Zhang Xusheng, Li Mu, Lian Dameng, Zheng Xiufen, Zhang Zhu-Xu, Ichim Thomas E, Xia Xiaoping, Huang Xuyan, Vladau Costin, Suzuki Motohiko, Garcia Bertha, Jevnikar Anthony M, Min Wei-Ping
Department of Surgery, University of Western Ontario, Canada.
Clin Immunol. 2008 Jun;127(3):313-21. doi: 10.1016/j.clim.2008.01.013. Epub 2008 Mar 20.
Tolerogenic dendritic cells (Tol-DCs) and regulatory T cells (Treg) are key factors in the induction and maintenance of transplantation tolerance. We previously demonstrated that ex vivo-isolated Tol-DCs promote Treg generation, and vice versa, in an in vitro co-culture system. Here we demonstrate the occurrence of such an immune regulatory feedback loop in vivo. Tol-DC generated in vitro by treatment with LF 15-0195 exhibited features of immature DC and express low levels of MHC class II, CD86 and CD40. These Tol-DCs were capable of augmenting CD4(+)CD25(+)CTLA4(+) and FoxP3(+) Treg cell numbers and activity in cardiac allograft recipients. On the other hand, Tol-DCs possessed an ability to generate Treg cells in vitro. The adoptive transfer of these in vitro-generated Treg cells resulted in an increase of Tol-DC in vivo, suggesting that an immune regulatory feedback loop, between Tol-DC and Treg, exists in vivo. Furthermore, the administration of in vitro-generated Tol-DCs or Treg cells prevented rejection of allografts. Co-administration of Tol-DC and Treg synergized efficacy of promoting allograft survival heart transplantation. The present study highlights the therapeutic potential of preventing allograft rejection using in vitro-generated Tol-DCs and Treg.
耐受性树突状细胞（Tol-DCs）和调节性T细胞（Treg）是诱导和维持移植耐受性的关键因素。我们之前证明，在体外共培养系统中，体外分离的Tol-DCs可促进Treg的产生，反之亦然。在此，我们证明了这种免疫调节反馈环在体内的存在。用LF 15-0195处理体外生成的Tol-DC表现出未成熟DC的特征，且MHC II类分子、CD86和CD40表达水平较低。这些Tol-DCs能够增加心脏同种异体移植受者中CD4(+)CD25(+)CTLA4(+)和FoxP3(+) Treg细胞的数量及活性。另一方面，Tol-DCs具有在体外产生Treg细胞的能力。这些体外产生的Treg细胞的过继转移导致体内Tol-DC增加，表明在体内Tol-DC和Treg之间存在免疫调节反馈环。此外，给予体外产生的Tol-DCs或Treg细胞可预防同种异体移植的排斥反应。Tol-DC和Treg的联合给药协同促进同种异体移植心脏存活的疗效。本研究突出了使用体外产生的Tol-DCs和Treg预防同种异体移植排斥反应的治疗潜力。
