CELL MEDIATED IMMUNE MECHANISMS IN ACCELERATED GRAFT ARTERIOSCLEROSIS (AGA)

项目5的主要目标是确定细胞介导的免疫 加速移植物生长的机制 动脉硬化（阿加）。在这一过程中要检验的核心原则之一， 项目是，阿加与CsA治疗的关联是由于或 由MHC II类的异常“自身免疫”识别加剧 抗原介导这种慢性炎症的“自身反应性”T细胞 炎症反应是CsA治疗的直接结果， 抑制一个独特的T细胞亚群的克隆缺失， 混杂地识别自体和异体MHC II类决定簇。这 研究结果支持了这一假设：1）阿加是积极的 CsA诱导的自身反应性T细胞 介导与慢性排斥一致的炎症过程;以及3） CsA治疗期间移植物内可检测到“自身反应性”T细胞 治疗此外，不同品种的动物， 磁化率也表现出不同的影响CsA的诱导 关于阿加。这种独特的自身反应细胞的产生和定位 移植物的植入促进了阿加的发展 MHC II类决定簇在内皮细胞上的表达上调， 移植物有几个因素导致MHC II类分子的上调 决定因素，包括最初的同种异体识别和释放的v- 干扰素、局部缺血和巨细胞病毒感染。这些因素还 有助于阿加的发展，不依赖于CsA治疗 表明其他免疫机制也有助于这种慢性 炎症过程。因此，本项目的具体目标是： 1)确定导致AG的细胞介导的同种异体和自身免疫机制 特别是研究CsA诱导的MHC II类反应性T细胞的作用， 细胞，2）解剖负责的移植物内细胞免疫机制 和3）定义自身免疫识别的要求， 血管内皮细胞在阿加，以开发新的治疗 战略布局这些战略的制定部分是基于 最近的研究表明，CsA诱导的自身反应性T细胞 识别来自由MHC呈递的MHC II类不变链的肽 II类行列式。阻断识别的肽抗体 与肽复合的二价可溶性MHC II类抗原将 评估其预防阿加的有效性。

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.