The Role Of IL-23/IL-17Axis In Cardiac Allografts Rejection In Human And Mice

Part ⅠDynamic changes in IL-23/IL-17Axis in patients with acute cellular rejection after cardiac transplantationObjective:To study the role of IL-23/IL-17Axis in the acute rejection after cardiac transplantationMethods:In a cross-sectional study, peripheral blood and endomyocardial biopsies (EMB) of17heart transplant recipients were analyzed. Patients were divided in two groups:stable and acute rejection (AR). The gene expressions including T-bet, IFN-y, RORyt, IL-17, IL-23, GATA3, and FoxP3, the functional marker of Thl, Th17, Th2, and FoxP3+CD4+T cells were quantified at the mRNA or protein level in combination with the cell profiles. And then, these CD4+T-cell subsets in peripheral blood and endomyocardial biopsies (EMB) in patients with stable-graft and acute cellular rejection was analysis.Results:We observed that the IL-23/IL-17axis related gene expressions including T-bet, IFN-y, RORyt, IL-17and IL-23, were elevated in EMB samples from patients with acute graft rejection. Accordingly, the percentages of circulating Thl, Thl7, and FoxP3+CD4+T cells were also significantly increased.Conclusions:The data suggest that IL-23/IL-17axis and-related CD4+T cells are associated with acute graft rejection in patients with cardiac transplantation Part IIThe experimental study on antagonist IL-23/17Axis to attenuate chronic rejection of cardiac allograft in miceObjective:To study the effect and mechanism of the antagonistic anti-p40antibody on chronic cardiac rejection.Methods:Hearts of the B6.C-H2bm12/KhEg mice were transplanted into MHC class II-mismatched C57B1/6J mice (Wild Type, γδTCR-/-and IL-17-/-). It is an established murine model of chronic allograft rejection without immunosuppression. The mice were treated with control IgG or200μg anti-p40monoclonal antibody on postoperative days, respectively. Abdominal palpation and echocardiography were used to monitor the survival of the grafts. The immunohistochemical method, flow cytometry and Quantitative real-time polymerase chain reactiona (Q-PCR) were used to study the expression of inflammation cytokines and immunity cells.Results:The mice administrated with anti-p40antibody showed a significant promotion in graft survival (median survival time>100d), and histological analyses revealed that the cardiac allograft rejection was attenuated. Q-PCR and immunofluorescence analyses demonstrated that anti-p40antibody downregulated the level of ingraft cytokine and chemokine expression (IL-6, IFN-7, IL-17a, CCL2and CCL20). Flow cytometry analyses shown that y8T cells was important ingraft source of IFN-y and IL-17a and inhibited to produce inflammation cytokine by anti-p40antibody. Compared with the wild type group, the survival time of graft in the γδTCR-/-and IL-17-/-mice was significantly prolonged.Conclusion:Target on IL-23/IL-17axis is effective in protecting cardiac allograft in mice.