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: 7477870
• 负责人: IAN N HINES
• 金额: $ 11.58万
• 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/7477870
• 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（由申请人提供）：肝纤维化是许多慢性肝脏病变的结果，包括酒精性肝病，病毒感染和胆道流出阻塞。越来越多的实验证据暗示了产生的细胞因子类别，特别是表达的T助手（Th）细胞因子表型，作为纤维化反应的关键调节剂。实际上，尽管Th1型细胞因子（例如干扰素伽马（IFNG）或白介素（IL）12）与肝炎和急性炎症有关，但Th2型细胞因子IL4，IL5和IL13的表达驱动纤维化的发育。此外，似乎在慢性肝脏疾病中发生了一个开关，在这种开关中，平衡或Th1降低的细胞因子反应被不平衡的TH2占主导的细胞因子表型所取代。天然杀伤剂T（NKT）细胞约占肝内淋巴细胞的50％，并且能够同时产生Th1和Th2型细胞因子，从而使它们成为肝细胞因子平衡的潜在调节剂。该细胞种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纤维性TH2型细胞因子来限制肝细胞炎症并促进肝纤维化。利用啮齿动物中肝纤维化的两个良好描述的模型，四氯化碳给药或胆管连接，以及两种NKT细胞缺乏症的小鼠模型，CD1D - / - 小鼠和JA281 - / - 小鼠，NKT细胞在纤维化反应中起着NKT细胞的作用。在第一个目的中，将确定肝NKT细胞缺乏肝纤维化发生的直接结果。此外，还将检查NKT细胞和NKT细胞衍生因子在激活原代肝星状细胞中的作用。在第二个目标中，肝NKT细胞群体将在肝纤维化的发展之前和期间详尽地表征，重点是其细胞因子表型。第三个目标将扩展这些发现，并使用一种新型的收养转移方法来确定NKT细胞得出的细胞因子的作用，其中NKT细胞缺乏小鼠与某些细胞因子缺乏的NKT细胞重构，包括IFNG缺乏症和IL4缺陷细胞。最终目的将解决IL12的作用，IL12是NKT细胞功能的已知抑制剂，在实验纤维化的发展和发展中的作用。总之，这些研究将为T细胞介导的肝纤维化的机理提供新的见解。