Bim-mediated attrition of virus-specific CD8 T cells in chronic HBV infection

Bim 介导的慢性 HBV 感染中病毒特异性 CD8 T 细胞的损耗

• 批准号: G0801213/1
• 负责人: Mala Maini
• 金额: $ 66.41万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0801213%2F1
• 关键词: Bim; mediated; attrition; virus; specific

Hepatitis B virus remains one of the top ten killers in the world today, causing around a million deaths every year from chronic liver disease, leading to liver failure and liver cancer. There is a vaccine to prevent spread, but this is of no use to the 400 million people estimated to already be chronically infected. There are now a number of drugs available to treat hepatitis B infection but these typically only suppress the virus rather than clear it; when the patient stops the treatment the virus level comes back up. The goal of the work proposed here is to allow us to develop a type of treatment supplement to boost immune control, such that costly and potentially toxic antiviral drugs would only need to be given for a short period. We will address this by parallel experiments using both a mouse model and also cells studied directly from patients, including those on the latest treatments available for hepatitis B virus infection. We have identified a critical defect in T cells (a key type of killer immune cell), which could account for their failure to control hepatitis B virus in patients with chronic infection. We have found that their T cells are triggered to commit suicide when they encounter hepatitis B virus; too few of these cells then survive to control the infection. This proposal aims to work out what drives this cell suicide and whether it can be safely blocked to allow a recovery of T cells. This could then switch the immune response back to the successful type seen in people who manage to control this infection naturally without requiring drug treatment.

丙型肝炎病毒仍然是当今世界上十大杀手之一，每年因慢性肝病而导致大约100万人死亡，导致肝癌和肝癌。有一种疫苗可以防止传播，但这对已经被长期感染的4亿人毫无用处。现在有许多药物可用于治疗丙型肝炎感染，但通常仅抑制病毒而不是清除病毒。当患者停止治疗时，病毒水平会恢复。这里提出的工作的目的是使我们能够开发一种治疗补充剂来增强免疫控制，从而使代价高昂的有毒抗病毒药只需要在短时间内服用。我们将通过使用小鼠模型和直接从患者研究的细胞（包括用于乙型肝炎病毒感染的最新疗法的细胞）来解决此问题。我们已经确定了T细胞（一种关键的杀手型免疫细胞）中的临界缺陷，这可能解释了他们无法控制慢性感染患者的乙型肝炎病毒。我们发现，当他们遇到乙型肝炎病毒时，他们的T细胞被触发自杀。然后，这些细胞中的很少有生存以控制感染。该提案旨在弄清驱动这种细胞自杀的原因以及是否可以安全地阻止它以恢复T细胞。然后，这可以将免疫反应转移回到自然控制这种感染而无需药物治疗的人们中看到的成功类型。