Mechanisms of Chronic Pathobiology in Allografts

慢性排斥反应是一种免疫促进的同种异体移植组织的病理重塑，严重到足以损害生理功能。要了解这一重塑过程，需要了解将同种免疫与组织发生联系起来的因素。一种重要的连接剂，即转化生长因子β，它可以改变白细胞的行为，刺激纤维组织重塑。我们认为，慢性转化生长因子β的产生代表了慢性排斥反应在不同组织中出现的许多不同组织学特征的基本病理刺激。我们已经组建了一个具有不同科学专业知识的PI团队来研究产生TGFbeta的同种异体免疫过程，以及TGFbeta促进同种移植物发病的机制。项目1将使用完整的动物模型来测试这一假设，即同种异体抗体通过巨噬细胞刺激纤维化重塑事件，使它们通过慢性FcGamma和凋亡受体参与产生TGFbeta。项目2将使用人巨噬细胞的体外研究来研究同种异体抗体通过FcGammaR刺激巨噬细胞时所使用的细胞间信号系统，使其能够避免凋亡并产生促炎细胞因子，包括TGFbeta。项目3将对人类和小鼠同种异体移植进行研究，以检验这样一种假设：在慢性同种异体移植排斥反应中观察到的许多病理变化是由转化生长因子β可诱导基因调节因子MSY1对基质细胞的转录重新编程所驱动的。因此，PI将在系统、细胞和遗传层面上解决这个问题。他们还将为彼此提供独特的见解和宝贵的研究工具。这些项目将得到两个核心设施的协助：行政/统计核心(核心A)和组织病理学/形态计量学核心(核心B)。核心A将提供组织支助、秘书服务、预算会计和统计服务。核心B将提供经验丰富的移植病理学家的专业知识，以及组织切片、组织学和免疫组织学组织染色以及染色组织的显微镜和形态计量分析的技术能力。总体而言，该项目反映了一支热情和高度互动的调查团队的努力。他们利用他们不同的科学兴趣，提出了几个独特的假说和令人信服的关于慢性同种异体移植排斥反应的基本生物学的初步数据。他们组织良好，并得到了他们所在机构的有力、积极的支持。

Chronic allograft rejection is an immune-promoted pathologic remodeling of allograft tissues which is severe enough to compromise physiologic function. An understanding of this remodeling process requires an understanding of agents that connect alloimmunity with histogenesis. One important connecting agent if TGFbeta which alters leukocyte behavior and stimulates fibrotic tissue remodeling. We believe that chronic TGFbeta production represents a basic pathologic stimulus for the many different histologic features of chronic rejection that appear in different tissues. We have assembled a team of PIs with diverse scientific expertise to study the alloimmune processes that generate TGFbeta, and the mechanisms by which TGFbeta promotes pathogenesis in allografts. Project 1 will use intact animal models to test the hypothesis that alloantibodies stimulate fibrotic remodeling events through macrophages, causing them to produce TGFbeta through chronic Fcgamma and apoptosis receptor engagement. Project 2 will use in vitro studies with human macrophages to investigate the intercellular signaling systems employed when alloantibodies stimulate macrophages via FcgammaR, allowing them to avoid apoptosis and to produce pro- inflammatory cytokines, including TGFbeta. Project 3 will study human and murine allografts to test the hypothesis that transcription reprogramming of stromal cells by the TGFbeta-inducible gene regulator MSY1 drives many of the pathologic developments observed during chronic allograft rejection. Thus, the PIs will attach this problem at the systemic, cellular and genetic levels. They will also provide each other with unique insights and valuable research tools. These projects will be assisted by two core facilities: an Administrative/Statistical Core (Core A) and a Histopathology/Morphometrics Core (Core B). Core A will provider organizational support, secretarial services, budget accounting, and statistical services. Core B will provide the expertise of a veteran transplant pathologist, as well as the technical capabilities for tissue sectioning, histologic and immunohistologic tissue staining, and microscopic and morphometric analyses of stained tissues. In general, this Program Project reflects the efforts of an enthusiastic and highly interactive team of investigators. They have taken advantage of their diverse scientific interests to develop several unique hypotheses and compelling preliminary data regarding the basic biology of chronic allograft rejection. They are well organized, and have strong, active support from their institution.