T Cell Immunity in Collagen Biosynthesis of Scleroderma

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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.