COMPLEMENT AND ANTIBODY IN THE PATHOGENESIS OF AGA

这个项目的总体工作假设是，有多个 补体(C)和诱导抗体(Ab)激活的阶段 这些反应可能与AGA的发病机制有关。第一个具体 目的是研究供体心脏热缺血，这是一种独立的 C活化的危险因素--以及AGA。初步调查结果， 表明围术期心内膜心肌的C沉积 活检与缺血性损伤相关，将每年延长一次 冠脉造影术以确定潜在的相关性 AGA的后续发展。第二个具体目标集中在 能激活C.我们的被动转移的抗体的类别和亚类 研究表明，同种异体抗血清可以引起大鼠AGA 利用对已知MHC具有不同特异性的单抗进行扩展 合成热休克蛋白(HSP)的I类表位和抗体 多肽，或它们的组合(自体或 同种异体MHC)，以鉴定它们通过C基因增强AGA的能力 激活。这些结果将与抑制的研究相关 用CTLAR4Ig阻断特定异体抗体亚类的生产 AGA的发展。 我们最近发现，C6缺陷大鼠的心脏移植持续 不会进展为AGA的严重、可逆性内皮炎 表明膜攻击复合体(MAC)具有潜在的关键作用 因此，我们的第三个具体目标是评估C组件的作用 参与AGA的这一初始阶段，而第四个具体目标是 确定C6沉积和平滑肌增殖之间的中介因素 在AGA的后续阶段。SCR1，它抑制C3和C5 转换酶和抑制性抗C3a和C5a抗体将被用来评估 特定C组分对AGA第一阶段的贡献。基座 C5b-C9(MAC)在内皮细胞上沉积的体外证据 导致其释放，将检测血小板衍生生长因子(PDGF) 作为AGA第二阶段的潜在调解人。 这些目标在本节目高度互动的背景下是可行的 项目。将对不同阶段的AGA病变进行形态分析 补充了弗拉瓦汉博士的生理评估(L项目)。 C介导的PDGF产生的研究将扩展到CMV诱导 与Hayward博士合作的PDGF(项目2)，以及与Dr。 巴勒曼(项目3)。自身抗原抗体反应的研究 (HSP)将补充细胞自身免疫研究。 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).