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

基本信息

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
项目类别：
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

项目摘要

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。鉴于迫切需要可治疗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。