Transforming Growth Factor-Beta and the Dark Side of Cyclosporine (1999)

The introduction of cyclosporine as an immunosuppressive agent revolutionized the field of organ transplantation. However, during therapy with cyclosporine or the related agent tacrolimus, a fine balance must be maintained between the beneficial effect of preventing rejection and the development of adverse clinical effects, including nephrotoxicity, hypertension, and the development of malignancies. After organ transplantation in children, a major concern is the high frequency of post-transplant lymphoproliferative disease, the prevalence of which increases with the amount of immunosuppression, younger age, and primary Epstein-Barr virus infection after transplantation. Cyclosporine acts as an inhibitor of the phosphatase calcineurin to prevent the dephosphorylation and migration of nuclear factor of activated T cells (NF-AT) into the nucleus of lymphocytes (Fig. 1) (Cell 1999;96:611-14 ). When NF-AT is held in the cytoplasm, it is unable to activate transcription of immunostimulatory cytokines, including interleukin-2, thereby resulting in immune suppression. Until now, the accepted explanation for the increased incidence of malignancies during cyclosporine therapy has been the failure of the suppressed immune system to recognize and eliminate malignant cells.FIG. 1: Mechanisms of action of cyclosporine. Cyclosporine (CyA) binds to cyclophilin in the cytoplasm of T cells, which inhibits the dephosphorylation of NF-AT by calcineurin and thereby prevents the nuclear translocation of NF-AT and resulting activation of transcription of cytokines, including interleukin-2 (IL-2). In addition, cyclosporine promotes the transcription and production of TGF-β by an unknown mechanism.Although the exact mechanism remains unclear, both in vitro and in vivo studies indicate that cyclosporine induces expression of transforming growth factor-beta (TGF-β) at the messenger RNA and protein levels (Transplantation 1998;65:313-18 ). Like cyclosporine, TGF-β exhibits immunosuppressive effects, including inhibition of both T-cell proliferation and cytokine production. Furthermore, evidence from studies in mice suggests that the fibrogenic activity of TGF-β could mediate the nephrotoxicity associated with cyclosporine therapy (Transplant Proc 1998;30:944-45 ). Transforming growth factor-beta can also act as both a tumor promoter and a tumor suppressor. In the February 11 issue of Nature (1999;397:530-4) , Hojo et al. provide evidence that cyclosporine-stimulated TGF-β production is responsible, at least in part, for the observed increased incidence of cancers. Both in vitro evidence and in vivo findings in a murine model of metastatic disease were provided to show that cyclosporine promotes tumor growth independent of its effects on the immune system. Cyclosporine treatment induced morphologic changes in adenocarcinoma cells in vitro, including increased cell motility and enhanced anchorage-independent growth, which were prevented by pretreatment with anti-TGF-β antibodies. Cyclosporine-treated SCID-beige mice injected intravenously with tumor cells had increased metastatic growth of tumor cells compared with untreated mice. Furthermore, in mice who received both antagonistic TGF-β antibodies and cyclosporine, the enhanced metastatic potential of injected tumor cells was abrogated. Thus, cyclosporine appears to promote tumor growth by acting directly on cancer cells via TGF-β to enhance their malignant phenotype. This new finding suggests that current therapies aimed at treating cyclosporine-associated malignancies could benefit from treatment using anti-TGF-β antibodies. However, because TGF-β has both tumor-promoting and tumor-suppressing activities, carefully designed studies in animal models are now required to determine the potential efficacy of anti-TGF-β therapies. Clarification of the mechanisms underlying the adverse effects of cyclosporine also should promote the future development of potent immunosuppressive agents with reduced toxicity and less malignant potential. Nicola L. Jones MD, FRCPC Carol A. Durno, MD, FRCPC The Hospital for Sick Children, University of Toronto, Toronto, Canada