 100 mg daily. A therapeutically effective amount of quercetin may be up to 1 gram daily orally. A therapeutically effective amount of an angiotensin II receptor antagonist (e.g., losartan) can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. A therapeutically effective amount of losartan is typically 50mg to 100mg, taken once a day orally. Further included are methods involving administration of senomorphic agents such as mTOR kinase inhibitors, anti-hypoglycemic agents, stilbenoids, nonsteroidal anti-inflammatory drugs, and statins. Therapeutically effective amounts may be administered as follows. A therapeutically effective amount of a mTOR kinase inhibitor (e.g., rapamycin) can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. A therapeutically effective amount of rapamycin is typically 0.5 mg to 40 mg, taken once a day orally. A therapeutically effective amount of an anti-hyperglycemic agent (e.g., metformin) can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about PATENT Attorney Docket No.: 51834-002WO2 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, or about 2600 mg. A therapeutically effective amount of metformin is typically 500 mg to 2550 mg, taken once or twice a day orally. A therapeutically effective amount of a stilbenoid (e.g., resveratrol) can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, about 3650 mg, about 3700 mg, about 3750 mg, about 3800 mg, about 3850 mg, about 3900 mg, about 3950 mg, about 4000 mg, about 4050 mg, about 4100 mg, about 4150 mg, about 4200 mg, about 4250 mg, about 4300 mg, about 4350 mg, about 4400 mg, about 4450 mg, about 4500 mg, about 4550 mg, about 4600 mg, about 4650 mg, about 4700 mg, about 4750 mg, about 4800 mg, about 4850 mg, about 4900 mg, about 4950 mg, or about 5000 mg. A therapeutically effective amount of resveratrol is typically 1 mg to 5000 mg, taken once a day orally. A therapeutically effective amount of a nonsteroidal anti-inflammatory drug (e.g., aspirin) can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, PATENT Attorney Docket No.: 51834-002WO2 about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, about 3650 mg, about 3700 mg, about 3750 mg, about 3800 mg, about 3850 mg, about 3900 mg, about 3950 mg, or about 4000 mg. A therapeutically effective amount of aspirin is typically 50 mg to 4000 mg, taken once a day orally, twice a day orally, three times a day orally, four times a day orally, five times a day orally, six times a day orally, or once a day intravenously. A therapeutically effective amount of a statin (e.g., atorvastatin) can be from about 0.05 mg to about 1000 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg. A therapeutically effective amount of atorvastatin is typically 10 mg to 80 mg, taken once a day orally. In some embodiments, administration of senolytics or angiotensin II receptor antagonist or a senomorphic agent to a transplant recipient (e.g., a mammal such as a human) occurs prior to a transplant procedure. In some embodiments, a senolytic agent and angiotensin II receptor antagonist are administered simultaneously. In some embodiments, the senolytic agent is administered prior to administering an angiotensin II receptor antagonist. In still other embodiments, the angiotensin II receptor antagonist is administered prior to the senolytic agent. Kits Additionally provided herein are kits for carrying out the methods according to the disclosure. The kits typically include at least one senolytic agent and at least one angiotensin II receptor antagonist. In certain embodiments, the kits further comprise instructions for use. The instructions may be in a tangible form. In additional embodiments, the kits include materials and / or instructions for assessment of an enhanced therapeutic outcome. In some embodiments, the kits typically include at least one senolytic agent and at least one senomorphic agent. In some embodiments, the kits typically include at least one senolytic agent, at least one angiotensin II receptor antagonist, and at least one senomorphic agents. EXAMPLES The following examples provide those of ordinary skill in the art with a disclosure and description of how to make and use the methods and compositions of the disclosure, and are not intended to limit the PATENT Attorney Docket No.: 51834-002WO2 scope of the disclosure. Below it is demonstrated that chronic allograft rejection represents a process of accelerated aging. Targeting senescent cells (with senolytics) and key factors of SASP (with Losartan) resulted in graft survival beyond 100 days (end of observation period) in the majority of transplants while untreated grafts stopped functioning after 34.5 days (MST, p< 0.001). Example 1 -- Chronic Rejection Represents a Process of Accelerated Aging SuccessfullyTreated with a Combinatorial Application Targeting Senescent Cells and Fibrotic Pathways Chronic rejection characterized by progressive fibrosis continues to compromise long-term graft outcomes. Cellular senescence represents a process in which senescent cells accumulate, secreting an inflammatory senescence-associated secretory phenotype (SASP) leading to chronic inflammation and fibrosis (FIG.1). Chronic allograft deterioration may accordingly be conceptualized as a process of accelerated aging, driven by chronic inflammation and leading to the activation of fibrogenic signaling. RESULTS Fully MHC-mismatched heterotopic heart transplantations were performed from BALB / c to C57BL / 6 mice (FIG.2); recipients were treated with CTLA4-Ig to facilitate long-term graft survival while developing characteristic signs of cardiac allograft vasculopathy. Morphological characteristic signs in parallel to an accumulation of senescent cells and SASP related inflammation were prominent in chronically rejected cardiac allografts on day 21. Treatment with senolytics (Dasatinib and Quercetin, DQ) reduced cellular infiltrates, depleted senescent cells and diminished SASP factors. Profiling alloimmune responses revealed systemically increased Tregs, decreased Th1 and Th17 (5.5% vs.8.1%, 11.1% vs.5.3%, 9.4% vs.7.3%, resp.) after DQ treatment; intragraft, CD4+T and CD8+T cells, neutrophils, and macrophages were reduced (1255 vs.450, 777 vs.320, 29 vs.18, 33 vs.22 cell counts / mg graft, resp.). Senolytics also prolonged graft survival significantly (MST=34.5 vs.49.0 days) (FIG.3). However, graft fibrosis, a hallmark of chronic rejection, improved only modestly (FIG.3). A combinatorial treatment of senolytics and losartan to block fibrotic signaling was next applied (FIG.4). While losartan alone did not prolong graft survival significantly, the combined treatment extended graft survival in the vast majority to >100 days, accompanied by diminished graft fibrosis and cellular infiltration (fibrotic area 20.4% vs.9.9%, cellular infiltrate score 2.67 vs.1.20), as well as improved vascular injury (0.36 vs.0.16) (FIG.5). The combined treatment also reduced intragraft IFNγ+ CD4 T cell (38.7% vs, 15.8%) while Tregs were increased (6.8% vs. 18.3%) (FIG 6). Mixed lymphocyte reaction from the recipients showed compromised CD4 T cell proliferation (34.7% vs 19.6%), which supports the dampened alloantigen-specific immune response. FIG.7 further shows that DQ and losartan treatment significantly reduced donor-specific antibody. DQ and losartan treatment was also demonstrated to dampen alloantigen specific T cell proliferation ex vivo in a mixed lymphocyte reaction (FIG.8). Measurement of cytokine secretion in a mixed lymphocyte reaction culture further demonstrated that DQ and losartan increased IL-10 and enhanced VEGF and TGF- β1 secretion of allogeneic T cells (FIG.9). PATENT Attorney Docket No.: 51834-002WO2 As is demonstrated above, treatment with senolytics and losartan (1) prolonged heart allograft survival and reduced graft fibrosis, (2) reduced total T cells, IFNγ+ CD4 T cells and increased Tregs in the graft, (3) reduced total myeloid cells and macrophages in the graft, (4) in mixed lymphocyte reactions CD4 and CD8 T cell proliferation was inhibited, and (4) in mixed lymphocyte reactions, IL-10 and VEGF secretions were increased. This data supports accelerated senescence as a driver of chronic rejection. This study provides evidence that a dual therapy of depleting senescent cells in conjunction with blocking the fibrogenic pathway significantly prolongs graft survival while halting fibrosis and graft inflammation. Embodiments It will be appreciated by those skilled in the art that while the disclosed subject matter is described above in connection with particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples, uses, modifications and departures from the embodiments, examples and uses are intended to be encompassed by the claims attached hereto. Each reference cited herein is incorporated by reference in its entirety.

