Complement and Antibody in the Pathogenesis of AGA

AGA发病机制中的补体和抗体

• 批准号: 6739494
• 负责人: William M Baldwin
• 金额: $ 30.64万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739494
• 关键词: B lymphocyte; arteriosclerosis; clinical research; complement; complement pathway; heart transplantation; histocompatibility antigens; human subject; human tissue; humoral immunity; isoantibody; laboratory rat; leukocyte activation /transformation; monoclonal antibody; myocardial ischemia /hypoxia; platelet derived growth factor; pregnancy; pregnancy immunology; selectins; stress proteins; tissue donors; transplantation immunology; vascular endothelium

This project will use clinical and experimental approaches to advance the hypothesis that activation of complement causes vascular injury in allografts and promotes AGA. The clinical finding that is most relevant to the renewal is that complement is deposited and can be detected in human heart transplants. Diffuse pericapillary deposits of complement were found in the first posttransplant endomyocardial biopsy from 25 of the 86 (29%) patients who received cardiac transplants at Johns Hopkins. Complement deposition correlated with early macrophage infiltration and subsequently with a higher incidence of AGA. In addition, complement deposition was more frequent in hearts transplanted to female recipients and in hearts from female and older donors. The animal model revealed that release of von Willebrand factor and p-selectin from endothelial cells and platelets is a primary feature of complement-mediated arterial injury. Based on these data, we have generated the hypothesis that complement and antibody mediate activation of macrophages and b cells in transplants. We will focus on the following testable model: (1) antibodies (elicited by previous pregnancies in women) bind endothelial cells and activate complement, (2) the complement split product C3b stimulates macrophage activation, (3) its end product C3d augments b cell production of antibodies to HLA and auto-antigens, (4) these elicited antibodies activate additional complement, and (5) arteries in hearts from female and older donors are more susceptible to complement mediated injury due to expressing lower levels of regulators complement activation. Each of these specific aims will be tested both in clinical material and experimental models. The clinical studies will validate data from the more easily manipulated experimental models in rats. We will make effective use of the Clinical/Pathology core for human specimens and the Animal Core for cardiac allografts in rats.

本项目将使用临床和实验方法来推进补体激活导致同种异体移植物血管损伤并促进阿加的假设。与更新最相关的临床发现是补体在人类心脏移植物中沉积并可检测到。在约翰霍普金斯接受心脏移植的86例患者中，有25例（29%）在首次移植后肌内膜活检中发现弥漫性毛细血管周围补体沉积。补体沉积与早期巨噬细胞浸润相关，随后与较高的阿加发病率相关。此外，在移植给女性受体的心脏以及来自女性和老年供体的心脏中，补体沉积更频繁。动物模型显示，血管性血友病因子和p-选择素的释放 来自内皮细胞和血小板的损伤是补体介导的动脉损伤的主要特征。基于这些数据，我们提出了补体和抗体介导移植物中巨噬细胞和B细胞活化的假设。我们将重点关注以下可测试模型：（1）抗体（由妇女先前怀孕引起）结合内皮细胞并激活补体，（2）补体分裂产物C3 B刺激巨噬细胞激活，（3）其终产物C3 d增加B细胞产生针对HLA和自身抗原的抗体，（4）这些引起的抗体激活额外的补体，和（5）来自女性和老年供体的心脏中的动脉由于表达较低水平的调节因子补体活化而更易受补体介导的损伤。这些具体目标中的每一个都将在临床材料和实验模型中进行测试。临床研究将更容易验证来自 在大鼠中操纵实验模型。我们将有效地利用临床/病理学核心用于人体标本，并利用动物核心用于大鼠心脏同种异体移植物。