Involvement of Natural Killer T cells in Hepatic Fibrogenesis

自然杀伤 T 细胞参与肝纤维形成

• 批准号: 7185965
• 负责人: IAN N HINES
• 金额: $ 11.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185965
• 关键词: Acute Hepatitis; Address; Adoptive Transfer; Alcoholic Liver Diseases; Biliary; Carbon Tetrachloride; Cell physiology; Cells; Chronic; Class; Coculture Techniques; Collagen; Cytokine Activation; Development; Equilibrium; Fibrosis; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; IL4 gene; IL5 gene; In Vitro; Inflammation; Interferon Type II; Interleukin-12; Interleukin-13; Interleukin-4; Interleukin-5; Ligation; Liver; Liver Fibrosis; Liver diseases; Lymphocyte; Mediating; Modeling; Mouse Strains; Mus; Numbers; Obstruction; Pathology; Phenotype; Play; Population; Production; Rodent; Role; T-Lymphocyte; Testing; Virus Diseases; bile duct; cytokine; inhibitor/antagonist; insight; intrahepatic; killer T cell; mouse model; novel; reconstitution; response; stellate cell

DESCRIPTION (provided by applicant): Hepatic fibrosis is a consequence of a number of chronic liver pathologies including alcoholic liver disease, viral infection, and biliary outflow obstruction. Growing experimental evidence implicates the class of cytokines produced, specifically the T helper (Th) cytokine phenotype expressed, as a key regulator of the fibrotic response. Indeed, while Th1 type cytokines such as interferon gamma (IFNg) or interleukin (IL) 12 are associated with hepatitis and acute inflammation, expression of the Th2 type cytokines IL4, IL5, and IL13 drive fibrosis development. Moreover, it appears that during chronic liver diseases a switch occurs in which a balanced or perhaps Th1 -shifted cytokine response is replaced by an unbalanced Th2 predominated cytokine phenotype. Natural killer T (NKT) cells make up approximately 50% of the intrahepatic lymphocytes and are capable of producing both Th1 and Th2 type cytokines making them a potential regulator of the hepatic Th cytokine balance. The impact this cell population has on the hepatic fibrotic response is not known. It is hypothesized that NKT cells limit hepatocellular inflammation and promote hepatic fibrosis through production of key regulatory and pro-fibrotic Th2 type cytokines. Utilizing two well described models of hepatic fibrosis in rodents, carbon tetrachloride administration or bile duct ligation, and two mouse models of NKT cell deficiency, CD1d-/- mice and Ja281-/- mice, the role that NKT cells play in the fibrotic response will be evaluated. In the first aim, the direct consequence of a deficiency in hepatic NKT cells in the development of hepatic fibrogenesis will be determined. Furthermore, using in vitro cell coculture, the role of NKT cells and NKT cell derived factors in the activation primary hepatic stellate cells will also be examined. In the second aim, hepatic NKT cell populations will be exhaustively characterized prior to and during the development of hepatic fibrosis focusing on their Th cytokine phenotype. The third aim will extend these findings and determine the role of NKT cell derived cytokines specifically using a novel adoptive transfer approach where NKT cell deficient mice are reconstituted with certain cytokine deficient NKT cells including IFNg deficient and IL4 deficient cells. The final aim will address the role of IL12, a known inhibitor of NKT cell function and survival, in the development and progression of experimental fibrosis. Together, these studies will provide new insight into the mechanisms of T cell-mediated hepatic fibrosis.

描述（由申请方提供）：肝纤维化是许多慢性肝脏病理的结果，包括酒精性肝病、病毒感染和胆道流出道梗阻。越来越多的实验证据表明，产生的细胞因子，特别是T辅助细胞（Th）细胞因子表型表达，作为纤维化反应的关键调节因子。实际上，虽然Th 1型细胞因子如干扰素γ（IFNg）或白细胞介素（IL）12与肝炎和急性炎症相关，但Th 2型细胞因子IL 4、IL 5和IL 13的表达驱动纤维化发展。此外，似乎在慢性肝病过程中发生了一种转换，其中平衡的或可能是Th 1移位的细胞因子应答被不平衡的Th 2占主导地位的细胞因子表型所取代。自然杀伤T（NKT）细胞占肝内淋巴细胞的大约50%，并且能够产生Th 1和Th 2型细胞因子，使其成为肝Th细胞因子平衡的潜在调节剂。该细胞群对肝纤维化反应的影响尚不清楚。假设NKT细胞通过产生关键的调节性和促纤维化Th 2型细胞因子来限制肝细胞炎症并促进肝纤维化。利用两种描述良好的啮齿动物肝纤维化模型（四氯化碳给药或胆管结扎）和两种NKT细胞缺乏小鼠模型（CD 1d-/-小鼠和Ja 281-/-小鼠），将评价NKT细胞在纤维化反应中的作用。在第一个目标中，将确定肝NKT细胞缺乏在肝纤维化发展中的直接后果。此外，使用体外细胞共培养，还将检查NKT细胞和NKT细胞衍生因子在活化原代肝星状细胞中的作用。在第二个目标中，肝NKT细胞群将在肝纤维化发生之前和过程中进行详尽的表征，重点是其Th细胞因子表型。第三个目标将扩展这些发现并确定NKT细胞衍生的细胞因子的作用，特别是使用新的过继转移方法，其中NKT细胞缺陷型小鼠用某些细胞因子缺陷型NKT细胞（包括IFNg缺陷型和IL 4缺陷型细胞）重建。最终的目标是解决IL 12，一种已知的NKT细胞功能和存活抑制剂，在实验性纤维化的发展和进展中的作用。总之，这些研究将为T细胞介导的肝纤维化机制提供新的见解。