Cyclosporine (CSA), by virtue of its immunosuppressive action and lack of myelotoxicity, has greatly improved the rate of success of organ transplantation. Despite its widespread clinical use, however, the exact mechanism by which CSA exerts its selective immunosuppression is not well detailed. It was initially thought that most of CSA effects can be explained by its inhibition of interleukin 2 (IL2) secretion. Recent studies have cast doubt about this being the sole effect of CSA. In particular, CSA appears to inhibit IL2 responsiveness (as determined by proliferation); this inhibition appears to be far more profound than, and does not have stringent correlation with, the inhibition of IL2 receptor (IL2R) expression. However, most of these studies were done utilizing unfractionated lymphocyte populations. We hypothesize that CSA may or may not inhibit IL2 responisveness depending on the lymphocyte subset examined. The mechanisms for such differential inhibitory action will be studied. Recent evidence in animal models suggests that some of the immunosuppressive properties of CSA administered in vivo may be dependent on the presence of an intact thymus. This possibility has received little attention. This proposal will test the hypothesis that CSA exerts significant effects on thymocyte subsets and the thymic epithelium. This hypothesis will be tested both in vivo and in vitro. Once documented, the role of CSA- induced thymic alterations in the development of tolerance to the transplanted organ and in the induction of autoreactive clones will be addressed.
