MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs.
MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs.
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DOI：
10.1172/jci21087
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发表时间：
2004-04
期刊：
影响因子：
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通讯作者：
G. Sitia;M. Isogawa;M. Iannacone;I. Campbell;F. Chisari;L. Guidotti
中科院分区：
文献类型：
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作者：
G. Sitia;M. Isogawa;M. Iannacone;I. Campbell;F. Chisari;L. Guidotti
我们最近发现，当将B型肝炎病毒（HBV）特异性CTL注射到HBV转基因小鼠中时，抗原非特异性炎症细胞被招募到肝脏中，并且该过程放大了肝脏疾病的严重程度。我们还发现，CTL诱导的肝病的严重程度通过Gr-1（+）细胞（Gr-1是中性粒细胞高度表达的抗原）的耗竭而得到改善，其次，尽管趋化因子基因表达的强烈诱导，但Gr-1（-）细胞的耗竭消除了所有抗原非特异性Gr-1（-）单核细胞（NK和NKT细胞、T和B淋巴细胞、单核细胞、巨噬细胞、树突状细胞）的肝内募集。这些结果表明，除了趋化因子的表达，CTL诱导的功能是必要的单核细胞募集发生。我们现在报道，已知由Gr-1（+）细胞产生的MMPs在注射CTL的小鼠的肝脏中被快速诱导。MMP活性的抑制减少了抗原非特异性单核细胞的肝内募集和大部分参与肝脏疾病，而不影响抗原特异性CTL的迁移或抗病毒潜力。MMP活性的抑制与抗病毒作用的维持有关，但减少了组织损伤，这一概念可能对开发治疗慢性HBV感染的免疫方法具有重要意义。
We recently showed that antigen-nonspecific inflammatory cells are recruited into the liver when hepatitis B virus (HBV)-specific CTLs are injected into HBV transgenic mice, and that this process amplifies the severity of liver disease. We also showed that the severity of CTL-induced liver disease is ameliorated by the depletion of Gr-1(+) cells (Gr-1 is an antigen highly expressed by neutrophils), which, secondarily, abolishes the intrahepatic recruitment of all antigen-nonspecific Gr-1(-) mononuclear cells (NK and NKT cells, T and B lymphocytes, monocytes, macrophages, dendritic cells) despite the strong induction of chemokine gene expression. Those results suggested that in addition to chemokine expression, CTL-induced functions are necessary for mononuclear cell recruitment to occur. We now report that MMPs known to be produced by Gr-1(+) cells are rapidly induced in the livers of CTL-injected mice. The inhibition of MMP activity reduced the intrahepatic recruitment of antigen-nonspecific mononuclear cells and much of the attending liver disease without affecting the migration or antiviral potential of antigen-specific CTLs. The notion that the inhibition of MMP activity is associated with maintenance of antiviral effects but diminished tissue damage may be significant for the development of immunotherapeutic approaches for the treatment of chronic HBV infection.