Cyclosporine (CS) is a potent immunosuppressive agent which under some circumstances paradoxically augments DTH responses, aggravates some autoimmune diseases, and induces specific forms of autoimmunity. The enhancement of DTH and other immune responses is closely related to the timing of CS administration relative to immunization. CS inhibits IL-2 production (and several other lymphokines) at a pretranscriptional level, but does not usually prevent the antigen-specific priming of T cells, such that T cells may be poised to respond as soon as CS is withdrawn. Thus, accelerated GVHD and allograft rejection may occur after withdrawal of CS. CS has been shown to aggravate and/or induce relapse in several autoimmune diseases including collagen-induced arthritis, EAE, autoimmune thyroiditis, uveitis in SDA chickens, and an autoimmune form of myocarditis in mice. CS may enhance immune responses by inactivating suppressor cells, by altering Th1/Th2 antagonism (e.g., CS promotes a protective Th1-type response in BALB/c mice infected with Leishmania major), or by promoting T cell activation through a CS-resistant IL-2-independent T cell activation/differentiation pathway. At least three forms of CS-induced autoimmunity have been described: Syngeneic or autologous GVHD which occurs in CS-treated syngeneic or autologous bone marrow transplant recipients after CS is withdrawn in rats, mice, and humans; a systemic autoimmune disease with polyarthritis and glomerulonephritis which occurs in irradiated CBA/N mice treated with CS; and organ-specific autoimmune diseases which occur in mice treated with CS during the neonatal period. The precise mechanisms by which CS induces these autoimmune diseases are not clear, however, CS affects immune tolerance at three levels. CS induces thymic medullary involution with loss of medullary Ia+ cells, and appears to at least partially block the transition from double positive (CD4+CD8+) to single positive (mature type) thymocytes. In syngeneic bone marrow chimeras, CS appears to inhibit the intrathymic deletion of clones with relatively low affinity, but not those with high affinity, to self antigens. CS appears to inhibit the action of suppressor T cells which normally maintain an innate form of resistance to autoimmunity. Finally, CS has been shown to prevent the development of T cell clonal anergy. There is redundancy in immune tolerance mechanisms, i.e., clonal deletion, clonal anergy, and suppressor cells can each maintain tolerance to similar antigens, such that it is likely that CS must cripple more than one tolerance mechanism for autoimmunity to occur.

SummaryCyclosporin A (CsA) is a well-known immunosuppressive agent that modulates immune tolerance in many ways. CsA can give rise to a state of long-term nonimmunosuppressed transplantation tolerance, but it can also aggravate autoimmune diseases, and provoke specific forms of antoimmunity. These effects, which are often paradoxical, remain largely unexplained. In this study, we investigated the effects of CsA on superantigen (superAg)-reactive peripheral T cells. The intravenous injection of either staphylococcal enterotoxin B (SEB), or Mls-1 a cells into Mls-1 b recipients, causes longterm in vitro nonresponsiveness (anergy) and partial elimination of the peripheral T call receptor (TCR) VB8+/CD4 + and -VB6+/CD4 + T cell subsets, respectively. We report that CsA markedly enhances the peripheral elimination of SEB-and Mls-la-reactive T cells such that up to 90% of the targeted CD4 +/V3 subpopulations are deleted. The degree of deletion depends on the dose and the schedule of CsA administration, and the number of superAg injections. In situations where the extent of deletion is only moderate, we find that the remaining superAgreactive T cells fail to develop anergy, unlike the T cells of control superAg-immunized mice.Higher doses of CsA are required to enhance T cell deletion (t>25 mg/kg/d, i.p.) than to impair anergy induction (>16.25 mg/kg/d, i.p.). In view of these results, it appears that the degree of tolerance in CsA/superAg-treated mice depends on the balance between these opposing effects, i.e., enhancement of peripheral elimination versus the abrogation of anergy. The possibility of enhancing or preventing immune tolerance with a drug may have important clinical implications.

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