Mechanisms of Chronic Pathobiology in Allografts

慢性同种异体移植排斥反应是一种免疫促进的病理性移植组织重建，严重时可损害移植组织的生理功能。要了解这种重塑过程，需要了解将同种免疫与组织发生联系起来的试剂。一种重要的连接剂是TGF β，其改变白细胞行为并刺激纤维化组织重塑。我们认为，慢性TGF β产生代表了出现在不同组织中的慢性排斥反应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，以研究产生TGF β的同种免疫过程，以及TGF β促进同种异体移植物发病机制的机制。项目1将使用完整的动物模型来检验同种抗体通过巨噬细胞刺激纤维化重塑事件，导致它们通过慢性Fc γ和凋亡受体结合产生TGF β的假设。项目2将使用人巨噬细胞的体外研究来研究当同种抗体通过Fc γ R刺激巨噬细胞时所采用的细胞间信号传导系统，从而使它们避免凋亡并产生促炎细胞因子，包括TGF β。项目3将研究人类和小鼠的同种异体移植物，以检验以下假设：TGF β诱导的基因调节因子MSY 1对基质细胞的转录重编程驱动了慢性同种异体移植物排斥反应期间观察到的许多病理发展。因此，PI将在系统，细胞和遗传水平上解决这个问题。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）和历史学/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学分析的技术能力。总的来说，这个计划项目反映了一个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，发展了几个独特的假设和令人信服的初步数据有关的慢性同种异体移植排斥反应的基础生物学。他们组织良好，并得到其机构的有力、积极支持。

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.