Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model
Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model
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DOI：
10.1038/sj.gt.3303051
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发表时间：
2008-02-01
期刊：
影响因子：
5.1
通讯作者：
Yasukawa, M.
中科院分区：
文献类型：
--
作者：
Hasegawa, H.;Inoue, A.;Yasukawa, M.
CD 4（+）CD 25（+）调节性T细胞的连续转移已被证明在实验性移植物抗宿主病（GVHD）模型中具有治疗效果。趋化因子在GVHD中同种异体反应性供体T细胞向靶器官的募集中起重要作用。在这项研究中，我们研究了通过转染趋化因子受体靶向递送CD 4（+）CD 25（+）调节性T细胞对减少急性GVHD期间器官损伤的有效性。在GVHD诱导的受体小鼠的肝、肺和肠中观察到Th 1相关趋化因子（CXCL 9、CXCL 10和CXCL 11）及其受体CXCR 3的高水平表达。与接受了CD 4（+）CD 25（+）Foxp 3（+）T细胞（Treg细胞）或天然存在的CD 4（+）CD 25（+）调节性T细胞的受体小鼠相比，接受了CD 4（+）CD 25（+）Foxp 3（+）CXCR 3转染的T细胞（CXCR 3-Treg细胞）的受体小鼠显示出肝脏、肺和肠中GVHD变化的显著改善。这是由于CXCR 3-Treg细胞的迁移更明显，并且在Th 1相关趋化因子表达器官中定位时间更长，从而产生更强的抑制活性。我们成功地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。该方法可能为急性GVHD的器官损害提供一种新的治疗途径。
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.