Blood Engineering Laboratory, Shanghai Blood Center, Shanghai, China; Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
Scand J Immunol. 2013 Dec;78(6):486-96. doi: 10.1111/sji.12113.
Tolerogenic dendritic cells (tDCs) potently induce and maintain tolerance based on their distinct characteristics compared with conventional DCs. Recent reports show that donor or host tDCs promote allograft survival in mice. In this study, the efficacy of third-party tDCs in the prevention of acute graft-versus-host disease (aGVHD) was evaluated. In vitro, tDCs derived from the bone marrow (BM) of D1 mice were induced by GM-CSF, IL-10 and TGF-β1. The phenotypes, expression of cytokines and suppression of tDCs were analysed. In vivo, the effects of adoptive transfer of third-party-tDCs were evaluated in an MHC-mismatched aGVHD mouse model. Survival, body weight, GVHD scoring, histopathological specimens and serum cytokines were analysed in tDC-treated mice and untreated controls. Tolerogenic DCs had low expression of MHC and co-stimulatory molecules, expressed high levels of 'immunosuppressive' cytokines and suppressed allo-CD4(+) T cell proliferation. In the B6→D2 mouse model, all aGVHD mice died within 18 days. Fortunately, third-party tDCs transferred at low doses (10(4)) effectively prolonged survival after allo-BMT. Furthermore, in the mice treated with 10(4) tDCs, serum levels of IL-10/TGF-β were significantly higher and the percentage of Foxp3(+) cells continually increased compared with the mice treated with other doses of tDCs. Third-party tDCs play a crucial role in reducing the severity of aGVHD by modulating the secretion of various cytokines and expanding Foxp3(+) regulatory T cells, which suggests the possibility of using third-party tDCs for therapeutic applications. Furthermore, special attention should be paid to the optimal range of tDCs for preventing allograft rejection.
耐受性树突状细胞（tDC）具有独特的特征，能够有效地诱导和维持耐受性，与传统树突状细胞相比。最近的报告显示，供体或宿主 tDC 可促进小鼠同种异体移植物的存活。在这项研究中，评估了第三方 tDC 在预防急性移植物抗宿主病（aGVHD）中的疗效。在体外，通过 GM-CSF、IL-10 和 TGF-β1 从 D1 小鼠的骨髓（BM）中诱导产生 tDC。分析了其表型、细胞因子的表达和抑制作用。在体内，在 MHC 不匹配的 aGVHD 小鼠模型中评估了过继转移第三方 tDC 的效果。在 tDC 处理的小鼠和未处理的对照小鼠中分析了生存、体重、GVHD 评分、组织病理学标本和血清细胞因子。耐受性 DC 表达低水平的 MHC 和共刺激分子，表达高水平的“免疫抑制”细胞因子，并抑制同种异体 CD4+T 细胞的增殖。在 B6→D2 小鼠模型中，所有 aGVHD 小鼠均在 18 天内死亡。幸运的是，低剂量（10（4））的第三方 tDC 转移可有效延长同种异体 BMT 后的生存时间。此外，在接受 10（4）tDC 治疗的小鼠中，与接受其他剂量 tDC 治疗的小鼠相比，血清中 IL-10/TGF-β 的水平显著升高，Foxp3+细胞的比例持续增加。第三方 tDC 通过调节各种细胞因子的分泌和扩增 Foxp3+调节性 T 细胞在减轻 aGVHD 的严重程度方面起着至关重要的作用，这表明使用第三方 tDC 进行治疗应用的可能性。此外，应特别注意预防同种异体排斥反应的 tDC 最佳范围。
