EFFECT OF TREATMENTS WITH CYCLOSPORINE-A AND ANTI-INTERFERON-GAMMA ANTIBODIES ON THE MECHANISMS OF IMMUNE TOLERANCE IN STAPHYLOCOCCAL-ENTEROTOXIN-B PRIMED MICE

The authors were interested to investigate the effect of Cyclosporin A (CsA), known to block interleukin-2 (IL-2) production, or of anti-int erferon-gamma antibodies (anti-IFN-gamma Abs) in a model of T cell tol erance induced by the injection of the superantigen Staphylococcal Ent erotoxin B (SEE) in BALB/c mice. After SEE immunization, tolerance was mainly achieved through deletion and anergy of SEE-reactive V beta 8( +) T cells. Association of CsA treatment with SEE led to a greater dec rease of the percentage of V beta 8(+)CD4(+) lymphocytes in the spleen and an abolition of clonal anergy. In contrast, treatment of SEE prim ed mice with anti-IFN-gamma Abs resulted in an increased percentage of V beta 8(+) CD4(+) cells without affecting the induction of clonal an ergy. The authors found that 1-2 h after SEE priming, splenic mRNA lev els of IFN-gamma and IL-4 were decreased by either CsA and anti-IFN-ga mma Abs, whereas Fast, Ecl-2, p. 53, and c-myc levels were not influen ced by either treatment. However, SEE-induced IL-2 and IL-10 mRNA expr ession was suppressed only by CsA, whereas tumour necrosis factor-alph a (TNF-alpha) was decreased only by anti-IFN-gamma Abs. To investigate whether the effect of CsA on the tolerance mechanisms was related to suppression of IL-2, CsA was administered together with recombinant IL -2. Whereas anergy was not influenced, the decreased percentage of V b eta 8(+) CD4(+) cells seen in CsA-treated animals in the second week a fter SEE injection was partially corrected by the administration of IL -2. Experiments involving bromodeoxiuridine incorporation revealed tha t the latter effect of IL-2 was mainly due to a correction of the defe ctive proliferation of V beta 8(+) T cells after SEE injection in CsA- treated mice. These results suggest that the effect of CsA and anti-IF N-gamma Abs on tolerance mechanisms are in part explained by their act ion on cytokines.