COMPLEMENT AND ANTIBODY IN THE PATHOGENESIS OF AGA

该项目的总体工作假设是， 激活补体（C）和诱发抗体（Ab）的阶段 这些反应可能导致阿加的发病机制。第一特定 目的是探讨供心热缺血，这是一个独立的 以及阿加。初步调查结果， 这表明围手术期子宫内膜异位症中的C沉积 与缺血性损伤相关的活检，将每年延长一次 冠状动脉造影，以确定与 阿加后续发展。第二个具体目标侧重于 类和亚类的抗体，可以激活C。我们的被动转移 证明同种抗血清可在大鼠中引起阿加的研究将是 通过使用对已知MHC具有不同特异性的单克隆抗体进行延伸 合成热休克蛋白（HSP）的I类表位和抗体 肽，或这些的组合（自体或 同种异体MHC），以鉴定它们通过C activation.这些结果将与抑制 使用CTLAR 4 Ig阻断特异性同种抗体亚类的产生， 阿加的发展。 我们最近发现，C6缺乏大鼠的心脏移植维持了 不进展为阿加的严重、可逆性内皮炎 表明膜攻击复合物（MAC）的潜在关键作用 梭因此，我们的第三个具体目标是评估C组件的作用 参与阿加初始阶段，第四个具体目标是 鉴定C6沉积和平滑肌增殖之间介质 在阿加的后续阶段。sCR 1，抑制C3和C5 转化酶和抑制性抗C3 a和C5 a Ab将用于评估 特定碳组分对阿加第一相的贡献。基于 体外证据表明C5 b-C9（MAC）沉积在内皮细胞上 导致其释放，将检查血小板衍生生长因子（PDGF） 作为阿加第二阶段的潜在中介体。 这些目标是可行的，在高度互动的设置，这一计划 项目将对不同阶段的阿加病变进行形态学分析 由Flavahan博士进行生理评估（项目1）。 对C介导的PDGF产生的研究将扩展到CMV诱导， PDGF与海沃德博士（项目2），和体外研究与博士。 Ballermann（项目3）。自身抗原抗体应答的研究 (HSP)将补充研究细胞自身免疫的博士。 Hess（项目5）。

The overall working hypothesis of this project is that there are multiple stages at which activation of complement (C) and evoked antibody (Ab) responses can contribute to the pathogenesis of AGA. The first specific aim is to investigate donor heart warm ischemia, which is an independent risk factor for C activation -- as well as AGA. Preliminary findings, which demonstrate that C deposition in perioperative endomyocardial biopsies correlates with ischemic damage, will be extended by yearly coronary angiography to identify potential associations with the subsequent development of AGA. The second specific aim focuses on those classes and subclasses of Ab that can activate C. Our passive transfer studies demonstrating that alloantisera can cause AGA in rats will be extended by using monoclonal Ab of different specificities to known MHC class I epitopes and Ab elicited to synthetic heat shock protein (HSP) peptides, or combinations of these (HSP peptides in autologous or allogeneic MHC), to identify their ability to augment AGA through C activation. These results will be correlated with studies inhibiting particular alloAb subclass production using CTLAR4Ig to block the development of AGA. Our recent finding that cardiac transplants in C6 deficient rats sustain profound, reversible endothelialitis which does not progress onto AGA indicates a potential critical role for the membrane attack complex (MAC) of C. Thus, our third specific aim is to assess the role of C components involved in this initial phase of AGA, while the fourth specific aim is to identify mediators between C6 deposition and smooth muscle proliferation in the subsequent phase of AGA. sCR1, which inhibits the C3 and C5 convertases, and inhibitory anti-C3a and C5a Ab, will be used to assess the contribution of specific C components to the first phase of AGA. Based on in vitro evidence that C5b-C9 (MAC) deposition on endothelial cells causes its release, platelet derived growth factor (PDGF) will be examined as a potential mediator in the second phase of AGA. These aims are feasible in the highly interactive setting of this program project. Morphological analysis of different stages of AGA lesions will be augmented with physiological assessments by Dr. Flavahan (Project l). Studies on C mediated PDGF production will be extended to CMV induction of PDGF with Drs. Hayward (Project 2), and in vitro studies with Dr. Ballermann (Project 3). Studies of antibody responses to autoantigens (HSP) will be supplemented with studies of cellular autoimmunity by Dr. Hess (Project 5).