| Acute rejection is main cause of allograft loss. The principal mechanism underlying the acute rejection is the vigorous adaptive immune response mounted by recipient T lymphocytes against allogeneic antigen. The activation of T cell need two different signals: signal 1 from pMHC complex and signal 2 which is so-called costimulatory signal, and these two signals were provided by APCs. According to the 'danger model theory', the release of endogenous danger signal triggered by transplant surgery and necrosis due to ischemia/reperfusion injury is enough to initiate maturation and migration of graft-resident and graft-infiltrating DCs, and thus, activte alloreactive T cell to initiate and enhance adaptive immune response. So blocking the danger signal is the key strategy to prevent acute rejection.The intranuclear architectural protein that is termed high mobility group box protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator when present extracellularly. HMGB1 has been demonstrated to be a long-searched-for nuclear danger signal passively released by necrotic cells that will induce inflammation. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes. Extracellular HMGB1 acts as a cytokine to mediate non-specific inflammatory responses, and most importantly, as a endogenous danger signal to initiate and enhance adaptive immune response. So HMGB1 may play an important role in allorejection and blocking the activity of HMGB1 can be a prospective strategy to prevent acute rejection.In the present study we first examine the change of HMGB1, TNF-α and IFN-γ in allograft during the allogeneic rejection in a mouse cardiac transplantation model (BALB/c -C57BL/6) . The result shows that the mRNA level of HMGB1 and TNF-α were increased 1 day post-transplantation in both syngeneic and allogeneic groups, but in allograft, the mRNA level of HMGB1 and TNF-α were increased heavily 3 days post-transplantation and reach the peak value 7 days post-transplantation which is statistically different compared with syngeneic control (p < 0.05). These results suggest that HMGB1 and TNF-α may act cooperatively in both non-specific inflammatory response and the specfic allogeneic response during allotransplantation.Based on the observation above, HMGB1 specific antagonist A-box protein was produced and given intraperitoneally to the recipient at the doses of 1mg daily from 1 day pre-transplantation to 4 days post-transplantation. The result shows that A-box effectively prolonged the mean graft survival time (MST) of cardiac allografts to 12.5±1.87 d, which is statistically different compared with syngeneic control (p<0.05) . A-box administration dramatically decreases the number of splenic IFN- γ -producing T cells, and inhibits the ability of recipient splenic dendritic cells to express costimulatory molecules, as determined by flow cytometry. These results suggest that the anti-rejection effect of A-box may mediated through suppressing the polarization of T cell and inhibiting the maturation of DC.We next investigated the effect of A-box on DCs in vitro. Our results shows that the mouse dendritic cells actively release their own HMGB1 into the extracellular milieu upon activation. This secreted HMGB1 is necessary for the up-regulation of CD80 and CD86 surface markers of mouse dendritic cells and thus play an important role in the process of DC maturation.In summary, our results indicate that HMGB1 is an important allorejection associated molecule. Counteracting extracellular HMGB1 with a specific HMGB1 antagonist may offer a new method for the successful treatment of allorejection.
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