Claims

PATENT Attorney Docket No.: 51834-002WO2 What is claimed is: CLAIMS 1. A method of treating chronic allograft rejection in a transplant recipient comprising administering a senolytic agent and an angiotensin II receptor antagonist, each in a therapeutically effective amount, thereby treating chronic allograft rejection.

2. The method of claim 1, wherein the senolytic agent is a senolytic combination.

3. The method of claim 2, wherein the senolytic combination is dasatinib and quercetin.

4. The method of claim 3, wherein the therapeutically effective amount of dasatinib is about 100 mg orally per day.

5. The method of claim 3, wherein the therapeutically effective amount of quercetin is about 1,000 mg orally per day.

6. The method of claim 1, wherein the angiotensin II receptor antagonist is losartan.

7. The method of claim 6, wherein the therapeutically effective amount of losartan is between 10mg to 100mg orally per day.

8. The method of claim 1, wherein the senolytic agent and angiotensin II receptor antagonist are administered orally.

9. The method of claim 1, wherein the senolytic agent and angiotensin II receptor antagonist are administered intravenously.

10. The method of claim 1, wherein the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient.

11. The method of claim 10, wherein the recipient is a heart transplant recipient.

12. The method of claim 1, wherein the senolytic agent and angiotensin II receptor antagonist are administered simultaneously.

