SUPPRESSION OF ALLOGRAFT RESPONSES INDUCED BY INTERLEUKIN-6, WHICH SELECTIVELY MODULATES INTERFERON-GAMMA BUT NOT INTERLEUKIN-2 PRODUCTION

Background. Interferon (IFN)-gamma produced by activated T cells repre sents an important effector cytokine in mediating an inflammatory resp onse. Methods. The present study investigated the modulation of allogr aft responses by inhibiting IFN-gamma production, C57BL/6 (B6) lymph n ode cells were stimulated with class II Ha-disparate B6-C-H-2(bm12) (b m12) spleen cells. Results. Addition of interleukin (IL)-6 to the prim ary B6 anti-bm12 mixed lymphocyte reaction (MLR) inhibited neither pro liferative responses nor IL-2 production. However, IL-6 induced a dose -dependent suppression of IFN-gamma production in the same MLR culture s. B6 mice were engrafted with bm12 shin grafts, and IL-6 was given to bm12 skin graft recipients every other day. T cells from these recipi ent mice produced significantly less IFN-gamma in secondary B6 anti-bm 12 MLR than those from bm12 skin graft recipients that had not receive d IL-6 injections. IFN-gamma production by these T cells was suppresse d more strongly when the secondary MLR was conducted in the presence o f IL-6. In addition to suppression of IFN-gamma expression, IL-6 injec tions resulted in prolongation of bm12 skin graft survival. The critic al involvement of IFN-gamma in anti-bm12 rejection responses was subst antiated by evidence that administration of anti-IFN-gamma monoclonal antibody strikingly prolonged bm12 skin graft survival. The prolongati on of graft survival by in vivo treatment with either IL-6 or anti-IFN -gamma monoclonal antibody was found to be induced without blocking ce llular infiltration of the grafts. Conclusions. These results indicate that IFN-gamma acts as a key cytokine in a B6 anti-bm12 allograft res ponse and that IL-6 may down-regulate this response by inhibiting IFN- gamma production of alloreactive T cells.