Mechanisms of CD8+ T Cell Dynamics in Recurrent Ocular Herpetic Disease

CD8 T 细胞动态在复发性眼部疱疹病中的机制

• 批准号: 9183816
• 负责人: Lbachir BenMohamed
• 金额: $ 38.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9183816
• 关键词: Acute; Address; Adult; Affect; Afferent Neurons; Antiviral Agents; Blindness; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Cornea; Corneal Diseases; Defense Mechanisms; Development; Disease; Disease model; Epitopes; Experimental Models; Eye; Eye diseases; Foundations; Frequencies; Genes; Goals; HLA Antigens; HLA-A gene; HLA-DR Antigens; Herpesviridae Infections; Herpesvirus 1; Herpetic Keratitis; Human; Immune; Immune system; Immunity; Immunization; Immunologic Monitoring; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Intervention; Knowledge; Lead; Longevity; Memory; Modeling; Mus; Nature; Phenotype; Play; Prevention; Proteins; Publishing; Recurrence; Recurrent disease; Research Project Grants; Role; Scientist; Severities; Severity of illness; Side; Simplexvirus; Structure of trigeminal ganglion; T Virus; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Transgenic Mice; Translational Research; UV induced; United States; Vaccination; Vaccines; Viral; Virus; Virus Shedding; Vision; adaptive immunity; base; exhaust; exhaustion; innovation; irradiation; latency associated transcript; latent infection; mouse model; multidisciplinary; novel; pathogen; peripheral blood; pre-clinical research; prevent; prophylactic; protective efficacy; reactivation from latency; response; small molecule; therapeutic vaccine

PROJECT SUMMARY/ABSTRACT Recurrent herpetic disease, caused by an immuno-pathological response to herpes simplex virus (HSV-1), is a major cause of infectious blindness in the United States. Although most individuals shed HSV-1 in their tears following reactivation of latent (dormant) virus from the trigeminal ganglia (TG), they never develop recurrent ocular herpetic disease and are asymptomatic (ASYMP). In contrast, a small number of individuals are symptomatic (SYMP), with frequent bouts of recurrent disease. Our long-term goal is to delineate the immune mechanisms that control recurrent herpetic disease, with an eye toward developing a long-lasting antiviral immuno-therapy that successfully prevents or ameliorates recurrent ocular herpes. It has been established that: (1) adaptive immunity, and particularly antiviral CD8+ T cells, protect, in vitro, from HSV-1 reactivation in latently infected TG; and (2) the HSV-1 latency associated transcript (LAT), the only gene that is expressed during latency, restrains the function of antiviral CD8+ T cells. However, key knowledge gaps still remain including: (1) the mechanisms by which CD8+ T cells protect from reactivation, virus shedding in tears, and recurrent disease; and (2) the immune evasion strategies evolved by the virus as a counter-defense against the host’s CD8+ T cells. We recently made four discoveries that serve as the foundation for this proposal: (1) Peripheral blood-derived HSV-specific CD8+ T cells from ASYMP individuals are mostly effector memory (TEM) cell subset, in contrast to mostly central memory (TCM) cell subset in SYMP individuals. (2) Using our novel double transgenic mouse model, expressing Human Leukocyte Antigens HLA-DR and HLA-A*02:01 (HLA Tg mice), multiple recurrences of ocular herpetic disease can be induced by UV-B irradiation, closely mimicking SYMP clinical recurrent herpetic disease. (3) TG-resident CD8+ TRM cells are associated with ASYMP herpes infection of HLA Tg mice. (4) Exhausted (dysfunctional) CD8+ TRM cells in the cornea and TG are associated with SYMP recurrent disease. Building on these preliminary and published findings, our central hypothesis is that interactions between specific subsets of TG- and cornea-resident CD8+ T cells and viral factors determine the development of recurrent herpetic disease. We propose the following Specific Aims: Aim 1: Test the hypothesis that, similar to humans, HSV-specific CD8+ T cells from latently infected ASYMP HLA Tg mice are mostly TEM/TRM, while in SYMP HLA Tg mice (one or more episodes of UV-B induced recurrent disease) they are mostly TCM. Aim 2: Test the hypothesis that therapeutic vaccination with ASYMP CD8+ TEM/TRM cell epitopes, but not with SYMP CD8+ TCM epitopes, will reduce virus reactivation and lessen recurrent herpetic disease in HLA Tg mice. This translational research project, which gathers a multidisciplinary team, addresses the current NEI Audacious Goals Initiative: “Development of new treatments through small molecules approach to treat eye disease and to restore sight.” Successful completion of this project will lay the foundation toward developing an effective immunotherapeutic intervention to prevent blinding recurrent herpetic disease.

项目总结/摘要 由对单纯疱疹病毒（HSV-1）的免疫病理反应引起的复发性疱疹病是一种 是美国传染性失明的主要原因。虽然大多数人在他们的眼泪中流出HSV-1 在三叉神经节（TG）的潜伏（休眠）病毒重新激活后， 眼疱疹性疾病和无症状（ASYMP）。相比之下，少数人 症状性（SYMP），经常发作的复发性疾病。我们的长期目标是描绘免疫系统 控制复发性疱疹疾病的机制，着眼于开发一种持久的抗病毒药物 免疫疗法，成功地预防或改善复发性眼疱疹。现已确定： (1)获得性免疫，特别是抗病毒CD8 + T细胞，在体外保护HSV-1潜伏性再活化， 感染的TG;和（2）HSV-1潜伏期相关转录本（LAT），唯一的基因，表达期间 潜伏期，抑制抗病毒CD8 + T细胞的功能。然而，关键的知识差距仍然存在，包括：（1） CD8 + T细胞防止再活化、病毒在眼泪中脱落和疾病复发的机制; 以及（2）由病毒进化的免疫逃避策略作为对宿主的CD8 + T细胞的反防御。 我们最近有四个发现作为这个提议的基础：（1）外周血来源的 来自ASYMP个体的HSV特异性CD8 + T细胞主要是效应记忆（TEM）细胞亚群，与之相反， 主要是中央记忆（TCM）细胞亚群在SYMP个体。(2)使用我们的新型双转基因小鼠 模型，表达人类白细胞抗原HLA-DR和HLA-A * 02：01（HLA Tg小鼠），多次复发 的眼部疱疹性疾病可由UV-B照射诱导，非常类似于SYMP临床复发性疱疹 疾病(3)TG驻留的CD8 + TRM细胞与HLA Tg小鼠的ASYMP疱疹感染相关。（四） 角膜和TG中耗尽（功能障碍）的CD8 + TRM细胞与SYMP复发性疾病相关。 基于这些初步和已发表的研究结果，我们的中心假设是， TG和角膜驻留的CD8 + T细胞的特定亚群和病毒因子决定了 复发性疱疹病我们提出以下具体目标：目标1：检验假设，类似于 在人类中，来自潜伏感染的ASYMP HLA Tg小鼠的HSV特异性CD8 + T细胞主要是TEM/TRM，而在 SYMP HLA Tg小鼠（一次或多次UV-B诱导的复发性疾病发作），它们大多是TCM。目标2：测试 假设用ASYMP CD8 + TEM/TRM细胞表位而不是用SYMP CD8+治疗性疫苗接种 TCM表位，将减少病毒再活化，减少HLA-Tg小鼠中复发的疱疹性疾病。这 翻译研究项目，其中聚集了一个多学科的团队，解决目前的NEI大胆 目标倡议："通过小分子方法开发新的治疗方法来治疗眼病， 恢复视力"该项目的成功完成将为制定有效的 免疫干预预防复发性疱疹性致盲。