Zhang Zheng, Kaptanoglu Levent, Tang Yueming, Ivancic David, Rao Sambasiva M, Luster Andrew, Barrett Terrence A, Fryer Jonathan
Department of Surgery, Division of Organ Transplantation, Northwesern University Medical School, Chicago, Illinois 60611, USA.
Gastroenterology. 2004 Mar;126(3):809-18. doi: 10.1053/j.gastro.2003.12.014.
BACKGROUND & AIMS: Chemokines mediate cell trafficking in inflammatory states such as allograft rejection. However, their role in small-bowel allograft rejection has not been defined. The aim of this study was to examine the roles of type 1 helper T-cell chemokines in small-bowel allograft rejection.
Mucosal histology, chemokine messenger RNA (real-time polymerase chain reaction), and cell isolates were examined in small-bowel allografts and isografts. Interferon-gamma-inducible protein-10/CXC chemokine receptor (CXCR) 3 interactions were specifically evaluated by using allografts from interferon-gamma-inducible protein-10(-/-) donors and adoptive transfer of CXCR3(-/-) T cells into recombination activating gene (RAG)-1(-/-) recipients of small-bowel allografts.
Type 1 helper T-cell cytokine (interferon-gamma) and chemokine (interferon-gamma-inducible protein-10, monokine induced by interferon-gamma, macrophage-inflammatory protein-1 alpha, and regulated on activation, normal T cells expressed and secreted) messenger RNA up-regulation was detected (real-time polymerase chain reaction) by postoperative day 3 in small-bowel allografts. Interferon-gamma-inducible protein-10(+/+) small-bowel allograft rejection was associated with a dramatic (>7-fold) increase in CXCR3(+) host T cells in the graft lamina propria. With interferon-gamma-inducible protein-10(-/-) small-bowel allografts, CXCR3(+) host T-cell infiltration of the graft lamina propria was markedly decreased and rejection was significantly delayed. Whereas adoptive transfer of wild-type B6 (CXCR3(+/+)) T cells into B6 (RAG-1(-/-)) recipients induced rapid rejection of CB6F1 small-bowel allografts, rejection was significantly delayed (29.2 +/- 8.7 days vs. 16.5 +/- 3.1 days; P < 0.01) in B6 (RAG-1(-/-)) mice reconstituted with T cells from B6 (CXCR3(-/-)) mice.
Recruitment of CXCR3(+) host T cells by donor derived interferon-gamma-inducible protein-10 may precipitate small-bowel allograft rejection. These data highlight the importance of type 1 helper T cell-related chemokines in promoting cell-mediated rejection responses in small-bowel allografts and suggest that interferon-gamma-inducible protein-10 is an attractive therapeutic target for humanized monoclonal antibody strategies.
趋化因子在诸如同种异体移植排斥等炎症状态下介导细胞迁移。然而，它们在小肠同种异体移植排斥中的作用尚未明确。本研究的目的是检测1型辅助性T细胞趋化因子在小肠同种异体移植排斥中的作用。
对小肠同种异体移植和同基因移植的黏膜组织学、趋化因子信使核糖核酸（实时聚合酶链反应）及细胞分离物进行检测。通过使用来自干扰素γ诱导蛋白10基因敲除（-/-）供体的同种异体移植以及将CXCR3基因敲除（-/-）T细胞过继转移至小肠同种异体移植的重组激活基因（RAG）-1基因敲除（-/-）受体中，特异性评估干扰素γ诱导蛋白10/CXC趋化因子受体（CXCR）3的相互作用。
在小肠同种异体移植术后第3天，通过实时聚合酶链反应检测到1型辅助性T细胞细胞因子（干扰素γ）和趋化因子（干扰素γ诱导蛋白10、干扰素γ诱导的单核因子即巨噬细胞炎性蛋白-1α、正常T细胞激活后表达和分泌的调节蛋白）信使核糖核酸上调。干扰素γ诱导蛋白10基因敲除（-/-）小肠同种异体移植排斥与移植黏膜固有层中CXCR3阳性宿主T细胞显著（>7倍）增加相关。对于干扰素γ诱导蛋白10基因敲除（-/-）小肠同种异体移植，移植黏膜固有层中CXCR3阳性宿主T细胞浸润明显减少，排斥显著延迟。虽然将野生型B6（CXCR3基因敲除（+/+））T细胞过继转移至B6（RAG-1基因敲除（-/-））受体可诱导CB6F1小肠同种异体移植快速排斥，但在用B6（CXCR3基因敲除（-/-））小鼠的T细胞重建的B6（RAG-1基因敲除（-/-））小鼠中，排斥显著延迟（29.2±8.7天对16.5±3.1天；P<0.01）。
供体来源的干扰素γ诱导蛋白10对CXCR3阳性宿主T细胞的募集可能促使小肠同种异体移植排斥。这些数据突出了1型辅助性T细胞相关趋化因子在促进小肠同种异体移植细胞介导的排斥反应中的重要性，并表明干扰素γ诱导蛋白10是人性化单克隆抗体策略的一个有吸引力的治疗靶点。
