CELL MEDIATED IMMUNE MECHANISMS IN ACCELERATED GRAFT ARTERIOSCLEROSIS (AGA)

项目5的主要目标是定义细胞介导的免疫 加速移植物形成的机制 动脉硬化(AGA)。在这方面要检验的核心原则之一 项目是AGA与CsA治疗的关联是由于或 MHC II类分子异常的“自身免疫”识别加剧了病情的恶化 抗原。介导这一慢性疾病的“自身反应性”T细胞 炎症反应是CsA治疗的直接结果， 抑制唯一的T细胞亚群的克隆性删除 混杂地识别AUTO和ALLO MHC Class Il行列式。这 研究结果支持这一假设：1)AGA是正的 与CsA的使用相关；2)CsA诱导的“自身反应性”T细胞 调节与慢性排斥反应一致的炎症过程；以及3) 在环孢素A治疗期间，移植物内可检测到“自身反应性”T细胞 治疗。此外，不同品系的动物 敏感度也表现出CsA对诱导的不同影响。 AGA的。这种独特的自体反应细胞的生产和定位 人口对移植物的认可促进了AGA的发展 MHC II类决定簇在血管内皮细胞上的表达 嫁接。导致MHC II类分子上调的几个因素 决定因素，包括初始同种异体识别和v- 干扰素、缺血和巨细胞病毒感染。这些因素还包括 有助于独立于CsA治疗的AGA的发展 这表明其他免疫机制导致了这一慢性疾病 炎症过程。因此，这个项目的具体目标是 1)明确细胞介导的同种异体免疫和自身免疫导致AG的机制 特别是CsA诱导的MHC-II类反应性T细胞的作用 细胞，2)解剖移植物内的细胞免疫机制 对于AGA和3)定义自身免疫识别的要求 血管内皮细胞在AGA中的应用以开发新的治疗方法 战略。这些战略的发展在一定程度上是基于 新近研究表明，CsA诱导的自身反应性T细胞 从MHC提出的MHC类Il不变链中识别多肽 Il类行列式。阻断识别的多肽抗体 和与多肽Will络合的二价可溶性MHC Class Il抗原 对其预防AGA的有效性进行评估。

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.