Role of CXCR3-induced donor T-cell migration in acute GVHD
Role of CXCR3-induced donor T-cell migration in acute GVHD
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DOI：
10.1016/s0301-472x(03)00198-x
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发表时间：
2003-10-01
影响因子：
2.6
通讯作者：
Ferrara, JLM
中科院分区：
文献类型：
--
作者：
Duffner, U;Lu, B;Ferrara, JLM
Objective.趋化因子受体CXCR 3在效应T细胞的迁移中具有重要作用。为了研究CXCR 3对供体细胞在急性移植物抗宿主病（GVHD）中的作用，我们使用了一种定义明确的实验性骨髓移植（BMT）模型，其中急性GVHD由供体CD 8（+）T细胞介导对抗次要组织相容性抗原。方法.致死性照射的C3H.SW受体从野生型B6或CXCR 3（-/-）B6供体移植。通过FACS分析受体脾和小肠中的供体T细胞扩增。通过细胞因子分泌分析供体T细胞功能。通过肠道和肝脏的组织病理学分析、GVHD临床评分和BMT后的存活率来评估急性GVHD的严重程度。与供体野生型T细胞相比，在第+7天和第+14天在脾脏中发现供体CD 8（+）CXCR 3（-/-）T细胞的数量显著更高。相比之下，来自CXCR 3（-/-）供体的BMT受体小肠中的CD 8 + T细胞数量比野生型供体低7倍。两组间INF-γ和TNF-α的全身浓度相当。接受CXCR 3（-/-）供体T细胞的动物表现出胃肠道和肝脏损伤的减轻，并且与野生型供体细胞的接受者相比，BMT后的存活率提高（43% vs 0%，p < 0.001）。供体CD 8（+）T细胞向GVHD靶器官（如肠）的迁移依赖于CXCR 3的表达，并显著促进GVHD损伤和总体死亡率。(C)2003年国际实验血液学学会。爱思唯尔公司出版
Objective. The chemokine receptor CXCR3 has an important role in the migration of effector T cells. To investigate the role of CXCR3 on donor cells in acute graft vs host disease (GVHD) we used a well-defined experimental bone marrow transplantation (BMT) model where acute GVHD is mediated by donor CD8(+) T cells against minor histocompatibility antigens. Methods. Lethally irradiated C3H.SW recipients were transplanted from either wild-type B6 or CXCR3(-/-) B6 donors. Donor T-cell expansion was analyzed in the spleen and small intestine of recipients by FACS. Donor T-cell function was analyzed by cytokine secretion. The severity of acute GVHD was assessed by histopathological analysis of intestine and liver, GVHD clinical scores, and survival after BMT.Results. Significantly higher numbers of donor CD8(+) CXCR3(-/-) T cells were found in the spleen on days +7 and +14 compared to donor wild-type T cells. By contrast, the number of CD8+ T cells in the small bowel of BMT recipients from CXCR3(-/-) donors was sevenfold lower than from wild-type donors. Systemic concentrations of INF-gamma and TNF-alpha were equivalent between groups. Animals that received CXCR3(-/-) donor T cells demonstrated diminished GI tract and liver damage and showed improved survival after BMT compared to recipients of wild-type donor cells (43% vs 0%, p < 0.001).Conclusion. The migration of donor CD8(+) T cells to GVHD target organs such as the intestine depends on the expression of CXCR3 and contributes significantly to GVHD damage and overall mortality. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc.