不同途径过继回输致耐受树突状细胞延长小鼠移植心脏存活研究的系统评价

Adoptive Transfusion of Tolerance Dendritic Cells Prolongs the Survival of Cardiac Allograft: A Systematic Review of 44 Basic Studies in Mice

目的系统评价采用不同途径过继回输致耐受树突状细胞(tolerogenic dendritic cells,Tol-DCs)对移植心脏存活的影响及可能机制。方法计算机检索PubMed、EMbase和ISI,查找关于过继回输Tol-DCs对移植物存活影响的动物实验,检索时限均从建库至2011年3月5日。参照循证医学系统评价的方法,以同种异体移植心脏存活时间为终点指标,分析Tol-DCs对移植心脏存活的影响;通过整合纳入文献信息,总结Tol-DCs延长移植物存活的机制。结果最终纳入44篇文献,含4种Tol-DCs诱导方式,包括过继回输基因修饰、药物干预、细胞因子诱导及其他源性(脾源、肝源)Tol-DCs。纳入研究多数采用一次性尾静脉输注2×106Tol-DCs。我们采用森林图呈现实验组和未处理组移植心脏存活时间,半定量评价4种诱导方式产生的Tol-DCs对移植心脏存活时间的影响。结果显示4种Tol-DCs均能有效延长移植心脏的存活时间,基因修饰组平均延长存活时间为22.02±21.9 d(3.2倍于对照组),药物诱导组为25.94±16.9 d(4.3倍),细胞因子诱导组为9.00±8.13 d(1.9倍),其他源性Tol-DCs组为10.69±9.94 d(2.1倍)。与英文摘要保持一致:过继回输Tol-DC延长移植物存活的机制有:(1)诱导T细胞低反应性(MLR);(2)削弱对移植物的细胞毒性杀伤效应(CTL);(3)诱导T细胞向2偏移(CK)(;4)诱生Treg。结论对MHC全错配近交系同种异体心脏移植受者小鼠,过继回输基因修饰、药物干预、细胞因子诱导及其他源性(脾源、肝源)Tol-DCs均可显著延长移植物存活或诱导免疫耐受。其中以基因修饰和药物诱导的Tol-DCs延长存活时间效果最为显著,且过继回输基因修饰的可靠性和稳定性强于药物诱导。

Objective Tolerogenic DCs （Tol-DCs）, a group of cells with imDC phenotype, can stably induce T cells low-reactivity and immune tolerance. We systematically reviewed the adoptive transfusion of Tol-DCs induced by different ways to prolong cardiac allograft survival and its possible mechanism. Method MEDLINE （1966 to March 2011）, EMbase （1980 to March 2011）, and ISI （inception to March 2011） were searched for identification of relevant studies. We used allogeneic heart graft survival time as endpoint outcome to analyze the effect of adoptive transfusion of Tol-DC on cardiac allograft. By integrating studies＇ information, we summarized the mechanisms of Tol-DC in prolonging cardiac grafts. Results Four methods were used to induce Tol-DC in all of the 44 included studies including gene-modified, drug-intervened, cytokine-induced, and other-derived （liver-derived ＆ spleen-derived） DCs. The results showed that all types of ToI-DC can effectively prolong graft survival, and the average extension of graft survival time for each group was as follows： 22.02 ± 21.9 days （3.2 folds to control group） in the gene modified group, 25.94 ± 16.9 days （4.3 folds） in the drug-intervened groups, 9.00 ± 8.13 days （1.9 folds） in the cytokine-induced group, and 10.69 ±9.94 days （2.1 folds） in the other-derived group, qhe main mechanisms of Tol-DCs to prolong graft survival were as follows： a） induceT-cell hyporeactivity （detected by MLR）; b） reduce the effect of cytotoxic lymphocyte （CTL）; c） promote Th2 differentiation;d） induce Treg; e） induce chimerism. Condusion For fully MHC mismatched allogeneic heart transplant recipients ol inbred mouse, adoptive transfusion of Tol-DC, which can be gene-modified, drug-intervened, cytokine-induced, spleen- derived or liver-derived, can clearly prolong the survival of cardiac allograft or induce immune tolerance. Gene-modified and drug-induced Tol-DC can prolong graft survival most obviously. Having better reliability and stability than drug- induction, gene-modification is the best way to induce Tol-DCs at present. One-time intravenous infusion of 2 × 10^6 Tol- DC is a simple and feasible way to induce long-term graft survival. Multiple infusions will prolong it but increase the risk and cost. Adoptive transfusion of Tol-DC in conjunction with immunosuppressive agents may also prolong the graft survival time.