T-CELL-MEDIATED HEPATITIS IN MICE INFECTED WITH LYMPHOCYTIC CHORIOMENINGITIS VIRUS - LIVER-CELL DESTRUCTION BY H-2 CLASS-I-RESTRICTED VIRUS-SPECIFIC CYTOTOXIC T-CELLS AS A PHYSIOLOGICAL CORRELATE OF THE CR-51 RELEASE ASSAY
T-CELL-MEDIATED HEPATITIS IN MICE INFECTED WITH LYMPHOCYTIC CHORIOMENINGITIS VIRUS - LIVER-CELL DESTRUCTION BY H-2 CLASS-I-RESTRICTED VIRUS-SPECIFIC CYTOTOXIC T-CELLS AS A PHYSIOLOGICAL CORRELATE OF THE CR-51 RELEASE ASSAY
复制标题
DOI：
10.1084/jem.164.4.1075
复制
发表时间：
1986-10-01
影响因子：
15.3
通讯作者：
ALTHAGE, A
中科院分区：
文献类型：
--
作者：
ZINKERNAGEL, RM;HAENSELER, E;ALTHAGE, A
用淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染小鼠，建立了免疫性T细胞介导的肝炎模型。肝炎的严重程度进行了监测组织学和酶丙氨酸氨基转移酶（ALT），天冬氨酸氨基转移酶（AST），谷氨酸脱氢酶（GLDH）和碱性磷酸酶（AP）的血清水平的变化的测定。组织学疾病表现的动力学、血清中肝酶水平的增加以及肝脏和脾脏中的细胞毒性T细胞活性都与以下几个参数相关并依赖于以下几个参数：（a）LCMV-分离株; LCMV-WE引起广泛性肝炎，LCMV-Armstrong几乎不引起肝炎;（B）病毒剂量。(C)感染途径;静脉或腹腔感染引起肝炎，而感染到脚垫没有。(d)小鼠宿主的一般遗传背景;在检测的品系中，Swiss小鼠和A品系小鼠比C57 BL或CBA小鼠更敏感; BALB/c和DBA/2小鼠最不敏感。(e)小鼠宿主的免疫活性程度; T细胞缺陷型nu/nu小鼠从未发生肝炎，而nu/+或+/+小鼠总是发生肝炎。B细胞耗尽抗IgM治疗的小鼠发生免疫介导的乙型肝炎，甚至比对照小鼠更广泛。(f)局部细胞毒性T细胞活性;在显性肝炎期间从肝脏分离的单核细胞比同等数量的脾细胞活性高2至5倍。将尼龙毛非粘附性抗Thy-1.2和抗Lyt-2加C敏感、抗L3 T4加C抗性淋巴细胞连续转移到预先感染LCMV-WE的辐射小鼠中，引起血清酶水平的快速时间和剂量依赖性线性增加。如果免疫细胞供体和受体小鼠共享I类抗原，则这种增加是由淋巴细胞的过继转移引起的，但当它们共享II类组织相容性抗原时则不是。这些酶的供体细胞剂量依赖性增加在用2 × 10 - 3转移后6-18小时首次可测量。108个细胞或3 ×106个细胞。通过过继转移1-2 × 10 - 6个细胞引起的时间依赖性增加是可能的。108个细胞在长达25-40 h的时间内呈严格线性。这些结果表明肝细胞死亡的单次打击动力学，并表明效应T细胞通过直接接触而不是通过可溶性毒性介质破坏受感染的肝细胞。结果可能代表了迄今为止已分析的体外51 Cr释放测定的最佳体内相关性，并强烈支持抗病毒细胞毒性T细胞在体内直接溶细胞的观点。这种LCMV-WE诱导的小鼠肝炎是由T细胞介导的受感染肝细胞破坏引起的免疫病理介导的疾病。总的来说，这种疾病与人类急性病毒性肝炎的许多方面相似，急性病毒性肝炎由B型肝炎病毒引起。
A model for immunologically T cell-mediated hepatitis was established in mice infected with lymphocytic choriomeningitis virus (LCMV). The severity of hepatitis was monitored histologically and by determination of changes in serum levels of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), and alkaline phoshatase (AP). Kinetics of histological disease manifestations, increases of liver enzyme levels in the serum, and cytotoxic T cell activities in livers and spleens all correlated and were dependent upon several parameters: (a) LCMV-isolate; LCMV-WE caused extensive hepatitis, LCMV-Armstrong virtually none, (b) Virus dose. (C) Route of infection; i.v. or i.p. infection caused hepatitis, whereas infection into the footpad did not. (d) The general genetic background of the murine host; of the strains tested, Swiss mice and A-strain mice were more susceptible than C57BL or CBA mice; BALB/c and DBA/2 mice were least susceptible. (e) The degree of immunocompetence of the murine host; T cell deficient nu/nu mice never developed hepatitis, whereas nu/+ or +/+ mice always did. B cell-depleted anti-IgM-treated mice developed immune-mediated hepatitis comparably or even more extensively than control mice. (f) Local cytotoxic T cell activity; mononuclear cells isolated from livers during the period of overt hepatitis were two to five times more active than equal numbers of spleen cells. Adoptive transfer of nylon wool-nonadherent anti-Thy-1.2 and anti-Lyt-2 plus C-sensitive, anti-L3T4 plus C-resistant lymphocytes into irradiated mice preinfected with LCMV-WE caused a rapid time- and dose-dependent linear increase of serum enzyme levels. This increase was caused by adoptive transfer of lymphocytes if immune cell donors and recipient mice shared class I, but not when they shared class II histocompatibility antigens. The donor cell dose-dependent increase of these enzymes was first measurable 6-18 h after transfer with 2 .times. 108 cells or 3 .times. 106 cells, respectively. The time-dependent increase caused by the adoptive transfer of 1-2 .times. 108 cells was strictly linear during a period of up to 25-40 h. These results indicate single-hit kinetics of liver cell death and suggest that effector T cells destroy infected liver cells via direct contact rather than via soluble toxic mediators. The results may represent the best in vivo correlate of the in vitro 51Cr-release assay that has been analyzed so far, and strongly support the view that antiviral cytotoxic T cells are directly cytolytic in vivo. This LCMV-WE-induced hepatitis in mice is an immunopathologically mediated disease caused by T cell-mediated destruction of infected liver cells. Overall, this disease parallels many aspects of acute viral hepatitis in humans, which is caused by hepatitis B virus.