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：
10407461
负责人：
Benjamin J Burwitz
金额：
$ 57.12万
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/10407461
关键词：
Acute Adoptive Transfer Adult Affect Alleles Animals Avidity Biological Assay CD8-Positive T-Lymphocytes Cell Line 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 Proteins Research Retroviridae Rhesus SIV Sampling 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 base 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.

项目摘要慢性丙型肝炎病毒感染（CHB）被认为是全球主要的健康问题。 CHB影响247 全球有百万人民，每年有887,000人死于相关的肝脏并发症。这种高发病 CHB治疗很少治愈的事实加剧了死亡率。因此，仍然有一个迫切需要为CHB开发新的治疗方法，这将导致清除或持久的抑制感染。在这里，我们提出了一种通过使用MHC-E限制的CD8+ T细胞靶向HBV的新方法。只有人口中的两个MHC-E等位基因在功能上是等效的。因此，HBV特异性受MHC-E限制的CD8+ T细胞应在所有CHB患者中有效。我们将表征T单元接种恒河猴CMV载体的恒河猕猴中MHC-E限制的CD8+ T细胞的受体（TCR）这会产生大量这些独特的回应。然后，我们将测试这些TCR的能力识别并抑制HBV感染。鉴于迫切需要CHB疗法，我们相信本文提出的研究具有最高的意义。