Experimental hepatitis and role of cytokines.
Experimental hepatitis and role of cytokines.
复制标题
DOI：
--
复制
发表时间：
1997-04
影响因子：
1.5
通讯作者：
G. Tiegs
中科院分区：
文献类型：
--
作者：
G. Tiegs
激活的T淋巴细胞似乎是慢性活动性肝炎和自身免疫性肝病中肝脏损伤的原因。我们描述了三种实验性小鼠T细胞依赖性肝损伤模型。在T细胞激活抗cd3单克隆抗体（mAb）或超抗原葡萄球菌肠毒素B （SEB）刺激下，d -半乳糖胺（GalN）致敏小鼠发生严重的肝损伤，其特征是核小体间DNA断裂以及肝细胞凋亡的组织特征，两者都在血浆转氨酶增加之前。给未致敏的小鼠注射T细胞有丝分裂原concanavin A （Con A）也会导致肝细胞凋亡和随之而来的坏死。抗cd3单抗以及SEB或Con A诱导全身肿瘤坏死因子（TNF）、干扰素γ (IFN γ)和各种其他细胞因子的释放。TNF被动免疫或环孢素A、fk506或地塞米松等免疫抑制药物预处理可保护小鼠免受肝损伤。T淋巴细胞在体内被鉴定为Con A的效应细胞i)通过证明胸腺炎裸鼠对Con A的抗性和ii)通过从对照小鼠转移淋巴细胞恢复裸鼠的敏感性。此外，CD4+ T细胞的抗体依赖性耗竭完全保护了Con A，而CD8+ T细胞的耗竭未能防止肝损伤。这些结果表明，细胞因子是在辅助性T细胞激活后释放的，而不是细胞毒性T细胞介导的肝损伤。我们最近发现IFN γ也是Con - a诱导的肝损伤的关键介质。总之，这些炎症性肝损伤的T细胞依赖模型允许研究与T细胞活化和浸润相关的肝脏疾病的基本原理，以及用于开发肝保护药物的体内药理研究。
Activated T lymphocytes appear to be responsible for liver damage in chronic active hepatitis and autoimmune liver disease. We described three experimental mouse models of T cell dependent liver injury. D-galactosamine (GalN)-sensitized mice challenged with either T cell activating anti-CD3 monoclonal antibody (mAb) or with the superantigen staphylococcal enterotoxin B (SEB) developed severe liver injury characterized by internucleosomal DNA fragmentation as well as by histological hallmarks of hepatocyte apoptosis, both preceding the increase of plasma transaminases. Administration of the T cell mitogen concanavalin A (Con A) to unsensitized mice also resulted in hepatic apoptosis and the ensuing necrosis. Anti-CD3 mAb as well as SEB or Con A induced the release of systemic tumor necrosis factor (TNF), interferon gamma (IFN gamma), and various other cytokines. Passive immunization against TNF or pretreatment with immunosuppressive drugs such as cyclosporin A, FK 506 or dexamethasone protected mice from liver injury. T lymphocytes were identified as effector cells of Con A in vivo i) by proof of resistance of athyrnic nude mice against Con A and ii) by restoration of susceptibility in nude by lymphocyte transfer from control mice. Moreover, antibody-dependent depletion of CD4+ T cells fully protected against Con A, whereas depletion of CD8+ T cells failed to prevent liver injury. These results indicated that cytokines released following T helper cell activation rather than cytotoxic T cells mediated liver injury. We recently found that IFN gamma is also a critical mediator of Con A-induced hepatic damage. In conclusion, these T cell-dependent models of inflammatory liver injury allow the investigation of basic principles of hepatic disorders associated with T cell activation and infiltration as well as pharmacological in vivo studies for the development of hepatoprotective drugs.