MURINE GRAFT-VERSUS-HOST DISEASE IN AN F-1-HYBRID MODEL USING IFN-GAMMA GENE KNOCKOUT DONORS

These experiments were performed to determine whether the absence of d onor-derived IFN-gamma would influence the outcome of acute graft-vs-h ost disease (GVHD), Graft-vs-host reactions were induced in B6D2F(1) h ybrids using grafts from either IFN-gamma gene knockout (gko) or wild- type, C57BL/6J, parental strain donors. GVHD was equally lethal in bot h groups, but IFN-gamma gko graft recipients developed a more protract ed form of the disease. These mice developed early wasting that persis ted until death. IFN-gamma was present in spleen cell cultures from wi ld-type graft recipients, but was absent in cultures from IFN-gamma gk o graft recipients. Both recipient groups showed macrophage priming fo r LPS-induced TNF-cu release. Engraftment of donor-derived CD4(+) and CD8(+) cells was greater in IFN-gamma gko graft recipients. Pathologic changes in IFN-gamma gko graft recipients were different from those t ypically seen in acute GVHD. The syndrome developing in IFN-gamma gko recipients consisted of patchy alopecia, corneal dryness and clouding, and lymphocytic infiltration of the liver, pancreas, salivary gland, lung, and kidney, Lymphocytic infiltrates were also present in the epi dermis and the epithelium of both bile and salivary gland ducts. Some of the lesions closely resembled those seen in the ''sicca''/Sjogren's -like syndrome associated with chronic GVHD; however, there was no evi dence of immune complex deposition in the kidney. These results indica te that GVHD in IFN-gamma gko graft recipients shares many features wi th acute GVHD, but both the duration of the disease and its pathologic manifestations are different. Our results suggest that IFN-gamma play s a significant role in the pathogenesis of acute GVHD by increasing t he rate at which mortality develops.