SUPPRESSION OF ALLOGRAFT RESPONSES INDUCED BY INTERLEUKIN-6, WHICH SELECTIVELY MODULATES INTERFERON-?? BUT NOT INTERLEUKIN-2 PRODUCTION1

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Abstract
Background. Interferon (IFN)-γ produced by activated T cells represents an important effector cytokine in mediating an inflammatory response. Methods. The present study investigated the modulation of allograft responses by inhibiting IFN-γ production. C57BL/6 (B6) lymph node cells were stimulated with class II H2-disparate B6-C-H-2bm12 (bm12) spleen cells. Results. Addition of interleukin (IL)-6 to the primary B6 anti-bm12 mixed lymphocyte reaction (MLR) inhibited neither proliferative responses nor IL-2 production. However, IL-6 induced a dose-dependent suppression of IFN-γ production in the same MLR cultures. B6 mice were engrafted with bm12 skin grafts, and IL-6 was given to bm12 skin graft recipients every other day. T cells from these recipient mice produced significantly less IFN-γ in secondary B6 anti-bm12 MLR than those from bm12 skin graft recipients that had not received IL-6 injections. IFN-γ production by these T cells was suppressed more strongly when the secondary MLR was conducted in the presence of IL-6. In addition to suppression of IFN-γ expression, IL-6 injections resulted in prolongation of bm12 skin graft survival. The critical involvement of IFN-γ in anti-bm12 rejection responses was substantiated by evidence that administration of anti-IFN-γ monoclonal antibody strikingly prolonged bm12 skin graft survival. The prolongation of graft survival by in vivo treatment with either IL-6 or anti-IFN-γ monoclonal antibody was found to be induced without blocking cellular infiltration of the grafts. Conclusions. These results indicate that IFN-γ acts as a key cytokine in a B6 anti-bm12 allograft response and that IL-6 may down-regulate this response by inhibiting IFN-γ production of alloreactive T cells.