CELL MEDIATED IMMUNE MECHANISMS IN ACCELERATED GRAFT ARTERIOSCLEROSIS (AGA)

加速移植动脉硬化（AGA）中细胞介导的免疫机制

• 批准号: 6642368
• 负责人: Allan D Hess
• 金额: $ 49.81万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642368
• 关键词: MHC class II antigen; T lymphocyte; arteriosclerosis; autoimmunity; autologous transplantation; blood vessel transplantation; cellular immunity; coronary artery; cyclosporines; heart transplantation; histocompatibility typing; histopathology; homologous transplantation; inflammation; laboratory rat; myocardial ischemia /hypoxia; passive immunization; vascular endothelium

The principal objective of project 5 is to define the cell-mediated immune mechanisms responsible for the development of accelerated graft arteriosclerosis (AGA). One of the central tenets to be tested in this project is that the association of AGA with CsA treatment is due to or exacerbated by the aberrant "autoimmune" recognition of MHC Class II antigens. The "autoreactive" T cells that mediate this chronic inflammatory response are the direct result of CsA treatment which inhibits the clonal deletion of a unique subset of T cells that promiscuously recognize both auto and allo MHC Class Il determinants. This hypothesis is supported by the findings that: 1) AGA is positively correlated with the use of CsA; 2) CsA induced "autoreactive" T cells mediate an inflammatory process consistent with chronic rejection; and 3) "autoreactive" T cells can be detected within he graft during CsA treatment. Moreover, strains of animals that differ in their susceptibility also exhibit a differential effect of CsA on the induction of AGA. The production and localization of this unique autoreactive cell population to the graft promotes the development of AGA due to recognition of MHC Class II determinants upregulated on endothelial cells within the graft. Several factors contribute to the upregulation of MHC Class II determinants and include initial allorecognition and the release of v- interferon, ischemia and infection with cytomegalovirus. The factors also contribute to the development of AGA independent of CsA treatment indicating that other immune mechanisms contribute to this chronic inflammatory process. Therefore, the specific aims of this project are to 1) define the cell-mediated allo and autoimmune mechanisms leading to AG particularly examining the role of CsA induced MHC Class II reactive T cells, 2) dissect the intragraft cellular immune mechanisms responsible for AGA and 3) define the requirements for autoimmune recognition of vascular endothelial cells in AGA in order to develop novel therapeutic strategies. The development of these strategies is based, in part, on the recent demonstration that the autoreactive T cells induced by CsA recognize a peptide from the MHC Class Il invariant chain presented by MHC Class Il determinants. Antibodies to the peptide that block recognition and divalent soluble MHC Class Il antigens complexed to the peptide will be assessed for their efficacy in preventing AGA.

项目5的主要目的是定义细胞介导的免疫 负责加速移植的机制 动脉硬化（AGA）。在此中要测试的中心宗旨之一 项目是AGA与CSA治疗的关联是由或 对MHC II类的异常“自身免疫性”识别而加剧 抗原。介导这种慢性的“自动反应性” T细胞 炎症反应是CSA治疗的直接结果 抑制T细胞的独特子集的克隆缺失 滥交同时识别自动和Allo MHC类决定因素。这 假设得到以下发现：1）AGA积极 与CSA的使用相关； 2）CSA诱导的“自动反应” T细胞 介导与慢性排斥一致的炎症过程； 3） 在CSA期间，可以在He移植中检测到“自动反应性” T细胞 治疗。此外，动物的菌株在它们的菌株中有所不同 易感性也表现出CSA对诱导的差异作用 Aga。这个独特的自动反应性细胞的生产和本地化 由于认可，人口促进了AGA的发展 MHC II类决定因素的上调在内皮细胞上的上调 接枝。有几个因素导致MHC II类上调 决定因素，包括初始同种识别和V-的释放 干扰素，缺血和巨细胞病毒感染。这些因素 为独立于CSA治疗的AGA的发展做出贡献 表明其他免疫机制有助于这种慢性 炎症过程。因此，该项目的具体目的是 1）定义导致Ag的细胞介导的Allo和自身免疫机制 特别检查CSA诱导的MHC II类反应性T的作用 细胞，2）剖析导致的手册内细胞免疫机制 对于AGA和3）定义自身免疫识别的要求 AGA中的血管内皮细胞，以发展新型治疗 策略。这些策略的制定部分基于 最近证明了CSA诱导的自动反应性T细胞 识别MHC提出的MHC类IL不变链的肽 级别的决定因素。对阻断识别的肽的抗体 和二价可溶性MHC类IL抗原与肽复合的抗原将 评估它们在预防AGA方面的功效。