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联合应用单克隆抗体延长小鼠加速性排斥模型中心脏移植物生存期的研究
时间:2011-01-23 浏览次数:1729次 无忧论文网
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外科学
移植免疫学移植免疫学
    目的:联合阻断效应性T细胞(effector T cell)与记忆性T细胞(memory T cell,Tm)诱导记忆性心脏移植的供者特异性耐受,探讨各种记忆性细胞在记忆性心脏移植中发挥作用的机制。
    方法:首先通过同种异体皮肤移植得到预致敏小鼠,过继转移同种反应性记忆性T细胞,构建小鼠同种异体心脏移植模型后再联合阻断效应及记忆性T细胞激活途径,观察移植物生存期的改变,并从移植物和模型鼠两个角度探讨其可能的作用机制;之后以同种异体皮肤移植预致敏小鼠为受体进行心脏移植(二次移植模型),联合应用anti-CD40L、anti-LFA-1、 anti-OX40L和/或anti-CD122治疗并观察其生存期。采集二次移植受体鼠脾脏、血清及移植物标本,检测不同疗法诱导耐受的机制。
    结果:①未处理小鼠脾脏中记忆性T 细胞占6.52%,而预致敏小鼠脾脏中记忆性T 细胞占26.5%;②平均生存期为对照组5.17天,联合应用CTLA4Ig和anti-CD40L(二联用药)组10.33天,再联合应用anti-LFA-1和anti-OX40L(四联用药)组均>100天;③移植物排斥对照组均为4级,二联用药组3B级,四联用药组为0级;④只有对照组脾脏物中CD44高表达;⑤对照组与二联用药组脾细胞增殖程度明显高于四联用药组;⑥治疗组的移植物中IL-2、IFN-和Foxp3基因的表达量明显低于对照组,并且四联用药组IL-10基因表达量明显升高; ⑦使用封闭性anti-OX40L可有效阻止CD4+ 记忆性T 细胞介导的移植排斥;⑧使用清除性anti-CD122可有效阻止CD8+记忆性T 细胞介导的移植排斥;⑨单独应用anti-CD40L、anti-LFA-1及联合应用anti-CD40L、anti-LFA-1、anti-OX40L和anti-CD122可有效延长二次移植移植物生存期,减轻移植物中炎细胞浸润,明显减少移植受者脾脏中两种记忆性T 细胞的数量并抑制其功能,减少移植物及血清中多种Th1型细胞因子的分泌,同时增加移植物及脾脏中CD4+Foxp3+Tregs(regulatory T cell,Tregs)的表达水平;⑩二次移植模型鼠体内可检测到大量记忆性B细胞(memory B cell,Bm),且血清含有大量同种异型抗体。
    结论:在过继转移同种反应性记忆性T细胞的移植模型中,联合阻断效应及记忆性T细胞可获得移植物长期耐受,其机制可能是明显降低移植物和移植受者细胞免疫应答水平的同时,诱导移植物中表达大量IL-10分泌性Tr1细胞;而在二次心脏移植模型中,抑制效应及记忆性T 细胞虽可明显延长移植物生存期,但并不能有效诱导供者特异性耐受,记忆性B细胞成为诱导二次移植免疫耐受的重要障碍。
     [英文摘要]:     Background:Donor-reactive memory T cells threaten the survival of transplanted organs via multiple pathways. However, the effect of costimulatory blockade in secondary allograft rejection has not been studied.
    Materials and methods:The first part of this study was undertaken to induce tolerance of cardiac allografts in mice, in which alloreactive memory T cells were adoptively transferred, by combined costimulatory blockade of both effector and memory T cells. In the second study, C57BL/6 mice that rejected BALB/c skin grafts for more than 4 weeks (defined as alloantigen-primed mice) were used as recipients. The recipient mice were treated with the mAbs to CD154, LFA-1, OX40L, and CD122 on days 0, 2, 4, and 6 after the secondary transplantation of BALB/c heart.
    Results:In the first study, we found that the median survival time (MST) of the grafts was 5.17 days in the untreated group, 10.33 days in the CTLA4Ig- and anti-CD40L-treated (2-combined) group, and more than 100 days in the CTLA4Ig-, anti-CD40L-, anti-LFA-1-, and anti-OX40L-treated (4-combined) group. Histological analysis revealed that the mean rejection level was Grade 4 in the untreated group, Grade 3 in the 2-combined treatment group, and Grade 0 in the 4-combined treatment group. CD44high T cells were detected only in the untreated group. The in vitro proliferation of lymphocytes of both untreated and 2-combined group was higher than that of the 4-combined treatment group (p < 0.01). Compared with the untreated group, the expression levels of IL-2, IFN- and Foxp3 were lower in the 2-combined treatment group; the expression levels of these genes were the lowest in the 4-combined treatment group. IL-10 expression was significantly higher in the 4-combined treatment group than in the other groups. In the second study, the mean survival time (MST) of secondary cardiac allografts in rats treated with antibodies to CD154 and LFA-1 (2-antibodies approach) and those treated with antibodies to CD154, LFA-1, OX40L, and CD122 (4-antibodies approach) were greater than that of the controls (MST = 6.7 days, 22.2 days, and 3.2 days, respectively). The 4-antibodies approach prevented lymphocytic infiltration in the grafts, inhibited memory T cells proliferation in the spleen, increased IL-10 secretion in the serum, and enhanced the expression of CD4+Foxp3+regulatory T cells (Tregs) in spleen. Expression levels of alloreactive antibodies were high in the recipient mice of experimental and control groups.
    Conclusions:These results demonstrate the inhibition efficacy of combined costimulation blockade in accelerated-rejection models and the possible mechanisms underlying the suppression of cellular immunity in mice receiving grafts as well as in inducing the activation of IL-10-producing Tr1 cells in grafts. Furthermore, inhibiting the memory T cells by costimulation blockade extended allograft survival in secondary transplant models, but could not induce tolerance of graft. Alloreactive antibodies may participate in alloresponse and play an important role in secondary cardiac allograft rejection.
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