IFN-GAMMA IN ISLET CELL ALLOGRAFT TOLERANCE INDUCTION

描述：(改编自申请者摘要)尽管取得了显著的成功， 近30年来临床器官移植的进展 接受者受到由全面性的 免疫抑制。此外，目前的免疫抑制剂还没有生产出 在过去的十年中，移植半衰期有了显著的改善。 考虑到这些令人沮丧的长期结果，移植的主要目标是 免疫学是定义免疫耐受的机制，并应用这些机制 在临床环境下的机制，以避免不可避免的并发症 免疫抑制和同种异体移植物最终失败。免疫球蛋白的研究进展 对移植器官的逻辑耐受性是一个复杂的、可能是多因素的 众多细胞信号通路的改变。令人惊讶的是，在许多情况下 移植耐受的临床前模型，Th1细胞的存在 需要细胞因子IL-2和干扰素-γ来促进长期同种异体移植 存活，暗示这些细胞因子在关键的免疫调节作用中。这个 本申请中概述的目标是检查干扰素- γ在胰岛细胞诱导中的调节细胞因子作用 同种异体移植耐受。 这一系列的实验利用了胰岛细胞移植模型系统 基因操作小鼠研究干扰素-γ易化机制 宽容。具体地说，使用单抗进行抗粘连治疗 抗LFA-1诱导胰岛细胞同种异体移植耐受，这是干扰素-γ依赖的。 假设CD8T细胞是胰岛细胞中的主要效应细胞 拒绝，并且它调解拒绝的能力在没有 ，在此描述的实验将确定是否性质 与其他淋巴细胞相比，干扰素-γ的调节处于CD8细胞的水平。 或者是先天免疫细胞。此应用程序将定义关键的蜂窝 干扰素-γ的生产者和应答者在诱导耐受中的作用 补充性体外研究确定干扰素参与的机制- 伽马调节。这些结果最终将导致更大的不足- 了解特定的细胞因子如何偏离免疫反应，并潜在- 最终将导致更多的定向治疗，旨在抑制已知的亲- 干扰素-γ的炎症特性及促进血管内皮细胞保护作用 干扰素-γ。

DESCRIPTION: (Adapted from Applicant's Abstract) Despite marked success and progress in clinical organ transplantation over the last 30 years, transplant recipients are plagued with side effects resulting from generalized immunosuppression. Further, current immunosuppressive agents have not produced significant improvements in the transplant half-life over the last decade. Given these discouraging long-term results, a primary goal of transplant immunology is to define mechanisms of immunologic tolerance and apply these mechanisms in the clinical setting, to avoid the inevitable complications of immunosuppression and ultimate allograft failure. The development of immuno- logic tolerance to transplanted organs is a complex, likely multifactorial alteration of numerous cellular signaling pathways. Surprisingly, in a number of preclinical models of transplantation tolerance, the presence of the Thl cytokines IL-2 and IFN-gamma are required to facilitate long-term allograft survival, implicating these cytokines in critical immunomodulatory roles. The objectives outlined in this application examine the mechanisms by which IFN- gamma functions as a regulatory cytokine in the induction of islet cell allograft tolerance. This series of experiments utilizes an islet cell transplant model system in genetically manipulated mice to study the mechanisms of IFN-gamma-facilitated tolerance. Specifically, anti-adhesion therapy using the monoclonal antibody anti-LFA-1 induces islet cell allograft tolerance that is IFN-gamma dependent. Given that the CD8 T cell is the primary effecter cell in islet cell rejection, and its ability to mediate rejection is enhanced in the absence of IFN-gamma, the experiments described herein will determine if the nature of IFN-gamma regulation is at the level of the CD8 cell versus other lymphocytes or innate immune cells. This application will define the critical cellular producers and responders of IFN-gamma in the induction of tolerance, with complementary in vitro studies determining the mechanisms involved in IFN- gamma regulation. These results will ultimately lead to a greater under- standing of how specific cytokines can deviate an immune response, and poten- tially will lead to more directed therapies aimed at inhibiting the known pro- inflammatory properties of IFN-gamma while promoting the protective actions of IFN-gamma.