IL-23-IL-17軸在心臟移植排斥反應(yīng)的免疫學(xué)機(jī)制研究.pdf

1、The role of IL-23/IL-17 Axis in Cardiac Allografts rejection in Human and Mice.
　　Part Ⅰ
　　Dynamic changes in IL-23/IL-17 Axis in patients with acute cellular rejection after cardiac transplantation.
　　Objective

2、: To study the role of IL-23/IL-17 Axis in the acute rejection after cardiac transplantation.
　　Methods: In a cross-sectional study, peripheral blood and endomyocardial biopsies (EMB) of 17 heart transplant recipients

3、 were analyzed.Patients were divided in two groups: stable and acute rejection (AR).The gene expressions including T-bet, IFN-γ, RORγt, IL-17, IL-23, GATA3, and FoxP3, the functional marker of Th1, Th17, Th2, and FoxP3+

4、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

5、acute cellular rejection was analysis.
　　Results: We observed that the IL-23/IL-17 axis related gene expressions including T-bet, IFN-γ, RORγt, IL-17 and IL-23, were elevated in EMB samples from patients with acute gr

6、aft rejection.Accordingly, the percentages of circulating Th1, Th17, and FoxP3+ CD4+ T cells were also significantly increased.
　　Conclusions: The data suggest that IL-23/IL-17 axis and -related CD4+ T cells are assoc

7、iated with acute graft rejection in patients with cardiac transplantation.
　　Part Ⅱ
　　The experimental study on antagonist IL-23/17 Axis to attenuate chronic rejection of cardiac allograft in mice.
　　Objective:

8、To study the effect and mechanism of the antagonistic anti-p40 antibody on chronic cardiac rejection.
　　Methods: Hearts of the B6.C-H2bm12/KhEg mice were transplanted into MHC class Ⅱ-mismatched C57Bl/6J mice (Wild Ty

9、pe, γδTCR -/- and IL-17-/-).It is an established murine model of chronic allograft rejection without immunosuppression.The mice were treated with control IgG or 200 μg anti-p40 monoclonal antibody on postoperative days,

10、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

11、 to study the expression of inflammation cytokines and immunity cells.
　　Results: The mice administrated with anti-p40 antibody showed a significant promotion in graft survival (median survival time > 100 d), and hist

12、ological analyses revealed that the cardiac allograft rejection was attenuated.Q-PCR and immunofluorescence analyses demonstrated that anti-p40 antibody downregulated the level of ingraft cytokine and chemokine expressio

13、n (IL-6, IFN-γ, IL-17a, CCL2 and CCL20).Flow cytometry analyses shown that γδ T cells was important ingraft source of IFN-γ and IL-17a and inhibited to produce inflammation cytokine by anti-p40 antibody.Compared with the