To investigate the role of interleukin (IL)-10 in late graft outcomes, we compared BALB/c donor hearts transplanted into immunosuppressed wild-type or IL-10 gene-deficient (-/-) C57BL recipients (n = 49) at 50 +/- 5 days. There was prominent leukocyte infiltration and parenchymal destruction with more severe vascular occlusion in grafts from IL-10 -/- recipients. An occlusive CD45+ arteritis with medial necrosis occurred with IL-10 deficiency instead of the a-smooth muscle actin-rich arteriosclerosis seen in wild-type recipients. Increased interferon (IFN)-gamma as well as Mac-1, inducible nitric oxide synthase, and allograft inflammatory factor-1 (but not CD3 and IL-4) transcript levels were seen in allografts from IL-10 -/- recipients as assessed by 32p reverse transcription polymerase chain reaction. We then evaluated the contribution of IFN-gamma-mediated responses by neutralizing IFN-gamma. Anti-IFN-gamma monoclonal antibody (MAb) treatment of IL-10 -/- recipients did not improve graft survival, parenchymal rejection, or occlusive arteritis, indicating that these processes are IFN-gamma independent. However, medial smooth muscle cell loss in IL-10 -/- recipients was attenuated by anti-IFN-gamma MAb. Hence, in this transplant model, IL-10 suppresses T cell and macrophage responses in the parenchyma and vasculature and confers a protective effect against late rejection.