Work by the investigator in the first funding period of this application led to the novel discovery that cyclosporine stimulates the expression of transforming growth factor beta (TGF-b), an immunosuppressive cytokine. In this competitive renewal application, the current paradigm for cyclosporine induced immunosuppression, the inhibition of interleukin-2 gene transcription in alloreactive T cells, is being challenged by the hypothesis that cyclosporine induced TGF-b hyperexpression is pivotal in the immunosuppressive effect of this drug. The hypothesis will be tested in a murine islet transplant model comparing wild-type and IL-2 deficient recipients and by blocking TGF-b activity with antisense oligodeoxynucleotides (ODN) and anti-TGF-b monoclonal antibodies. A parallel murine renal cancer metastasis model will be utilized to assess the effect of cyclosporine induced TGF-b hyperexpression on tumor progression both in wild-type and nude mice, allowing assessment of TGF-b- dependent inhibition of NK activity, which cannot be studied in the transplant model. Finally, the effect of cyclosporine-induced TGF-b hyperexpression will be examined in vitro on CTL and NK cell cytolytic activity, as well as on the expression of cytotoxic attack molecules and immunoregulatory cytokines.
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