IFN-GAMMA IN ISLET CELL ALLOGRAFT TOLERANCE INDUCTION

描述：（改编自申请人的摘要）尽管取得了显著的成功， 在过去的30年里，临床器官移植的进展，移植 收件人 困扰与 副作用 从广义 免疫抑制此外，目前的免疫抑制剂还没有产生 在过去的十年里，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 免疫学是定义免疫耐受的机制，并应用这些机制 在临床环境中的机制，以避免不可避免的并发症， 免疫抑制和最终同种异体移植失败。免疫学的发展， 对移植器官的逻辑耐受是一个复杂的，可能是多因素的， 许多细胞信号通路的改变。令人惊讶的是，在一些 在移植耐受的临床前模型中，Thl 需要细胞因子IL-2和IFN-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。的 本申请中概述的目标研究了干扰素- γ作为一种调节细胞因子在诱导胰岛细胞增殖中发挥作用， 同种异体移植耐受 这一系列实验利用胰岛细胞移植模型系统， 基因操作小鼠研究IFN-γ促进的机制， 宽容具体地，使用单克隆抗体的抗粘附治疗 抗LFA-1诱导IFN-γ依赖性的胰岛细胞同种异体移植耐受。 鉴于CD 8 T细胞是胰岛细胞中的主要效应细胞， 排斥反应，其介导排斥反应的能力在缺乏 IFN-γ，本文所述的实验将确定IFN-γ的性质是否与IFN-γ的性质有关。 IFN-γ的调节是在CD 8细胞相对于其他淋巴细胞的水平上 或先天免疫细胞。此应用程序将定义关键的蜂窝 IFN-γ的产生者和应答者在诱导耐受中的作用， 确定IFN-γ参与机制的补充体外研究 伽马调节 这些结果最终将导致更大的不足- 特定的细胞因子如何偏离免疫反应，并可能- 这将导致更直接的治疗，旨在抑制已知的亲， IFN-γ的炎症特性，同时促进 IFN-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.