T Cell Cytokines and Renal Allograft Survival

描述（由申请人提供）：在美国超过86，000人 共有307，967例患者接受了功能性肾移植 需要肾脏替代治疗尸体肾移植的选择 移植（CRT）与符合条件的患者的生存率增加相关。 末期肾病患者。在设备的整个使用寿命期间， 在同种异体移植中，受体暴露于长期的免疫抑制， 伴随的感染、恶性肿瘤和药物毒性风险。 了解与糖尿病相关的遗传和免疫因素， 移植物存活缩短或急性排斥反应的风险可能会导致 减少暴露于抗排斥药物以及延长 稀有肾移植物的功能。本次培训的主要目的 赠款提案是为了获得必要的技能，成为一个独立的 作为分子流行病学家的临床研究者， 肾移植该项目的具体目标是：1）获得 在先进的流行病学方法方面的博士水平培训; 2）获得 遗传学和免疫学培训; 3）获得分子生物学培训 生物学实验室技术;和4）利用分子生物学的这种培训 流行病学检查T细胞基因型的潜在关系 细胞因子、急性排斥反应和肾移植物存活。后一个目标将 通过在接受者中进行多中心前瞻性研究来完成， 特拉华州山谷的尸体肾移植本研究将探讨 假设编码细胞因子的基因的特殊多态性 调节T细胞，排斥过程的主要效应细胞， 与肾移植结局相关，独立于传统的 因素此外，这些细胞因子多态性的相互依赖性和 将探讨肾移植物的结局。将从捐赠者处收集数据 以及植入时和移植随访期间的受体。遗传 Th 1和Th 2细胞因子以及CTLA 4和Fas-配体的多态性将被 通过对来自受者的血液样本进行聚合酶链反应来确定。 将实施考克斯比例风险模型，以检查至 同种异体移植失败和首次急性排斥反应的时间。附加模型 将构建以探索Th 1/Th 2基因型， CTLA 4/Fas配体基因型及其与同种异体移植物的相互作用 衰竭和急性排斥反应。此外，基因型之间的相互作用和 将探讨接受者的种族。该项目将有助于 了解基因与环境相互作用的重要性 当代，临床移植，可能识别基因 可能需要强化或减量的不同患者亚组 免疫抑制以实现改善的长期同种异体移植物功能， 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.