T Cell Cytokines and Renal Allograft Survival

描述(申请人提供)：在美国，超过86,000人 共有307,967名流行患者进行功能性肾移植 在1997年需要肾脏替代治疗。身体肾的选择 移植(CRT)与提高符合条件的患者的存活率有关 终末期肾病患者。在整个功能生命周期中， 同种异体移植，受者暴露于长期的免疫抑制和 随之而来的感染、恶性肿瘤和药物中毒的风险。 了解与糖尿病相关的遗传和免疫学因素 同种异体移植存活时间缩短或急性排斥反应的风险可能使 减少接触抗排斥剂以及延长 稀缺同种异体肾移植的功能。本次培训的主要目标是 助学金提案是为了获得成为独立人士所需的技能 作为分子流行病学家的临床调查员在 肾移植。本项目的具体目标是：1)获得 博士级别的高级流行病学方法培训；2)获得 遗传学和免疫学培训；3)获得分子方面的培训 生物实验室技术；以及4)利用这种分子方面的培训 流行病学研究T细胞基因分型之间的潜在关系 细胞因子、急性排斥反应和移植肾存活。后一个目标将 通过在接受者中进行多中心前瞻性研究来实现 特拉华山谷的同种异体身体肾移植。这项研究将探索 假设编码细胞因子的基因的特定多态 调节T细胞，排斥过程的主要效应细胞， 与同种异体肾移植结果相关，独立于传统的 各种因素。此外，这些细胞因子基因多态之间的相互依赖与 将探讨同种异体肾移植的结果。数据将从捐赠者那里收集 以及植入时和移植随访期间的受者。基因 Th1和Th2细胞因子以及CTLA4和Fas配体的多态性将是 通过对受者的血液样本进行聚合酶链式反应确定。 将实施COX比例风险建模，以检查 同种异体移植失败和首次急性排斥反应。其他型号 将被构建来探索Th1/Th2基因类型之间的关联， CTLA4/Fas配体基因分型及其在同种异体移植中的相互作用 失败和急性排斥反应。此外，各基因型之间的相互作用和 将探讨受助人的种族。这一项目将有助于 对基因-环境相互作用的重要性的理解 当代临床移植，潜在的基因识别 可能需要强化或减少的不同患者亚群 免疫抑制以实现改善长期同种异体移植功能和 可能是病人的生存。

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.