13. The method of claim 1, wherein the senolytic agent is administered prior to administering an angiotensin II receptor antagonist.

14. The method of claim 1, wherein the angiotensin II receptor antagonist is administered prior to the senolytic agent.

15. A method of treating chronic allograft rejection in a transplant recipient comprising administering a senolytic agent and an angiotensin II receptor antagonist, each in a therapeutically effective amount, prior to a transplant procedure, thereby treating chronic allograft rejection.

16. The method of claim 15, wherein the senolytic agent is a senolytic combination.

17. The method of claim 16, wherein the senolytic combination is dasatinib and quercetin.

18. The method of claim 17, wherein the therapeutically effective amount of dasatinib is about 100 mg orally per day.

19. The method of claim 17, wherein the therapeutically effective amount of quercetin is about 1,000 mg orallyPATENT Attorney Docket No.: 51834-002WO2 per day.

20. The method of claim 15, wherein the angiotensin II receptor antagonist is losartan.

21. The method of claim 20, wherein the therapeutically effective amount of losartan is between 10mg to 100mg orally per day.

22. The method of claim 15, wherein the senolytic agent and angiotensin II receptor antagonist are administered orally.

23. The method of claim 15, wherein the senolytic agent and angiotensin II receptor antagonist are administered intravenously.

24. The method of claim 15, wherein the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient.

25. The method of claim 24, wherein the recipient is a heart transplant recipient.

26. A kit comprising a senolytic agent and an angiotensin II receptor antagonist.

27. The kit of claim 26, wherein the kit comprises dasatinib and quercetin as senolytic agents.

28. The kit of claim 26, wherein the kit comprises losartan as the angiotensin II receptor antagonist.

29. The kit of claim 26, comprising dasatinib, quercetin, and losartan.

30. A method of treating chronic allograft rejection in a transplant recipient comprising administering a senolytic agent and senomorphic agent, each in a therapeutically effective amount, thereby treating chronic allograft rejection.

31. The method of claim 30, wherein the senolytic agent is a senolytic combination.

32. The method of claim 31, wherein the senolytic combination is dasatinib and quercetin.

33. The method of claim 32, wherein the therapeutically effective amount of dasatinib is about 100 mg orally per day.

34. The method of claim 32, wherein the therapeutically effective amount of quercetin is about 1,000 mg orally per day.

35. The method of claim 30, wherein the senomorphic agent comprises rapamycin, metformin, quercetin, resveratrol, aspirin, or a statin.

36. The method of claim 30, wherein the senolytic agent senomorphic agent are administered orally.

37. The method of claim 30, wherein the senolytic agent and senomorphic agent are administered intravenously.

38. The method of claim 30, wherein the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient.

39. The method of claim 38, wherein the recipient is a heart transplant recipient.

40. The method of claim 30, wherein the senolytic agent and senomorphic agent are administered simultaneously.

41. The method of claim 30, wherein the senolytic agent is administered prior to administering a senomorphicPATENT Attorney Docket No.: 51834-002WO2 agent.

42. The method of claim 30, wherein the senomorphic agent is administered prior to the senolytic agent.

43. A method of treating chronic allograft rejection in a transplant recipient comprising administering a senolytic agent and a senomorphic agent, each in a therapeutically effective amount, prior to a transplant procedure, thereby treating chronic allograft rejection.

44. The method of claim 43, wherein the senolytic agent is a senolytic combination.

45. The method of claim 44, wherein the senolytic combination is dasatinib and quercetin.

46. The method of claim 45, wherein the therapeutically effective amount of dasatinib is about 100 mg orally per day.

47. The method of claim 45, wherein the therapeutically effective amount of quercetin is about 1,000 mg orally per day.

48. The method of claim 43, wherein the senomorphic agent comprises rapamycin, metformin, quercetin, resveratrol, aspirin, or a statin.

49. The method of claim 43, wherein the senolytic agent and the senomorphic agent are administered orally.

50. The method of claim 43, wherein the senolytic agent and the senomorphic agent are administered intravenously.

51. The method of claim 43, wherein the recipient is a kidney, lung, heart, liver, intestine, or pancreas transplant recipient.

52. The method of claim 51, wherein the recipient is a heart transplant recipient.

53. A kit comprising a senolytic agent and a senomorphic agent.

54. The kit of claim 53, wherein the kit comprises dasatinib and quercetin as senolytic agents.

55. The kit of claim 53, wherein the kit comprises rapamycin, metformin, quercetin, resveratrol, aspirin, and a statin or a combination thereof as a senomorphic agent.

56. The kit of claim 53, comprising (i) dasatinib and quercetin and (ii) rapamycin, metformin, quercetin, resveratrol, aspirin, or a statin.

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