Transforming Growth Factor beta1-knockout mice have been developed and characterized in our laboratories. We have shown that TGFbeta1-knockout mice die of a multisystemic inflammatory disease at 20-30 days of age. In a least 60% of the mutant mice there is a severe myositis involving at least the quadriceps, masseter and/or diaphragm. These lesions are characterized by lymphocytic infiltration with myocyte necrosis and fibrosis. To better understand the role of the inflammatory infiltrate on the disease process the TGFbeta1 mutation has been transferred to the scid background. These mice do not have any of the pathologic lesions seen in the TGFbeta1- mutants, and thus implicate the lymphocytic infiltration as a critical element in disease development. Scid mice are valuable for longevity studies and can be used as recipients of lymphocytes in autologous transfers from mutant non-scid mice to dissect the specific role of the lymphocytic infiltrate. We postulate that the myositis is a CD4+ T cell mediated autoimmune disease and propose to investigate the mechanisms of development and progression of inflammation as follows:
Specific Aim 1. Determine which lymphocyte population initiates skeletal muscle-lesions in TGFbeta1-deficient mice. Based on the observations that lymphocyte are critical to the pathogenesis of the inflammatory myopathy and that the principal cell type on histopathology is CD4+ lymphocytes, studies including neonatal thymectomy, anti-CD4 and anti-CD8 blocking experiments and lymphocyte transfer experiments.
Specific Aim 2. Test muscle tissue for cytokine profiles. The cytokines in the inflamed muscle from the TGFbeta1- knockout animals will be determined to be of the Th1, Th2 profiles or both. An approach which is based on the knowledge that the promotion of autoimmunity in some diseases is associated with a Th1 profile.
Specific Aim 3. Look for evidence of B cell involvement int he myositis.
Specific Aims 1 and 2 will identify the relative importance of T or B lymphocytes. The primary hypothesis suggests that CD4+ T cells would be central to pathogenesis, but this will not exclude a secondary role for B lymphocytes. These will be tested by examination for anti-muscle antibodies and immunohistochemical analysis of muscle.
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