Natural killer cell- and macrophage mediated discordant guinea pig -> rat xenograft rejection in the absence of complement, xenoantibody and T cell immunity

Background. The role of natural killer (NK) cells and macrophages (M phi s) in the absence of T cell immunity in discordant xenograft (xg) rejection w as investigated. Methods. Guinea pig hearts were transplanted into athymic nude rats receivi ng no treatment or antixeno-antibody (xAb), anticomplement (C), antinatural . killer (NK) cell therapy (antiasialo GM(1) [anti-ASGM(1)]) or their combi nations. For anti-xAb therapy, natural xAbs were absorbed/neutralized by pr etransplant guinea pig blood transfusion (pGPBT), followed by administratio n of the malononitriloamide MNA715. Cobra venom factor (CVF) was administer ed as anti-C therapy. FACScan analysis and a standard cytotoxicity assay de termined NK cell number and cytotoxicity, respectively. ELISA and the CH50 assay measured titers of xAb and C activity, respectively. Rejected Xgs wer e examined by light microscopy and by immunohistochemistry. Results. All hyperacutely (15+/-4 min) rejected Xgs from untreated rats sho wed deposits of C3 and IgM without cellular infiltrates, Combined anti-xAb and anti-C (pGPBT/MNA715/CVF) treatment significantly prolonged the surviva l of Xgs (3.7+/-0.6 days, P<0.001 vs. control group) showing NK cell and M phi, infiltration without deposition of xAbs or C3, NK cell depletion (day -12) followed by exposure of recovering NK cells to the guinea pig antigens failed to induce specific MR cell nonresponsiveness and to further prolong xg survival in combined anti-xAb/anti-C group. In contrast, adding of cont inuous and repetitive depletion of NR cells significantly further prolonged xg survival to 7.4+/-0.5 days (P<0.001 vs. the anti-xAb/anti-C group) with rejected Xgs densely infiltrated by activated M phi s without involvement of NK cells, C or xAbs. Conclusions. When xAb and C are suppressed in the discordant guinea pig-int o nude rat model, NK cells play an important role in xg rejection, When als o NK cells are suppressed, activated M phi s seem to reject discordant Xgs, The induction of specific NK cell nonresponsiveness fails in the guinea pi g-into-rat combination.