Chronic DTH and IFN-gamma in Human Graft Arteriosclerosis

描述(由申请人提供)： PPG的总体目标保持不变，即阐明移植物动脉硬化(GA)的发病机制，移植物动脉硬化(GA)是晚期同种异体心脏移植失败的主要原因，以开发预防、治疗和诊断这种疾病的新策略。GA是移植物管道动脉的一种快速进行性狭窄，导致缺血性移植物失败。我们的一般假设是，GA是由干扰素-γ引起的，这是一种主要由某些T细胞亚群产生的细胞因子。项目负责人J.S.Pober的项目将调查移植物内皮细胞的特征，这些特征导致宿主T细胞的选择性招募、分化和/或激活，宿主T细胞产生干扰素-γ和一氧化氮，这是GA的介质。Pober的项目还将开发用于分析人类GA的新的免疫缺陷小鼠模型，利用造血干细胞移植和血管组织工程方面的进展。Min的项目将调查通过SOCS-1作用的干扰素-γ如何与肿瘤坏死因子结合产生内皮功能障碍，这是GA的早期事件。G.Tellides的项目将调查干扰素-γ如何导致血管平滑肌细胞的增殖和/或死亡，这是血管重塑和狭窄的关键过程。Tellides的项目还将评估先天免疫和PPAR-伽马信号对这些过程的贡献。J.R.Bender的项目，将探索干扰素-γ、血管内皮生长因子和整合素在GA发病机制中的表达和激活之间的关系。Bender的项目还将为GA的非侵入性成像早期过程识别目标和试剂。行政核心(核心领导J.S.Pober)将管理PPG。显微外科核心(G.Tellides，核心领导者)将生产出具有人类异种或小鼠异基因动脉节段的免疫缺陷小鼠，这些模型是PPG的核心模型。显微外科中心还将探索使用免疫缺陷大鼠作为开发新的人类GA模型的基础。形态测量和生理学核心(W.C.Sessa，核心领导者)将提供最先进的分析工具来评估移植的血管节段。Apheresis Core(核心领导者E.L.Snyder)将对成年人类志愿者进行白细胞移植，提供人类淋巴细胞和造血干细胞，这是拟议中的实验的关键试剂。如果成功，四个项目和四个核心的整合努力不仅将产生对人类GA的新见解，还将增加我们对动脉粥样硬化和术后再狭窄等相关人类动脉病变的了解。

DESCRIPTION (provided by applicant): The overall goals of this PPG remain largely unchanged, namely to elucidate the pathogenesis graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, in order to develop new strategies to prevent, treat and diagnose this condition. GA is a rapidly progressive stenosis of graft conduit arteries that results in ischemic graft failure. Our general hypothesis is that GA is caused by IFN-gamma, a cytokine made predominantly by certain subsets of T cells. Project by J.S. Pober, project leader, will investigate features of graft endothelial cells that lead to selective recruitment, differentiation and/or activation of host T cells which make IFN-gamma and NO, mediators of GA. Project by Pober will also develop new immunodeficient mouse models for analysis of human GA, exploiting advances in hematopoietic stem cell transplantation and tissue engineering of blood vessels. Project by Min, will investigate how IFN-gamma, acting through SOCS-1, may combine with TNF to produce endothelial dysfunction, an early event in GA. Project by G. Tellides, will investigate how IFN-gamma can cause proliferation and/or death of vascular smooth muscle cells, key processes in vessel remodeling and stenosis. Project by Tellides will also evaluate the contributions of innate immunity and PPAR- gamma signaling to these processes. Project by J.R. Bender, will explore the relationships between IFN-gamma, VEGF and integrin expression and activation in the pathogenesis of GA. Project by Bender will also identify targets and reagents for noninvasive imaging early processes in GA. The Administrative Core (J.S. Pober, core leader) will administer the PPG. The Microsurgery Core (G. Tellides, core leader) will produce immunodeficient mice bearing human xenogeneic or mouse allogeneic arterial segments, models central to this PPG. The Microsurgery Core will also explore the use of immunodeficient rats as the basis for developing a new model for human GA. The Morphometry and Physiology Core (W.C. Sessa, core leader) will provide state-of-the-art analytic tools to evaluate transplanted blood vessel segments. The Apheresis Core (E.L. Snyder, core leader) will conduct leukaphereses of adult human volunteers, providing human lymphocytes and hematopoietic stem cells, crucial reagents for the proposed experiments. If successful, the integrated efforts of the four projects and four cores will not only produce new insights into human GA, but will also increase our understanding of related human arteriopathies such as atherosclerosis and post-procedure restenosis.