Combining Autologous Dendritic Cell Therapy with CD3 Antibodies Promotes Regulatory T Cells and Permanent Islet Allograft Acceptance
Combining Autologous Dendritic Cell Therapy with CD3 Antibodies Promotes Regulatory T Cells and Permanent Islet Allograft Acceptance
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DOI：
10.4049/jimmunol.1401423
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发表时间：
2014-11-01
影响因子：
4.4
通讯作者：
You, Sylvaine
中科院分区：
文献类型：
--
作者：
Baas, Marije C.;Kuhn, Chantal;You, Sylvaine
细胞治疗和使用干扰T细胞效应功能的单克隆抗体是控制同种异体移植排斥反应的有希望的方法。在目前的研究中，我们研究了一种将自体耐受性树突状细胞与cd3特异性抗体短期治疗相结合的新方法。在移植前一天接受联合治疗的小鼠实现了胰岛移植的永久性接受，但在单独接受任何一种治疗的受体中均未实现。联合治疗诱导浸润同种异体移植物的T细胞显著减少，抗供体反应持续减少。重要的是，CD4(+)Foxp3（+）调节性T细胞似乎在移植物的长期接受中起关键作用。其频率在脾脏、引流淋巴结和移植胰岛中显著增加，并长期保持升高；它们表现出增强的供体特异性抑制功能；并且在移植时将其切除，使联合治疗的治疗效果失效。这些结果支持了自体树突状细胞和低剂量CD3抗体联合治疗方案的治疗潜力，这两种方案目前都处于临床开发阶段，并且协同作用以控制异体免疫反应，并有利于移植物在完全不匹配的情况下存活。
Cell therapy and the use of mAbs that interfere with T cell effector functions constitute promising approaches for the control of allograft rejection. In the current study, we investigated a novel approach combining administration of autologous tolerogenic dendritic cells with short-term treatment with CD3-specific Abs. Permanent acceptance of pancreatic islet allografts was achieved in mice treated with the combination therapy the day before transplantation but not in recipients treated with either therapy alone. The combination treatment induced a marked decrease in T cells infiltrating the allografts and a sustained reduction of antidonor responses. Importantly, CD4(+)Foxp3(+) regulatory T cells appeared to play a crucial role in the long-term graft acceptance. Their frequency increased significantly in the spleen, draining lymph nodes, and transplanted islets and remained elevated over the long term; they exhibited increased donor-specific suppressive functions; and their removal at the time of transplantation abrogated the therapeutic effect of the combined therapy. These results support the therapeutic potential of protocols combining autologous dendritic cells and low-dose CD3 Abs, both currently in clinical development, and that act in synergy to control allogeneic immune responses and favor graft survival in a full-mismatch situation.