Ueno Y, Phillips J O, Ludwig J, Lichtman S N, LaRusso N F
Center for Basic Research in Digestive Diseases, Mayo Medical School, Clinic and Foundation, Rochester, MN 55905, USA.
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):216-20. doi: 10.1073/pnas.93.1.216.
The cholangiopathies are a group of hepatobiliary diseases in which intrahepatic bile duct epithelial cells, or cholangiocytes, are the target for a variety of destructive processes, including immune-mediated damage. We tested the hypothesis that cholangitis could be induced in rodents by immunization with highly purified cholangiocytes. Inbred Wistar rats were immunized with purified hyperplastic cholangiocytes isolated after bile duct ligation from either syngeneic Wistar or allogeneic Fischer 344 rats; control rats were immunized with bovine serum albumin (BSA) or hepatocytes. After immunization with cholangiocytes, recipient animals developed histologic evidence of nonsuppurative cholangitis without inflammation in other organs; groups immunized with BSA or hepatocytes showed no cholangitis. Immunohistochemical studies revealed that portal tract infiltrates around bile ducts consisted of CD3-positive lymphocytes, some of which expressed major histocompatibility complex class II antigen; B cells and exogenous monocytes/macrophages were essentially absent. Transfer of unfractionated ConA-stimulated spleen cells from cholangiocyte-immunized (but not BSA-immunized) rats into recipients also caused nonsuppurative cholangitis. Moreover, these splenocytes from cholangiocyte-immunized (but not BSA-immunized) rats were cytotoxic in vitro for cultured rodent cholangiocytes; no cytotoxicity was observed against a rat hepatocyte cell line. Also, a specific antibody response in sera of cholangiocyte-immunized rats was demonstrated by immunoblots against cholangiocyte proteins. Finally, cholangiograms in cholangiocyte-immunized rats showed distortion and tortuosity of the entire intrahepatic biliary ductal system. This unique rodent model of experimental cholangitis demonstrates the importance of immune mechanisms in the pathogenesis of cholangitis and will prove useful in exploring the mechanisms by which the immune system targets and damages cholangiocytes.
胆管疾病是一组肝胆疾病，其中肝内胆管上皮细胞，即胆管细胞，是包括免疫介导损伤在内的各种破坏过程的靶标。我们检验了通过用高度纯化的胆管细胞免疫来在啮齿动物中诱导胆管炎的假说。将同基因Wistar大鼠或异基因Fischer 344大鼠胆管结扎后分离得到的纯化增生胆管细胞免疫近交系Wistar大鼠；对照大鼠用牛血清白蛋白（BSA）或肝细胞免疫。用胆管细胞免疫后，受体动物出现非化脓性胆管炎的组织学证据，而其他器官无炎症；用BSA或肝细胞免疫的组未出现胆管炎。免疫组织化学研究显示，胆管周围的门管浸润由CD3阳性淋巴细胞组成，其中一些表达主要组织相容性复合体II类抗原；基本不存在B细胞和外源性单核细胞/巨噬细胞。将来自胆管细胞免疫（而非BSA免疫）大鼠的未分级伴刀豆球蛋白A刺激的脾细胞转移到受体中也会引起非化脓性胆管炎。此外，来自胆管细胞免疫（而非BSA免疫）大鼠的这些脾细胞在体外对培养的啮齿动物胆管细胞具有细胞毒性；对大鼠肝细胞系未观察到细胞毒性。而且，通过针对胆管细胞蛋白的免疫印迹证明了胆管细胞免疫大鼠血清中的特异性抗体反应。最后，胆管细胞免疫大鼠的胆管造影显示整个肝内胆管系统扭曲和迂曲。这种独特的实验性胆管炎啮齿动物模型证明了免疫机制在胆管炎发病机制中的重要性，并将有助于探索免疫系统靶向和损伤胆管细胞的机制。
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