Methods and Compositions for Determining a Graft Tolerant Phenotype in a Subject

Abstract

Methods are provided for determining whether a subject has a graft tolerant phenotype. In practicing the subject methods, the expression of at least 5 genes in a sample from the subject, e.g., a blood sample, is assayed to obtain a gene expression result for the at least 5 genes. The obtained gene expression result for the at least 5 genes is then employed to determine whether the subject has a graft tolerant phenotype. Also provided are compositions, systems and kits that find use in practicing the subject methods. The methods and compositions find use in a variety of applications, including the determination of an immunosuppressive therapy regimen.

Description

GOVERNMENT RIGHTS[0001]This invention was made with Government support under contract AI061739 awarded by the National Institutes of Health. The Government has certain rights in this invention.INTRODUCTIONBackground of the Invention[0002]Transplantation of a graft organ or tissue from a donor to a host patient is a feature of certain medical procedures and treatment protocols. Despite efforts to avoid graft rejection through host-donor tissue type matching, in transplantation procedures where a donor organ is introduced into a host, immunosuppressive therapy is generally required to the maintain viability of the donor organ in the host.[0003]A variety of immunosuppressive agents have been employed in transplantation procedures, including azathioprine, methotrexate, cyclophosphamide, FK-506, rapamycin and corticosteroids. Agents finding increased use in immunosuppressive therapy due to their preferential effect on T-cell mediated reactions are the cyclosporins.[0004]Following transpl...

AI Technical Summary

Benefits of technology

[0009]Aspects of the present invention include methods of determining whether a subject who has received an allograft has a graft tolerant phenotype, the method including: (a) evaluating the level of expression of at least 5 genes in a sample from the subject to obtain a gene expression result, wherein the at least 5 genes are selected from either Table 2 or Table 4; and (b) determining whether the subject has a graft tolerant phenotype based on the gene expression result. In certain embodiments, the allograft is a renal allograft. In certain embodiments, the sample is a blood sample, e.g., a peripheral blood sample. In certain embodiments, the evaluating step comprises assaying the sample for an expression product of the at least 5 genes. In certain embodiments, the expression product is selected from one both of: a nucleic acid transcript and a protein. In certain embodiments, the expression product is a nucleic acid transcript and the evaluating step comprises performing one or more of the following: a RT-PCR assay, a microarray assay, and a Northern blot. In certain of these embodiments, the microarray is a genomic array. In certain embodiments, the expression product is a protein and the evaluating step comprises employing a proteomic array. In certain embodiments, and the expression level of at least 10 genes from either Table 2 or Table 4 is evaluated. In certain embodiments, the expression level of all of the genes from either Table 2 or Table 4 is evaluated. In certain embodiments, the determining step comprises comparing the gene expression result to a reference gene expression profile. In certain embodiments, the reference gene expression profile is selected from: a graft tolerant phenotype gene expression profile and a graft intolerant phenotype gene expression profile.

[0010]Aspects of the present invention include methods of managing immunosuppressive therapy treatment in a subject having an allograft, the method comprising: (a) determining whether the subject has a graft tolerant phenotype as described above; and (b) managing future immunosuppressive therapy treatment in the subject based on the determining step (a). In certain embodiments, the method comprises at least reducing immunosuppression in the subject if said subject is found to have a graft tolerant phenotype. In certain embodiments, the method comprises discontinuing immunosuppression in the subject if the subject is found to have a graft tolerant phenotype.

Problems solved by technology

While use of immunosuppressive agents, such as Cyclosporin A, has been reported to prolong the survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine and lung, use of such agents is not without undesirable side effects.

Examples of undesirable side effects include increased risk of development of neoplastic disease conditions, e.g., skin cancer, lymphoma, etc.

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