Suzuki K, Narita T, Yui R, Asakura H, Fujiwara M
Animal Center for Biomedical Research, Faculty of Medicine, University of Tokyo, Japan.
Lab Invest. 1994 May;70(5):609-19.
We previously reported that primary biliary cirrhosis (PBC)-like hepatic lesions were induced in (bm12xB6)F1 mice undergoing graft-versus-host reaction with major histocompatibility complex class II disparity. In this paper, we report on a new experimental system, enabling establishment of more progressed stages of PBC-like lesions and clarification of the role of CD8+ cells in the development of the lesions.
Recipient (bm12xbm1)F1 mice were thymectomized and administered anti-Lyt-2 monoclonal antibodies intraperitoneally to deplete host CD8+ cells as completely as possible. The treatment was necessary to induce autoimmune hepatic lesions in this type of F1 mice. Recipients were divided into five groups: group 1 received B6 CD4+ cells on day 0 and 2 weeks later, B6 CD8+ cells; group 2, only B6 CD4+ cells on day 0; group 3, only B6 CD8+ cells on day 14; group 4, B6 CD4+ on day 0 plus F1 CD8+ cells 14 days later. Cell transfer was not done in group 5. All of the mice were killed on day 28 for examination by light and electron microscopy and also by immunohistochemistry.
PBC-like hepatic lesions without tissue destruction were induced in the mice of group 2, as was previously reported. In addition to similar lesions to group 2, destruction of hepatocytes and bile duct epithelia was induced in the mice of group 1. Weak lymphocytic infiltration and periductal concentric fibrosis were observed in the mice of group 3. PBC-like hepatic lesions without tissue destruction were induced in mice of group 4 as were those of group 2. However, the cellular infiltration was much weaker.
For the animal model of PBC, we have devised a new experimental system in which the role of donor or host type CD8+ cells is assessable. Tissue-destructive lesions were induced only in mice that received donor CD4+ cells followed by CD8+ cells. The PBC-like lesions were suppressed by host type CD8+ cells. These results suggest that destructive hepatic lesions of PBC might progress through CD8+ cells in cooperation with CD4+ cells, and that host type CD8+ cells could act as "regulatory" T cells for the progression of the lesions.
我们之前报道过，在经历主要组织相容性复合体II类不相容的移植物抗宿主反应的（bm12xB6）F1小鼠中可诱导出原发性胆汁性肝硬化（PBC）样肝损伤。在本文中，我们报道了一种新的实验系统，该系统能够建立更进展阶段的PBC样损伤，并阐明CD8 +细胞在损伤发展中的作用。
对受体（bm12xbm1）F1小鼠进行胸腺切除，并腹腔注射抗Lyt - 2单克隆抗体，以尽可能完全地清除宿主CD8 +细胞。对于诱导此类F1小鼠的自身免疫性肝损伤而言，该处理是必要的。将受体分为五组：第1组在第0天接受B6 CD4 +细胞，2周后接受B6 CD8 +细胞；第2组在第0天仅接受B6 CD4 +细胞；第3组在第14天仅接受B6 CD8 +细胞；第4组在第0天接受B6 CD4 +细胞，14天后接受F1 CD8 +细胞。第5组不进行细胞移植。所有小鼠在第28天处死，用于光镜、电镜检查及免疫组化分析。
如先前报道，第2组小鼠诱导出了无组织破坏的PBC样肝损伤。除了与第2组相似的损伤外，第1组小鼠还诱导出了肝细胞和胆管上皮的破坏。第3组小鼠观察到轻度淋巴细胞浸润和导管周围同心性纤维化。第4组小鼠诱导出了与第2组小鼠相似的无组织破坏的PBC样肝损伤。然而，细胞浸润要弱得多。
对于PBC动物模型，我们设计了一种新的实验系统，在该系统中可以评估供体或宿主类型CD8 +细胞的作用。仅在接受供体CD4 +细胞后再接受CD8 +细胞的小鼠中诱导出了组织破坏性损伤。PBC样损伤受到宿主类型CD8 +细胞的抑制。这些结果表明，PBC的破坏性肝损伤可能通过CD8 +细胞与CD4 +细胞协同作用而进展，并且宿主类型CD8 +细胞可能作为损伤进展的“调节性”T细胞发挥作用。
