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Exploring immune modulating strategies to restore antiviral effector functions of intrahepatic CD8 T cells

探索恢复肝内CD8 T细胞抗病毒效应功能的免疫调节策略

基本信息

批准号：
164645609
负责人：
Professor Dr. Reinhold Schirmbeck
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：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/164645609?language=en
关键词：
Exploring immune modulating strategies restore

项目摘要

Reconstitution of antiviral immunity by vaccination is an attractive option to specifically control chronic hepatitis B virus (HBV) infection. To characterize HBV-specific CD8 T cell responses in the presence of a liver that produces all HBV antigens, we established the 1.4HBV-Smut transgenic (tg) line that harbours a replicating HBV genome in the liver, produces HBV large/middle surface (S) and core/precore (C/E) antigens but secretes neither small S particles, nor HBV virions. DNA vaccines efficiently induce core- (but not S-) specific CD8 T cell responses that transiently suppress HBV replication in the liver of 1.4HBV-Smut tg mice. Intrahepatic, specific CD8 T cells in vaccinated 1.4HBV-Smut tg mice show reproducible changes in their phenotype and cytokine profile that coincide with their loss of antiviral activity (‘exhaustion’). The proposal aims to elucidate systemic and intrahepatic regulatory effects that set off ´exhaustion´ of specific CD8 T cells in vaccinated 1.4HBV-Smut tg mice. We will use 1.4HBV-Smut tg mice crossed to well-defined tg or KO lines (deficient for coinhibitory molecules, regulator cells or cytokines) and vaccinated with HBcAg- or HBsAg-encoding vaccines. We will combine specific vaccination with antiviral drug (Tenofovir®) treatment and/or immune modulating protocols in an attempt to maintain an antiviral phenotype in the specific, intrahepatic T cells. We are in particular interested in: (i) the characterization of the kinetics of primary and boosted CD8 T cell responses in wt versus tg animals; (ii) changes in phenotype and cytokine secretion of CD8 T cells and hepatocytes; and (iii) epitope specificities of CD8 T cells. To selectively analyze intrahepatic effector CD8 T cell responses, we will use adoptive transfer experiments (CD8 T cells from vaccinated wt or KO mice transferred into wt or KO 1.4HBV-Smut tg mice). These studies may help to rationally design specific immune intervention protocols that attenuate the functional ‘exhaustion’ of CD8 T cells in chronic infection with hepatotropic viruses.

通过疫苗接种重建抗病毒免疫是特异性控制慢性B型肝炎病毒（HBV）感染的有吸引力的选择。为了表征在产生所有HBV抗原的肝脏存在下HBV特异性CD 8 T细胞应答，我们建立了1. 4 HBV-Smut转基因（tg）系，其在肝脏中携带复制的HBV基因组，产生HBV大/中表面（S）和核心/前核心（C/E）抗原，但既不分泌小S颗粒，也不分泌HBV病毒粒子。DNA疫苗能有效诱导核心特异性（而非S特异性）CD 8 T细胞应答，并能瞬时抑制1. 4 HBV-Smut tg小鼠肝脏中的HBV复制。接种1. 4 HBV-Smut tg小鼠的肝内特异性CD 8 T细胞显示其表型和细胞因子谱的可重复变化，这与其抗病毒活性的丧失（“耗竭”）一致。该提案旨在阐明在接种1. 4 HBV-Smut tg小鼠中引发特异性CD 8 T细胞“耗竭”的全身和肝内调节作用。我们将使用与明确的tg或KO系（缺乏共抑制分子、调节细胞或细胞因子）杂交的1. 4 HBV-Smut tg小鼠，并接种HBcAg或HBsAg编码疫苗。我们将联合收割机特异性疫苗接种与抗病毒药物（替诺福韦®）治疗和/或免疫调节方案相结合，试图在特异性肝内T细胞中维持抗病毒表型。我们特别感兴趣的是：（i）在野生型与tg动物中的初级和加强的CD 8 T细胞应答的动力学表征;（ii）CD 8 T细胞和肝细胞的表型和细胞因子分泌的变化;和（iii）CD 8 T细胞的表位特异性。为了选择性地分析肝内效应CD 8 T细胞应答，我们将使用过继转移实验（来自接种疫苗的wt或KO小鼠的CD 8 T细胞转移到wt或KO 1. 4 HBV-Smut tg小鼠中）。这些研究可能有助于合理设计特异性免疫干预方案，以减轻嗜肝病毒慢性感染中CD 8 T细胞的功能性“衰竭”。