T Cell Immunity in Collagen Biosynthesis of Scleroderma

这项研究计划和培训都将在洛克菲勒大学（RU）进行，该大学位于纽约医院-康奈尔医学中心和特殊外科医院附近。临床研究将在完全资助的RU GCRC进行。我在这个项目中的短期目标是清楚地证明沙利度胺的免疫调节可以影响硬皮病患者的胶原合成。我的中间目标是证明选择性免疫增强可以与某些自身免疫性疾病（硬皮病、结节病）的临床益处相关。根据我的中期结果，我预期的长期目标将是探索导致个体对这些自身免疫性疾病易感性的因素。免疫性疾病硬皮病（SSc），其特点是过多的胶原蛋白产生，是抵抗免疫抑制治疗。由于SSc与th2型免疫反应相关，我们假设导致向th1型免疫反应转变的免疫调节干预可能改变胶原生物合成，从而改变疾病病程。我们设计了基于患者和体外的研究来验证这一假设。我们将使用沙利度胺，一种在体外和体内刺激th1型细胞因子产生的免疫调节药物，来调节SSc免疫反应，并诱导体外胶原合成的变化。具体来说，我们将1)确定在特定的SSc组织区室（血浆、血细胞、皮肤）中存在th2型免疫反应，2)证明在沙利度胺诱导的th1型免疫刺激期间这些组织区室的变化。我们还将3)通过免疫组织学分析细胞表型，通过定量rt - pcr分析沙利度胺治疗前后SSc皮肤活检组织的前胶原mRNA表达，4)使用体外胶原生物合成模型来验证Thl- vs. th2型细胞因子调节胶原生成的假设。本研究将为SSc的免疫发病机制提供新的信息。由此产生的见解可能有助于理解其他自身免疫性疾病的发病机制。

This research proposal and training will both take place at Rockefeller University (RU), located adjacent to New York Hospital-Cornell Medical Center and the Hospital for Special Surgery. The clinical studies will take place in the fully funded RU GCRC. My short term goals in this project are to clearly demonstrate that immune-modulation by thalidomide can affect collagen synthesis in scleroderma patients. My intermediate goals are to show that selective immune enhancement can be associated with clinical benefits in some autoimmune diseases (scleroderma, sarcoidosis). My anticipated long term goals, depending on my interim results, will be to explore the factors leading to individual susceptibility to these autoimmune diseases. The immune disorder scleroderma (SSc), characterized by excessive collagen production, is resistant to immune suppressive therapy. Because SSc is associated with a Th2-type immune response, we hypothesize that an immune-modulatory intervention that causes a shift to a Th1-type immune response may alter collagen biosynthesis and thereby the disease course. We designed patient-based and in vitro studies to test this hypothesis. We will use thalidomide, an immune modulatory drug that stimulates Th1-type cytokine production in vitro and in vivo, to modulate the SSc immune response as well as to induce changes in collagen synthesis in vitro. Specifically, we will 1) establish that there is a Th2-type immune response in specific SSc tissue compartments (plasma, blood cells, skin), and 2) demonstrate the changes in these tissue compartments during thalidomide-induced Th1-type immune stimulation. We will also 3) analyze SSc skin biopsies by immunohistology for cell phenotypes and by quantitative rtPCR for procollagen mRNA expression before and after thalidomide treatment, and 4) use an in vitro collagen biosynthesis model to test the hypothesis that Thl- vs. Th2-type cytokines regulate collagen production. This study will provide new information on SSc immunopathogenesis. The resulting insights may be helpful for understanding the pathogenesis of other autoimmune disorders.