Specific CD8+ T cell immunity in the murine liver

小鼠肝脏中的特异性 CD8 T 细胞免疫

• 批准号: 5349522
• 负责人: Professor Dr. Jörg Reimann
• 金额: --
• 依托单位: Klinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5349522?language=en
• 关键词: Specific; CD8+; cell; immunity; murine

The hepatic immune system is a critical interface between mucosal and systemic immunity. It promotes oral and systemic tolerance induction but can also support effective local immunity against pathogens (although hepatic T cell responses are prone to pathogenic dysregulations). Using established DNA- and protein-based vaccination protocols to prime B6 mice against different (HBV, SV40, OVA) antigens, we will define optimal conditions to (i) induce liver-homing anti-viral CTL responses; (ii) facilitate access of primed CTL to an antigen-bearing liver; and (iii) to establish a long-term, functional CTL memory in an antigen-bearing liver. Transgenic mouse lines that express transgene-encoded antigens in the liver will be used to facilitate studies of intrahepatic priming and restimulation of CD8+ T cells. Particular emphasis will be placed on the role of the hepatic innate immune system (NKT cells, NK cells, dendritic cells) in modulating the hepatic specific T cell system. The in vivo studies will be complemented by in vitro studies that will analyze the interaction of hepatic DC with NKT cells, NK cells and (CD4+ and CD8+) T cells. We will study the involvement of chemokines, the IL12/IL18/IFN pathway, the IFN/IL18 pathway, and TNF as well as LPS in supporting or eliminating an established T cell memory population in the liver. These preclinical investigations are considered of critical importance for the understanding and rational design of novel therapeutic approaches to the specific immunotherapy of chronic liver infections.

肝脏免疫系统是粘膜免疫和全身免疫之间的关键界面。它促进口服和全身耐受性诱导，但也可以支持有效的局部免疫对病原体（虽然肝T细胞反应容易致病失调）。使用已建立的基于DNA和蛋白质的疫苗接种方案，针对不同的（HBV，SV 40，OVA）抗原引发B6小鼠，我们将定义最佳条件，以（i）诱导肝脏归巢抗病毒CTL应答;（ii）促进引发的CTL进入携带抗原的肝脏;和（iii）在携带抗原的肝脏中建立长期的功能性CTL记忆。在肝脏中表达转基因编码抗原的转基因小鼠系将用于促进CD 8 + T细胞的肝内引发和再刺激的研究。将特别强调肝脏先天免疫系统（NKT细胞，NK细胞，树突状细胞）在调节肝脏特异性T细胞系统中的作用。体内研究将通过体外研究进行补充，体外研究将分析肝DC与NKT细胞、NK细胞和（CD 4+和CD 8+）T细胞的相互作用。我们将研究趋化因子、IL 12/IL 18/IFN途径、IFN/IL 18途径和TNF以及LPS在支持或消除肝脏中已建立的T细胞记忆群体中的参与。这些临床前研究被认为对于理解和合理设计慢性肝脏感染特异性免疫治疗的新治疗方法至关重要。