Interferon gamma regulatory mechanisms during acute graft-versus-host disease

The onset of acute graft-versus host disease (aGVHD) is accompanied by macrophage priming and the presence of bacteria derived lipopolysaccharide (LPS) in the sera and organs of transplanted animals. Priming of macrophages occurs despite suppression of T cell function. We have investigated whether interleukin 12 (IL-12) mediates the continued production of interferon gamma (IFN-$ gamma$) during the state of T cell immunosuppression accompanying aGVHD. AGVHD was induced in non-irradiated AxC57BL/6 mice by an injection of C57BL/6 lymphoid cells. Despite T cell immunosuppression, macrophages remained primed as shown by their expression of inducible nitric oxide synthase (iNOS) mRNA and production of nitric oxide (NO) in response to exogenous LPS. Continued exposure to IFN-$ gamma$ was found to be required in order to maintain the primed state of macrophages during aGVHD; IFN-$ gamma$ mRNA within target organs of aGVHD including thymus, salivary gland, and lung was increased between day 7 and 14 after transplantation and was accompanied by the induction of the p40 peptide of IL-12 and iNOS mRNA. p40 peptide mRNA was also increased in macrophages purified on day 14 of aGVHD. These results provide evidence for localized production of IFN-$ gamma$ in aGVHD target organs and suggest that it is mediated by LPS induced IL-12 production by macrophages