Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12

We have demonstrated that a single injection of interleukin (IL)-12 on the day of bone marrow transplantation (BMT) inhibits acute graft-versus-host d isease (GVHD) in mice. This effect of IL-12 can be diminished by anti-inter feron (IFN)-gamma mAb. To determine the mechanism by which IFN-gamma affect s IL-12-mediated GVHD protection, we have compared the effect of IL-12 on G VHD in C57BL/6 wild-type (WT) or IFN-gamma gene knockout (GKO) recipients o f fully major histocompatibility complex plus minor antigen-mismatched allo geneic BMT from WT or GKO BALBlc mice. Lethal acute GVHD was readily induce d in the absence of IFN-gamma, IL-12 inhibited GVHD mortality to a similar extent in WT and GKO recipients of WT allogeneic BMT, However, neither WT n or GKO recipients were protected by IL-12 from GVHD induced by GKO allogene ic BMT. Moreover, the effective inhibition of host-reactive donor T cell ac tivation and expansion that is associated with IL-12-mediated GVHD protecti on was dependent on the ability of BALB/c donors to produce IFN-gamma. Thes e results demonstrate that (a) acute GVHD can be induced in the absence of IFN-gamma, (b) host IFN-gamma does not play a critical role in IL-12-induce d GVHD protection, and (c) the protective effect of IL-12 against GVHD is d ependent on the ability of the donor to produce IFN-gamma.