Adoptive MHC-E-Restricted T Cell Therapy for the Treatment of Chronic Hepatitis B Virus Infection

过继性 MHC-E 限制性 T 细胞疗法治疗慢性乙型肝炎病毒感染

• 批准号: 10627809
• 负责人: Benjamin J Burwitz
• 金额: $ 67.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10627809
• 关键词: Acute; Adoptive Transfer; Adult; Affect; Alleles; Animals; Avidity; Biological Assay; CD8-Positive T-Lymphocytes; Cell Line; Cell Therapy; Cells; Chronic Hepatitis B; Clinic; Coculture Techniques; Cytomegalovirus; Development; Dose; Epitopes; Exhibits; Frequencies; Goals; HIV; Hepatitis B Antigens; Hepatitis B Infection; Hepatitis B Virus; Hepatocyte; Human; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Lead; Liver; MHC Class II Genes; Macaca mulatta; Measures; Methods; Morbidity - disease rate; Mus; Nature; Pathogenicity; Patients; Peptides; Persons; Physiologic pulse; Polymerase; Population; Primates; Proteins; Research; Retroviridae; Rhesus; SIV; Sampling; Sorting; Specificity; Surface; T cell receptor repertoire sequencing; T cell response; T cell therapy; T memory cell; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Traction; Translating; Transplant Recipients; Vaccinated; Vaccines; Virus Diseases; anti-viral efficacy; cytokine; design; exhaustion; extracellular; global health; humanized mouse; mortality; mouse model; novel; novel therapeutics; post-transplant; response; unvaccinated; vector

PROJECT SUMMARY Chronic hepatitis B virus infections (CHB) are recognized as a major global health concern. CHB affects 247 million people worldwide, and 887,000 die annually from associated liver complications. This high morbidity and mortality is exacerbated by the fact that treatments for CHB are rarely curative. Thus, there remains an urgent need to develop new therapeutic treatments for CHB that will lead to clearance or lasting suppression of infection. Here, we propose a new way to target HBV through the use of MHC-E-restricted CD8+ T cells. There are only two MHC-E alleles within the human population and they are functionally equivalent. Therefore, HBV-specific CD8+ T cells restricted by MHC-E should be effective in all patients with CHB. We will characterize the T cell receptors (TCRs) of MHC-E-restricted CD8+ T cells in rhesus macaques inoculated with a rhesus CMV vector that engenders large numbers of these unique responses. We will then test the ability of these TCRs to recognize and suppress HBV infection. Given the urgent need for tractable CHB therapeutics, we believe the research proposed herein to be of the highest significance.

项目概要 慢性乙型肝炎病毒感染（CHB）被认为是全球主要的健康问题。慢性乙型肝炎影响 247 全球有 100 万人，每年有 887,000 人死于相关的肝脏并发症。这种高发病率 由于慢性乙型肝炎的治疗很少能治愈，死亡率进一步上升。因此，仍然存在一个 迫切需要开发新的慢性乙型肝炎治疗方法，以清除或持久抑制慢性乙型肝炎 感染。 在这里，我们提出了一种通过使用 MHC-E 限制性 CD8+ T 细胞来靶向 HBV 的新方法。只有 人类中有两个 MHC-E 等位基因，它们在功能上是等效的。因此，乙肝病毒特异性 受 MHC-E 限制的 CD8+ T 细胞应该对所有 CHB 患者有效。我们将表征 T 细胞 接种恒河猴 CMV 载体的恒河猴中 MHC-E 限制性 CD8+ T 细胞的受体 (TCR) 这会产生大量这些独特的反应。然后我们将测试这些 TCR 的能力 识别并抑制乙型肝炎病毒感染。鉴于迫切需要可控制的慢性乙型肝炎治疗方法，我们相信 本文提出的研究具有最高的意义。