Regulation of the activation status in T effector cells in blood and livers of patients with autoimmune hepatitis (AIH)

自身免疫性肝炎（AIH）患者血液和肝脏中 T 效应细胞激活状态的调节

• 批准号: 315778787
• 负责人: Dr. Marcial Sebode
• 金额: --
• 依托单位: I. Medizinische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315778787?language=en
• 关键词: Regulation; activation; status; effector; cells

Autoimmune hepatitis (AIH) is a chronic inflammatory, progressive liver disease. Fatal liver damage can only be prevented by lifelong, non-selective immunosuppression which is associated with serious side effects. The pathogenesis of AIH is unknown, however, it is assumed that liver damage is promoted by proinflammatory T effector cells. It remains contentious why and how proinflammatory T effector cells are able to defy immune regulation. Our preliminary studies have shown a significantly lower expression of the regulating E3-ligase Cbl-b in CD4 positive T cells of AIH patients compared to healthy controls. These results might explain the impaired immune homeostasis of AIH patients and provide novel selective treatment options. This study aims at analysing the regulation of the activation status in T effector cells from patients with AIH. Our hypothesis is that AIH is associated with a dysbalanced regulation of T cell activation. To test this hypothesis, we will analyse relevant E3-ligases, such as Cbl-b, as well as co-stimulatory and co-inhibitory molecules, and correlate these with the proinflammatory activity of T effector cells. Moreover, we plan to assess the influence of anti-TNFalpha treatment on the activation status of T effector cells. The obtained findings will be validated for specific T cell responses to AIH-related antigen. The results of the project should help to clarify the pathogenesis of AIH and provide novel, more specific treatment options avoiding the side-effects of the standard treatment.

自身免疫性肝炎（AIH）是一种慢性炎症性进行性肝病。致命的肝损伤只能通过终生的非选择性免疫抑制来预防，而免疫抑制会带来严重的副作用。AIH的发病机制尚不清楚，然而，假设肝损伤是由促炎T效应细胞促进的。促炎T效应细胞为什么以及如何能够无视免疫调节仍然存在争议。我们的初步研究表明，AIH患者CD4阳性T细胞中调节e3连接酶Cbl-b的表达明显低于健康对照组。这些结果可能解释AIH患者免疫稳态受损的原因，并提供新的选择性治疗方案。本研究旨在分析AIH患者T效应细胞激活状态的调控。我们的假设是AIH与T细胞激活的失调调节有关。为了验证这一假设，我们将分析相关的e3连接酶，如cl -b，以及共刺激和共抑制分子，并将它们与T效应细胞的促炎活性联系起来。此外，我们计划评估抗tnfalpha治疗对T效应细胞激活状态的影响。获得的结果将验证特异性T细胞对aih相关抗原的反应。该项目的结果将有助于阐明AIH的发病机制，并提供新的、更具体的治疗方案，避免标准治疗的副作用。

项目成果

THU-005-Activation regulators of peripheral blood and intrahepatic T effector cells in autoimmune hepatitis

THU-005-自身免疫性肝炎中外周血和肝内T效应细胞的激活调节因子

• DOI: 10.1016/s0618-8278(19)30289-0
• 期刊: Journal of Hepatology
• 影响因子: 25.7
• 作者: P. Filpe;S. Weidemann;C. Weiler-Normann;A. W. Lohse;C. Schramm;J. Herkel;M. Sebode
• 通讯作者: M. Sebode

Aberrant expression of activation regulators CBL-B, CTLA-4 and PD-1 in intrahepatic Teff cells in autoimmune hepatitis

自身免疫性肝炎肝内Teff细胞激活调节因子CBL-B、CTLA-4和PD-1的异常表达

• DOI: 10.1055/s-0039-3402250
• 发表时间: 2020
• 期刊: Zeitschrift für Gastroenterologie
• 作者: P Filpe;A Wöstemeier;E De Martin;S Weidemann;R Taubert;C Schramm;AW Lohse;J Herkel;M Sebode
• 通讯作者: M Sebode