LEUKOCYTE-SUPPRESSING INFLUENCES OF INTERLEUKIN (IL)-10 IN CARDIAC ALLOGRAFTS - INSIGHTS FROM IL-10 KNOCKOUT MICE

To investigate the role of interleukin (IL)-10 in late graft outcomes, we compared BALB/c donor hearts transplanted into immunosuppressed wi ld-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 oc curred with IL-10 deficiency instead of the alpha-smooth muscle actin- rich arteriosclerosis seen in wild-type recipients. Increased interfer on (IFN)-gamma as well as Mac-1, inducible nitric oxide synthase, and allograft inflammatory factor-1 (but not CD3 and IL-4) transcript leve ls were seen in allografts from IL-10 -/- recipients as assessed by P- 32 reverse transcription polymerase chain reaction, We then evaluated the contribution of IFN-gamma-mediated responses by neutralizing IFN-g amma. Anti-IFN-gamma monoclonal antibody (MAb) treatment of IL-10 -/- recipients did not improve graft survival, parenchymal rejection, or o cclusive arteritis, indicating that these processes are IFN-gamma inde pendent, However, medial smooth muscle cell loss in IL-10 -/- recipien ts was attenuated by anti-IFN-gamma MAb. Hence, in this transplant mod el, IL-10 suppresses T cell and macrophage responses in the parenchyma and vasculature and confers a protective effect against late rejectio n.