Zhai Yuan, Shen Xiu-da, Hancock Wayne W, Gao Feng, Qiao Bo, Lassman Charles, Belperio John A, Strieter Robert M, Busuttil Ronald W, Kupiec-Weglinski Jerzy W
Department of Surgery, Division of Liver and Pancreas Transplantation, The Dumont-University of California Los Angeles (UCLA) Transplant Center, David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
J Immunol. 2006 May 15;176(10):6313-22. doi: 10.4049/jimmunol.176.10.6313.
Ischemia-reperfusion injury (IRI), an innate immune-dominated inflammatory response, develops in the absence of exogenous Ags. The recently highlighted role of T cells in IRI raises a question as to how T lymphocytes interact with the innate immune system and function with no Ag stimulation. This study dissected the mechanism of innate immune-induced T cell recruitment and activation in rat syngeneic orthotopic liver transplantation (OLT) model. Liver IRI was induced after cold storage (24-36 h) at 4 degrees C in University of Wisconsin solution. Gene products contributing to IRI were identified by cDNA microarray at 4-h posttransplant. IRI triggered increased intrahepatic expression of CXCL10, along with CXCL9 and 11. The significance of CXCR3 ligand induction was documented by the ability of neutralizing anti-CXCR3 Ab treatment to ameliorate hepatocellular damage and improve 14-day survival of 30-h cold-stored OLTs (95 vs 40% in controls; p < 0.01). Immunohistology analysis confirmed reduced CXCR3+ and CD4+ T cell infiltration in OLTs after treatment. Interestingly, anti-CXCR3 Ab did not suppress innate immune activation in the liver, as evidenced by increased levels of IL-1beta, IL-6, inducible NO synthase, and multiple neutrophil/monokine-targeted chemokine programs. In conclusion, this study demonstrates a novel mechanism of T cell recruitment and function in the absence of exogenous Ag stimulation. By documenting that the execution of innate immune function requires CXCR3+CD4+ T cells, it highlights the critical role of CXCR3 chemokine biology for the continuum of innate to adaptive immunity in the pathophysiology of liver IRI.
缺血再灌注损伤（IRI）是一种由先天免疫主导的炎症反应，在没有外源性抗原的情况下发生。最近T细胞在IRI中所凸显的作用引发了一个问题，即T淋巴细胞如何在没有抗原刺激的情况下与先天免疫系统相互作用并发挥功能。本研究剖析了大鼠同基因原位肝移植（OLT）模型中先天免疫诱导的T细胞募集和激活机制。在4℃下于威斯康星大学溶液中冷保存（24 - 36小时）后诱导肝脏IRI。通过移植后4小时的cDNA微阵列鉴定出促成IRI的基因产物。IRI引发肝内CXCL10以及CXCL9和11的表达增加。中和抗CXCR3抗体治疗能够改善肝细胞损伤并提高30小时冷保存OLT的14天生存率（95%对对照组的40%；p < 0.01），这证明了CXCR3配体诱导的重要性。免疫组织学分析证实治疗后OLT中CXCR3 +和CD4 + T细胞浸润减少。有趣的是，抗CXCR3抗体并未抑制肝脏中的先天免疫激活，白细胞介素 - 1β、白细胞介素 - 6、诱导型一氧化氮合酶以及多个针对中性粒细胞/单核因子的趋化因子程序水平升高证明了这一点。总之，本研究证明了在没有外源性抗原刺激的情况下T细胞募集和功能的新机制。通过证明先天免疫功能的执行需要CXCR3 + CD4 + T细胞，突出了CXCR3趋化因子生物学在肝脏IRI病理生理学中从先天免疫到适应性免疫连续过程中的关键作用。
