[en] Maturation arrest and interference with selection are two well-documented effects of cyclosporin-A (CsA) on the thymus. We recently hypothesized that these effects are related and owing to the reduced T-cell receptor (TCR)-CD3 complex-mediated signal transduction in thymocytes upon CsA treatment. In this hypothesis, the maturation arrest is the result of the additional depletion of thymocytes that normally survive by positive selection, whereas the impaired self-tolerance induction is caused by an increased survival of thymocytes that normally undergo negative selection. In this view, it is anticipated that CsA differentially affects thymocyte apoptosis during in vivo thymocyte maturation. Indeed, we report in this study a strong increase in apoptotic cells in the thymic cortex on in situ analysis. Simultaneously, the number of apoptotic cells had decreased at the cortico-medullary zone which is held to be the site for negative selection. Rapamycin (Rapa) also interferes with thymocyted maturation by inhibiting cytokine-driven proliferation. Hence, Rapa preferentially affects the early maturational stages of thymoctye development and is considered not to alter thymocyte selection and subsequent apoptotic events. Indeed, the number of apoptotic events appears not to be altered. However, possibly owing to the decrease in cortical macrophages, the apoptotic cells revealed an atypical enumeration around blood vessels. Taken together, our results favour the hypothesis that the dominant effect of CsA on the thymus is the reduction of the TCR-CD3 complex-mediated signal transduction in thymocytes upon interaction with stromal cells. Furthermore, the preferential localization of apoptotic cells next to blood vessels upon Rapa administration may indicate that endothelial cells are a back-up system for the removal of apoptotic cells.
Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today 1992;13:136-41.
Schreier MH, Baumann G, Zenke G. Inhibition of T-cell signaling pathways by immunophilin drug complexes: are side effects inherent to immunosuppressive properties? Transplant Proc 1993;25:502-7.
Abraham RT. Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol 1998;10:330-6.
Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998;31:335-40.
Gao EK, Lo D, Cheney R et al. Abnormal differentiation of thymocytes in mice treated with Cyclosporin A. Nature 1988;336:176-9.
Jenkins MK, Schwartz RH, Pardoll DM. Effects of Cyclosporin A on T cell development and clonal deletion. Science 1988;241:1655-8.
Urdahl KB, Pardoll DM, Jenkins MK. Cyclosporin A inhibits positive selection and delays negative selection in αβ TCR transgenic mice. J Immunol 1994;152:2853-9.
Homma M, van Breda Vriesman PJC, Damoiseaux JGMC. Defective de novo thymocyte maturation in cyclosporin A-induced autoimmunity: expression of costimulatory and activation molecules. Clin Exp Immunol 1997;110:79-85.
Damoiseaux JGMC, Beijleveld LJJ, van Breda Vriesman PJC. The effects of in vivo cyclosporin A administration on rat thymic dendritic cells. Clin Exp Immunol 1994;96:513-20.
Beijleveld LJJ, Damoiseaux JGMC, van Breda Vriesman PJC. The differential effects of X-irradiation and Cyclosporin-A administration on the thymus with respect to the generation of Cyclosporin-A induced Autoimmunity. Dev Immunol 1995;4:127-38.
Damoiseaux JGMC, Beijleveld LJJ, van Breda Vriesman PJC. Multiple effects of Cyclosporin-A on the thymus in relation to T-cell development and autoimmunity. Clin Immunol Immunopathol 1997;82:197-202.
Luo H, Duguid W, Chen H et al. The effect of rapamycin on T cell development in mice. Eur J Immunol 1994;24:692-701.
Damoiseaux JGMC, Beijleveld LJJ, Schuurman H-J et al. The effect of in vivo rapamycin treatment on de novo T-cell development in relation to induction of autoimmune-like immunopathology in the rat. Transplantation 1996;62:994-1001.
Glazier A, Tutschka PJ, Farmer ER et al. Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution. J Exp Med 1983;158:1-8.
Stuart MCA, Damoiseaux JGMC, Frederik PM et al. Surface exposure of phosphatidylserine during apoptosis of rat thymocytes precedes nuclear changes. Eur J Cell Biol 1998;76:77-83.
Dijkstra CD, Döpp EA, Joling P et al. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 1985;54:589-99.
Surh CD, Sprent. J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 1994;372:100-3.
Douek DC, Corley KTT, Zal T et al. Negative selection by endogenous antigen and superantigen occurs at multiple thymic sites. Int Immunol 1996;8:1413-20.
Wack A, Ladyman HM, Williams O et al. Direct visualization of thymocyte apoptosis in neglect, acute and steady-state negative selection. Int Immunol 1996;8:1537-48.
Milicevic NM, Milicevic Z, Colic M. Macrophages of the rat thymus after cyclosporin treatment: histochemical, enzymehistochemical and immunohistochemical study. Virchows Arch B 1989;57:237-44.
Van Ewijk W, Shores EW, Singer A. Crosstalk in the mouse thymus. Immunol Today 1994;15:214-7.
Van Ewijk W, Hollander G, Terhorst C et al. Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 2000;127:1583-91.
McCarthy SA, Cacchione RN, Mainwaring MS et al. The effects of immunosuppressive drugs on the regulation of activation-induced apoptotic cell death in thymocytes. Transplantation 1992;54:543-7.
Kawamata S, Sakaida H, Hori T et al. The upregulation of p27kipl by rapamycin results in G1 arrest in exponentially growing T-cell lines. Blood 1998;91:561-9.
Tsukiyama T, Ishida N, Shirane M et al. Down-regulation of p27Kip1 expression is required for development and function of T cells. J Immunol 2001;166:304-12.
Shortman K, Egerton M, Spangrude GJ et al. The generation and fate of thymocytes. Semin Immunol 1990;2:3-12.
Blazar BR, Taylor PA, Snover DC et al. Murine recipients of fully mismatched donor marrow are protected from lethal graft-versus-host disease by the in vivo administration of rapamycin but develop an autoimmune-like syndrome. J Immunol 1993;151:5726-41.
Blazar BR, Taylor PA, Panoskaltsis-Mortari A et al. In vivo inhibition of cytokine responsiveness and graft-versus-host disease mortality by rapamycin leads to a clinical-pathological syndrome discrete from that observed with cyclosporin A. Blood 1996;87:4001-9.
Zhang LH, Liu JO, Sanglifehrin A. A novel cyclophilin-binding immunosuppressant, inhibits IL-2-dependent T cell proliferation at the G1 phase of the cell cycle. J Immunol 2001;166:5611-8.