LIVER CONTROLS ALLOIMMUNE RESPONSE FOLLOWING DONOR SPLEEN CELLS INJECTION I

Abstract

273 Introduction: The tolerance of allografts after donor-specific injection (DSI) by intraportal or intravenously have been reported, therefore liver considered as an one of the immune-modulate organs. It is unknown, however, whether the underlying mechanisms after DSI involve the liver alone or a combination of other tissue/organ(s). In this study, we developed the new model to examine the relationship between a liver and extrahepatic tissue/organ(s) in the alloimmune responses induced by antigen inoculation. Methods: WS (RT 1k) rats were sensitized with 5×107 DA (RT 1a) spleen cells which were injected intravenously. One, two or three days after DSI, a total hepatectomy was performed and the liver was transplanted into another WS rat (sensitized-liver-grafted; SLG), the hepatectomized WS rat underwent liver transplantation from a naive WS rat (sensitized-liver-removed; SLR). In SLG, the alloantigens accumulated in liver on just time transplanted liver after DSI; in SLR, in the extrahepatic tissue/organ(s). Following these treatments, the animals were grafted with DA skin or heart (Tx) on 10 days after antigen administration. The immune responses following these treatments were evaluated in terms of allografts survival, Th1/Th2 cytokine profile and perforin mRNA in various organs, T cell response (allogeneic MLR before just Tx and delated-type hypersensitivity (DTH) response after Tx) and B cell response (complement-dependent cytotoxicity (CDC) titer and donor-specific immunogloburin after DSI and Tx). Results: SLG animals on one day vigorously rejected skin or heart allografts (5.5±0.2 days; vs other groups, p<0.005, 4.2±0.3 days; vs other groups, p<0.005) compared with non-treated controls (8.5±0.2, 11.6±0.5). In contrast, SLR animals rejected allografts in a significantly delayed fashion (16.5±1.1; vs other groups, p<0.005, 27.7±2.2, vs other groups, p<0.005). On the other hand, SLG and SLR animals transplanted liver on other days rejected in a manner similar to non-treated controls. When skin grafts from LEW (RT 1l) rats were used as a third party, SLG and SLR animals rejected in a manner similar to non-treated controls; when LEW rats were used as a source of spleen cells, these animals rejected DA skin grafts in a same manner. SLG animals on one day associated with a significant higher IFN-γ and perforin mRNA upregulation, CDC titer and DTH response after cardiac transplantation, SLR animals associated with the decrease of them. Before cardiac transplantation, Th1 cytokine levels in liver of SLG and in spleen of SLR on one day highly upregulated rapidly and decline thereafter, mixed lymphocyte proliferative reaction significantly increased in SLG (11412.4±2898.8 cpm; vs other groups, p<0.005) than SLR (87691.2±1308.2) and non-treated controls (87069.0±1944.5). There was no significant difference about the point of peak switched from a IgM to a IgG response in each group. Conclusion: Our results in vivo and vitro on one day after DSI clearly indicate that two compartments of the immune system (liver and other organs) behave differently to alloantigen, suggested early Th1 reaction in liver or spleen after DSI correlate with T cell clonal activation or suppression but not B cell before cardiac transplantation. The liver may play an important role to determine unresponsiveness or rejection after DSI.