Cyclosporin A (CyA) is a cyclic undecapeptide exhibiting potent humoral and cell-mediated immunosuppressive properties in both animals and man. While the drug is now accepted in the clinic and is widely used in organ transplant operations, little is known about how this compound actually produces it's profound and reversible immunosuppression. Basically, we know that CyA predominantly affects the activation of T lymphocytes, that it appears to bind to both cytosolic and membrane-associated receptors, and that it ultimately suppress the synthesis and release of Interleukin 2 (IL2). The nature of the CyA receptor, the signal transduction pathway(s) invoked or disrupted subsequent to binding of CyA to it's receptor(s), and the mechanism of (selective) gene repression are entirely unknown. The work outlined in this proposal (which addressed the """"""""signal transduction pathway"""""""" question) will involve the use of cloned human T cell lines to examine the concentration-dependent and coordinated effects of CyA on T cell proliferation and viability, alterations in protein kinase C activity and protein phosphorylation patterns, and effect on IL2 abundance.
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