Program in Immunology, Howard Hughes Medical Institute, and Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Immunol. 2013 Jan 15;190(2):526-30. doi: 10.4049/jimmunol.1202621. Epub 2012 Dec 17.
Inflammation of the normally tolerant liver microenvironment precedes the development of chronic liver disease. Study of the pathogenesis of autoimmune liver diseases, such as autoimmune hepatitis (AIH), has been hampered by a lack of autochthonous chronic animal models. Through our studies of T cell costimulation, we generated transgenic mice expressing a ligand specific for the CD28 receptor, which normally shares ligands with the related inhibitory receptor CTLA-4. The mice spontaneously develop chronic inflammatory liver disease with several pathologies found in AIH, including elevated serum aminotransferases in the context of normal alkaline phosphatase and bilirubin levels, lymphocytic inflammation, focal necrosis, oval cell hyperplasia, and fibrosis. The prevalence of IFN-γ-producing CD8(+) T cells in the livers of transgenic mice suggests a role for autoimmune cytotoxicity in the chronic disease state. The CD28 ligand-specific transgenic mice will facilitate evaluation of CD8(+) T cell function in liver disease pathologies found in AIH.
正常耐受的肝微环境的炎症先于慢性肝病的发展。对自身免疫性肝病（如自身免疫性肝炎（AIH））发病机制的研究因缺乏自发发生慢性的动物模型而受到阻碍。通过我们对 T 细胞共刺激的研究，我们生成了表达一种配体的转基因小鼠，该配体特异性针对 CD28 受体，而 CD28 受体通常与相关的抑制性受体 CTLA-4 共享配体。这些小鼠自发地发展为慢性炎症性肝病，并具有几种在 AIH 中发现的病理学特征，包括在碱性磷酸酶和胆红素水平正常的情况下血清转氨酶升高、淋巴细胞炎症、局灶性坏死、卵圆细胞增生和纤维化。在转基因小鼠肝脏中 IFN-γ 产生的 CD8+T 细胞的流行表明自身免疫性细胞毒性在慢性疾病状态中起作用。CD28 配体特异性转基因小鼠将有助于评估 AIH 中发现的肝脏疾病病理学中 CD8+T 细胞的功能。
