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.

该项目将采用临床和实验方法来推动以下假设，即补体的激活会导致同种异体移植引起血管损伤并促进AGA。与更新最相关的临床发现是补体被沉积，可以在人类心脏移植中检测到。从约翰·霍普金斯（Johns Hopkins）接受心脏移植的86例（29％）患者中的25例（29％）患者中，有25例（29％）患者中有25例（29％的患者中，发现了弥漫性毛细血管沉积物的补体沉积物。补体沉积与早期巨噬细胞浸润相关，随后与AGA的发生率更高。此外，在移植给女性接受者和女性和年龄较大捐助者的心脏中，补体沉积更为频繁。动物模型表明，von Willebrand因子和P-选择素的释放 来自内皮细胞和血小板是补体介导的动脉损伤的主要特征。基于这些数据，我们产生了以下假设：补体和抗体介导移植中巨噬细胞和B细胞的激活。 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来自女性和年长者的心脏更容易受到补充介导的损伤，这是由于调节剂补充激活的较低水平。这些特定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数据 大鼠操纵实验模型。我们将有效利用人类标本的临床/病理核心，以及大鼠心脏同种异体移植的动物核心。