Abstract
449 We previously reported that transplanting a Lewis rat heart into a BALB/c mouse produced vigorous rejection (MST: 6.0±0.6 days), while transplanting a Lewis heart into a C57BL/6 mouse produced "weak" rejection (MST: 20.6±4.9 days). The present study was undertaken to explore cellular and molecular mechanisms attributing the different pattern of rejection between these two recipient strains. Sequential routine and immunopathology, and cytokine expression measured by northern blotting were studied in both BALB/c and C57BL/6 mice with a Lewis heart xenograft. Vascular rejection characterized by vasculitis, infarction, thrombosis and hemorrhage was dominated in Lewis xenografts transplanted in BALB/c mice, while cellular rejection was dominant in those of C57BL/6 mice. Immunopathology studies further revealed that these infiltrating cells in C57BL/6 mice were CD4+ and CD8+ T cells, NK cells and macrophages. Notably, strong intragraft IFN-γ expression measured by northern blotting and immunopathology was found in heart xenografts in C57BL/6 mice compared to relatively weak expression in BALB/c mice. To further define the role of IFN-γ in xenograft rejection, Lewis heart grafts were transplanted into IFN-γ knock-out (IFN-γ−/−) mice. Interestingly, the heart xenograft survival was significantly shortened in IFN-γ−/− C57BL/6 mice (MST: 9.0±1.0 days) as compared with that of wild-type C57BL/6 mice (MST: 20.6±4.9 days, P <0.001). In contrast, there was no difference between wild-type BALB/c mice and IFN-γ−/− BALB/c mice (MST: 6.0±0.6 days vs. 6.1±1.5 days). Furthermore, the rejection pattern was shifted from cellular rejection to vascular rejection when IFN-γ was knocked out from C57BL/6 mice. We conclude that 1) predominant cellular rejection in C57BL/6 mice produces "weak" xenograft rejection; 2) high expression of IFN-γ is present in these grafts and 3) depleting IFN-γ gene shifts cellular rejection to vascular rejection, thereby accelerating xenograft rejection. These data indicate that IFN-γ may play a "protective" role in xenograft rejection. Studies are currently underway to see whether manipulating cytokine network could attenuate xenograft rejection.
Published Version
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