Hasegawa H, Inoue A, Kohno M, Lei J, Miyazaki T, Yoshie O, Nose M, Yasukawa M
Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
Gene Ther. 2008 Feb;15(3):171-82. doi: 10.1038/sj.gt.3303051. Epub 2007 Nov 8.
Adoptive transfer of CD4+CD25+ regulatory T cells has been shown to have therapeutic effects in experimental graft-vs-host disease (GVHD) models. Chemokines play an important role in the recruitment of alloreactive donor T cells into target organs during GVHD. In this study, we investigated the effectiveness of targeted delivery of CD4+CD25+ regulatory T cells via a transfected chemokine receptor on reduction of organ damage during acute GVHD. High levels of expression of Th1-associated chemokines (CXCL9, CXCL10 and CXCL11) and their receptor CXCR3 were observed in the liver, lung and intestine of GVHD-induced recipient mice. Recipient mice that had undergone transfer of CD4+CD25+Foxp3+ CXCR3-transfected T cells (CXCR3-Treg cells) showed significant amelioration of GVHD changes in the liver, lung and intestine in comparison with recipient mice that had received CD4+CD25+Foxp3+ T cells (Treg cells) or naturally occurring CD4+CD25+ regulatory T cells. This was due to more pronounced migration of CXCR3-Treg cells and their localization for a longer time in Th1-associated chemokine-expressing organs, resulting in stronger suppressive activity. We succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.
在实验性移植物抗宿主病（GVHD）模型中，已证明过继转移CD4+CD25+调节性T细胞具有治疗作用。趋化因子在GVHD期间将同种异体反应性供体T细胞募集到靶器官中发挥重要作用。在本研究中，我们调查了通过转染的趋化因子受体靶向递送CD4+CD25+调节性T细胞对减轻急性GVHD期间器官损伤的有效性。在GVHD诱导的受体小鼠的肝脏、肺和肠道中观察到Th1相关趋化因子（CXCL9、CXCL10和CXCL11）及其受体CXCR3的高水平表达。与接受CD4+CD25+Foxp3+T细胞（Treg细胞）或天然存在的CD4+CD25+调节性T细胞的受体小鼠相比，接受CD4+CD25+Foxp3+CXCR3转染T细胞（CXCR3-Treg细胞）的受体小鼠的肝脏、肺和肠道中的GVHD变化得到显著改善。这是由于CXCR3-Treg细胞更明显的迁移及其在表达Th1相关趋化因子的器官中更长时间的定位，从而导致更强的抑制活性。我们成功制备了表达趋化因子受体的Treg细胞，并证明了它们在靶器官中积累后改善疾病进展的能力。这种方法可能为急性GVHD中的器官损伤提供一种新的治疗方法。
