Cyclosporine A and adverse effects on organs: histochemical studies.

The discovery that cyclosporine A (CsA) was a powerful immunosuppressant had a significant impact on transplant medicine. Its molecular mechanism of action has been well defined in T cells and involved inhibition of critical signalling pathways that regulated T-cell activation. In fact, CsA inhibited calcineurin phosphatase activity and thereby activation of the transcription factor nuclear factor of activated T cells. Over 10 years, its use is limited by side effects, determining nephro- and hepatotoxicity, gingival hypertrophy, tremor and increased blood pressure. These negative effects have been identified through morphological alterations and/or clinical parameters, i.e. variation in glomerular filtration rate for nephrotoxicity. Nevertheless, CsA remains a therapeutic valuable agent and it is normally utilized into clinical practice even if different dose adjustments or discontinuations in a significant percentage of patients must be used. This review focuses on the following topics: mechanisms of action and drug metabolism, interactions with other drugs, clinical and morphological evaluation of toxic effects on target organs. In particular, the morphological evaluation of negative effects has been considered reporting light and ultrastructural studies on target organs both in normal and immunosuppressive conditions. Moreover, the histochemical and immunohistochemical variations in cellular metabolism and antigenic properties of cells present in the parenchyma of these organs are discussed.