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Translational studies of the induction and functional role of Th2 polarized CD4+ T-cells in chronic liver damage and hepatic fibrogenesis

Th2 极化 CD4 T 细胞在慢性肝损伤和肝纤维形成中的诱导和功能作用的转化研究

基本信息

批准号：
313701256
负责人：
Dr. Henning Zimmermann
金额：
--
依托单位：
Klinik für Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin (Med. Klinik III)
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/313701256?language=en
关键词：
Translational studies induction functional role

项目摘要

Immune mechanisms are critically involved in liver inflammation and subsequent fibrogenesis and cirrhosis. Extensive research has unravelled that the infiltration and local activation of cellular components of the innate as well as the adaptive immune system are prerequisites for the initiation of profibrotic cascades. This is clinical relevant because the therapeutical options are still limited despite the urgent need for effective antifibrotic treatments. Studies in other organs such as the lung have shown that the Th2 polarization of CD4+ T-helper cells is directly linked to remodeling proceses. During organ fibrosis prototypical Th2 cytokines including IL-4 and IL-13 activate mesenchymal cells which synthesize abundant amounts of extracellular matrix compounds. As a consequence, parenchyma is gradually replaced by connective tissue eventually leading to organ failure. Furthermore, Th2-cells can induce alternatively activated M2 macrophages ,that also display profibrotic properties, through cell-cell interaction, whereby organ fibrosis is further amplified. However, it is still widely unknown, whether the Th2-fibrosis paradigm also applies to the liver. There is robust evidence that Th2-poalrized CD4+ T-cells are critically involved in parasitic liver diseases, but their role in sterile, antigen-independent liver inflammation remains elusive. Aim of this proposed translational project is to dissect the differentiation of T-helper cells at different stages of liver fibrosis and to examine their contribution to matrix depostion in descriptive and functional studies. With the help of a comprehensive collection of tissue specimens of explanted diseased liver with different underlying etiologies, it will be possible to precisely characterize intrahepatic T-cell profiles and the local immune environment in liver fibrosis. In vitro cell-culture assays with primary human cells will allow to study mechanisms of hepatic recruitment and local induction of Th2 differentiated T-helper cells. The analysis of the reciprocal interplay between CD4+ T-cells and liver-resident parenchymal and non-parenchymal cells will be a major focus in the human part of this project. The obtained findings will be validated in experimental antigen-independent liver fibrosis models. At defined time points during fibrogenesis the signature of infiltrating T-cells will be characterized. Knockout animals with a genetic deficiency of Th2 key components will serve to study the functional relevance of this immune response in liver fibrosis. If these animals exhibit less fibrosis adoptive transfer of CD4+ T-cells is planned to unravel whether this cell class or members of the innate immune system, such as innate lymphoid cells or NKT-cells, which can also secrete Th2-related cytokines, essentially booster heptic fibrogenesis. By promoting our understanding of the pathogenesis of liver fibrosis this project may help to develop novel therapeutic tools to combat liver cirrhosis.

免疫机制在肝脏炎症、随后的肝纤维化和肝硬变中起关键作用。广泛的研究表明，先天细胞成分的渗透和局部激活以及获得性免疫系统是启动促纤维化级联反应的先决条件。这与临床相关，因为尽管迫切需要有效的抗纤维化治疗，但治疗选择仍然有限。对肺等其他器官的研究表明，CD4+T辅助细胞的Th2极化与重塑过程直接相关。在器官纤维化过程中，典型的Th2细胞因子包括IL-4和IL-13激活间充质细胞，合成大量的细胞外基质化合物。结果，实质组织逐渐被结缔组织取代，最终导致器官衰竭。此外，Th2-细胞可以诱导交替激活的M2巨噬细胞，这些巨噬细胞也通过细胞间的相互作用表现出促纤维化的特性，从而进一步放大器官纤维化。然而，Th2-纤维化模式是否也适用于肝脏仍是一个广泛的未知数。有强有力的证据表明，Th2阳性的CD4+T细胞在寄生性肝病中起关键作用，但它们在无菌、非抗原肝脏炎症中的作用仍然难以捉摸。这一翻译项目的目的是在描述性和功能性研究中剖析T辅助细胞在肝纤维化不同阶段的分化，并检查它们对基质沉积的贡献。在全面收集不同潜在病因的移植病变肝脏组织标本的帮助下，将有可能准确地表征肝内T细胞分布和肝纤维化的局部免疫环境。用原代人体细胞进行体外细胞培养试验，将有助于研究肝脏募集和局部诱导Th2分化的T辅助细胞的机制。分析CD4+T细胞与驻肝实质细胞和非实质细胞之间的相互作用将是该项目人类部分的主要焦点。获得的发现将在实验性的抗原非依赖性肝纤维化模型中得到验证。在纤维化形成过程中的特定时间点，将表征浸润性T细胞的特征。具有Th2关键成分遗传缺陷的基因敲除动物将用于研究这种免疫反应在肝纤维化中的功能相关性。如果这些动物表现出较少的纤维化，则计划采用CD4+T细胞的过继转移来解开这种细胞类别或先天免疫系统的成员，如先天淋巴样细胞或NKT细胞，它们也可以分泌Th2相关细胞因子，本质上促进了肝纤维化的形成。通过促进我们对肝纤维化发病机制的理解，该项目可能有助于开发新的治疗手段来对抗肝硬变。