KIDNEY TRANSPLANTATION AND DONOR-SPECIFIC TRANSFUSIONS

我们在此次续订申请中的目标是将获得的见解 在过去的八年里，研究了供者特异性输血(DST) 同种异体肾移植丢失临床问题的机制探讨 慢性排斥反应&移植后2年。这些见解包括：a) 通过发展抗独特型网络预防致敏 对DST的反应：B)早期(移植后6个月)急性 排斥反应与供体特异性的发展是一致的 细胞毒性T淋巴细胞的低反应性；c)人类白细胞抗原的易感性 不匹配的移植到移植后2年的晚期移植物丢失，原因是 慢性排斥反应；以及d)肝移植对 发生影响其他器官移植的晚期慢性排斥反应。 本项目分为四个部分：1)利用纯化的人类白细胞抗原 分析I类和纯化的抗人类白细胞抗原I类抗体的作用 T辅助细胞和B细胞亚群(Ig M和Ig G)在抗类抗体形成中的作用 I和抗独特型反应；2)我们将分析 比较CD4+T辅助细胞和供者特异性CTL的低反应性 CD8+/细胞毒抑制细胞在批量培养和限制中的功能 PBL的稀释分析；3)我们将比较抗体-I的产量 (抗人类白细胞抗原I类)，抗体-2，以及相应的TH和B细胞反应 肝肾移植受者，特别注意 与血清中可溶性I类水平的相关性；以及4)确定 如果一个连续来源的可溶性人类白细胞抗原I类可以抑制启动的T辅助细胞 和B细胞反应，我们将从高水平重建SCID小鼠的PBL 使患者致敏，并对他们进行重组可溶性治疗 用于确定对人类同种异体皮肤移植排斥反应的影响 抗-HLAIg G反应。所有四个部分生成的信息 这个项目将被用来开发新的移植物延长策略。 使用供体特异性抗原操控宿主。

Our objectives in this renewal application are to bring the insights gained over the past eight years of studying the donor-specific transfusion (DST) mechanisms to bear on the clinical problem of kidney allograft loss due to chronic rejection > 2 yr post-transplant. These insights include: a) the prevention of sensitization via development of anti-idiotypic network response to DST: b) the prevention of early (< 6 mo post-transplant) acute rejection coincident with the development of donor-specific hyporesponsiveness of cytotoxic T lymphocytes; c) susceptibility of HLA mismatched transplants to late graft loss > 2 years post-transplant due to chronic rejection; and d) the resistance of liver transplants to the development of late chronic rejection that affects other organ allografts. The project is divided into four parts: 1) we will utilize purified HLA class I and purified anti-HLA class I antibodies to analyze the role of T-helper and B cell subsets (IgM and IgG) in the development of anti-class I and anti-idiotypic responses; 2) we will analyze the mechanism of donor-specific CTL hyporesponsiveness by comparing CD4+ T-helper and CD8+/cytotoxic-suppressor cell function in bulk culture and in limiting dilution analysis of PBL; 3) we will compare the production of Ab-I (anti-HLA class I), Ab-2, and corresponding TH and B cell responses between liver and kidney transplant recipients, paying particular attention to the correlation with soluble class I levels in the serum; and 4) to determine if a continuous source of soluble HLA class I can inhibit primed T-helper and B cell responses, we will reconstitute scid mice with PBL from highly sensitized patients, and subject them to treatment with recombinant soluble HLA class I to determine the effect on human skin allograft rejection and anti-HLA IgG response. The information generated by all four sections of this project will be used to develop new strategies for graft prolongation using donor-specific antigen manipulation of the host.