T Cell Immunity in Collagen Biosynthesis of Scleroderma

这项研究计划和培训将在洛克菲勒大学（RU）进行，该大学毗邻纽约医院-康奈尔医疗中心和特殊外科医院。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蛋白合成。我的中间目标是表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），其特征在于过度的胶原蛋白产生，对免疫抑制治疗具有抗性。由于SSc与Th 2型免疫应答相关，我们假设导致向Th 1型免疫应答转变的免疫调节干预可能会改变胶原蛋白生物合成，从而改变疾病进程。我们设计了以患者为基础的体外研究来验证这一假设。我们将使用沙利度胺，一种免疫调节药物，刺激Th 1型细胞因子的生产在体外和体内，调节SSc免疫反应，以及诱导胶原蛋白合成的变化在体外。具体而言，我们将1）确定在特定SSc组织区室（血浆、血细胞、皮肤）中存在Th 2型免疫应答，2）证明在沙利度胺诱导的Th 1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SSc皮肤活组织检查的细胞表型，并通过定量rtPCR分析沙利度胺治疗前后的前胶原mRNA表达，以及4）使用体外胶原生物合成模型来检验Thl型细胞因子与Th 2型细胞因子调节胶原产生的假设。本研究为SSc免疫发病机制的研究提供了新的信息。由此产生的见解可能有助于了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.