This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Scleroderma, a disease of abnormal collagen biosynthesis, has been characterized as a Th2-type immune-driven disease. The investigators hypothesize that if this is the case, an immune modulatory intervention that shifts the disease to a Th1-type immune response should alter the disease course beneficially by altering collagen biosynthesis. To test whether such an effect in scleroderma can be accomplished, the investigators will expose patients to thalidomide, an immune modulatory drug that has been shown both in vitro and in vivo to stimulate the production of Th1-type cytokines. In this two-part study, including both in vivo and in vitro investigations, they will carry out a patient-based protocol to demonstrate that collagen biosynthesis in scleroderma skin is decreased during thalidomide treatment and that this is associated with a shift towards a Th1-type immune response. To confirm the effects of Th1 immune stimulation by thalidomide on scleroderma collagen biosynthesis, the investigators will also measure collagen and procollagen production in cultured dermal fibroblasts in the presence of exogenous cytokines (IFNg, IL-4, IL-10, IL-12) or activated T cells from normal volunteers and scleroderma patients treated or untreated with thalidomide. Thus far, patients have tolerated the study protocol without undue difficulty. Collection and processing of specimens and data have proceeded smoothly to date. Although the study is double-blinded, subjects have reported the appearance of dry skin and ulcer healing, noted in the investigators' prior, open-label study. Evaluation of the skin biopsy specimens or ELISAs on plasma samples have not yet begun. Cultured dermal fibroblast collagen production has been markedly decreased after exposure to culture supernatants from thalidomide-treated T cells, compared to supernatants from non-thalidomide-treated controls. This collagen-suppressive effect is seen even in the presence of TGFb activation of the fibroblasts. Additional study is required to identify how thalidomide mediates this effect.
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