Ikeda Tokunori, Hirata Shinya, Takamatsu Koutaro, Haruta Miwa, Tsukamoto Hirotake, Ito Takaaki, Uchino Makoto, Ando Yukio, Nagafuchi Seiho, Nishimura Yasuharu, Senju Satoru
Department of Immunogenetics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Japan Science and Technology Agency, CREST, Kawaguchi, Japan.
Department of Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
PLoS One. 2014 Dec 18;9(12):e115198. doi: 10.1371/journal.pone.0115198. eCollection 2014.
We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases.
我们在此使用两种自身免疫性疾病模型，即非肥胖糖尿病（NOD）小鼠和实验性自身免疫性脑脊髓炎（EAE），来证明胚胎干细胞来源的树突状细胞（ES-DCs）的免疫调节作用。用ES-DCs治疗糖尿病前期的NOD小鼠，在超过40周的观察期内几乎完全抑制了糖尿病的发展。ES-DCs预防糖尿病的同时，胰岛炎显著减轻，脾脏中Th1和Th17细胞数量减少。ES-DCs治疗也抑制了EAE的发展，即使在临床症状出现后给予ES-DCs也能获得治疗效果。用ES-DCs治疗EAE诱导的小鼠减少了炎症细胞向脊髓的浸润，并抑制了T细胞对髓鞘抗原的反应。重要的是，ES-DCs治疗不影响T细胞对外源抗原的反应。作为浸润性Th1细胞数量减少的潜在机制，我们观察到ES-DCs抑制了Th1细胞的分化和增殖。此外，ES-DCs显著抑制了Th1细胞上VLA-4α的表达。考虑到人类诱导多能干细胞相关技术的最新进展，这些结果表明多能干细胞来源的树突状细胞作为T细胞介导的自身免疫性疾病的一种治疗方法具有临床应用前景。
