T Cell Cytokines and Renal Allograft Survival

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DESCRIPTION (provided by applicant): In the United States over 86,000 people had functional renal allografts of a total of 307,967 prevalent patients requiring renal replacement therapy in 1997. The option of cadaveric renal transplantation (CRT) has been associated with increased survival for eligible persons with end-stage renal disease. Throughout the functional life of the allograft, the recipient is exposed to prolonged immunosuppression and the attendant risks of infections, malignancies, and drug toxicities. Understanding the genetic and immunologic factors that are associated with the risks of foreshortened allograft survival or acute rejection may allow a reduction in the exposure to anti-rejection agents as well as extending the function of scarce renal allografts. The principal objective of this training grant proposal is to acquire the necessary skills to become an independent clinical investigator as a molecular epidemiologist addressing questions in renal transplantation. The specific aims of this project are: 1) to obtain doctoral level training in advanced epidemiological methods; 2) to obtain training in Genetics and Immunology; 3) to obtain training in Molecular Biology laboratory techniques; and 4) to utilize this training in Molecular Epidemiology to examine the potential relationship of genotypes of T cell cytokines, acute rejection, and renal allograft survival. The latter aim will be accomplished via a multicenter prospective study among recipients of cadaveric renal allografts in the Delaware Valley. This study will explore the hypothesis that particular polymorphisms of genes that encode for cytokines that regulate T cells, the primary effector cells of the rejection process, are associated with renal allograft outcomes, independent of traditional factors. In addition, the interdependency of these cytokine polymorphisms and renal allograft outcomes will be explored. Data will be collected from donors and recipients at implantation and during transplant follow-up. The genetic polymorphisms of Thl and Th2 cytokines as well as CTLA4 and Fas-ligand will be determined by polymerase chain reactions of blood samples from the recipients. Cox proportional hazards modeling will be implemented to examine the time-to- allograft failure and the time-to-first acute rejection. Additional models will be constructed to explore the associations of Thl/Th2 genotypes, CTLA4/Fas-ligand genotypes, and the interactions of the genotypes on allograft failure and acute rejection. In addition, interactions among the genotypes and recipient ethnicity will be explored. This project will contribute to the understanding of the importance of gene-environment interactions in contemporary, clinical transplantation, potentially identifying genetically distinct subsets of patients who may require intensified or reduced immunosuppression to achieve improved long-term allograft function and possibly patient survival.