Multiple effects of cyclosporin A on the thymus in relation to T-cell development and autoimmunity.

The immunosuppressive reagent cyclosporin A paradoxically is able to generate autoimmunity. Cyclosporin A is known to interfere with the signal transduction upon T-cell receptor cross-linking, an event required not only for T-cell activation in the periphery but also for T-cell maturation and selection in the thymus. In this review the multiple effects of cyclosporin A on the thymus are explained in terms of a differential response of thymocyte subsets upon recognition of MHC-peptide complexes. This hypothesis holds the effects of cyclosporin A on the thymic stromal cells to be secondary to its effect on the thymocytes: generation of autoreactive cells is the result of direct interference with negative selection and is not due to the partial disappearance or alteration of thymic stromal cells and, depending on the concomitant reestablishment of the autoregulatory T-cell circuit in the periphery, autoimmunity may develop.