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

基本信息

批准号：
9752627
负责人：
Lbachir BenMohamed
金额：
$ 37.5万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752627
关键词：
Address Adult Affect Afferent Neurons Antiviral Agents Blindness CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular immunotherapy 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 Evasion Immune system Immunity Immunization Immunologic Monitoring Immunologics Immunotherapeutic agent Immunotherapy In Vitro Individual Industrialization Infection Intervention Knowledge Latent Virus Lead Longevity Memory Modeling Nature Pathologic 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 Vaccine Therapy Vaccines Viral Virus Virus Diseases Virus Latency Virus Shedding Vision acute infection 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

项目摘要

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.

项目概要/摘要复发性疱疹病是由对单纯疱疹病毒 (HSV-1) 的免疫病理反应引起的尽管大多数人在眼泪中传播 HSV-1，但它是导致美国感染性失明的主要原因。潜伏（休眠）病毒从三叉神经节（TG）重新激活后，它们永远不会复发相比之下，少数人患有眼部疱疹病且无症状。有症状（SYMP），疾病频繁发作，我们的长期目标是描绘免疫。控制复发性疱疹疾病的机制，着眼于开发长效抗病毒药物成功预防或改善复发性眼部疱疹的免疫疗法已确定： (1) 适应性免疫，特别是抗病毒 CD8+ T 细胞，在体外可防止 HSV-1 潜伏再激活受感染的 TG；以及 (2) HSV-1 潜伏期相关转录本 (LAT)，这是在此期间表达的唯一基因。然而，关键的知识差距仍然存在，包括：(1) CD8+ T 细胞防止再激活、眼泪中病毒脱落和疾病复发的机制； (2) 病毒进化出的免疫逃避策略，作为针对宿主 CD8+ T 细胞的反防御。我们最近有四个发现，作为该提案的基础：（1）外周血来源来自 ASYMP 个体的 HSV 特异性 CD8+ T 细胞主要是效应记忆 (TEM) 细胞子集，与主要是 SYMP 个体的中枢记忆 (TCM) 细胞亚群 (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 UV-B 照射可诱发眼部疱疹病，与 SYMP 临床复发性疱疹非常相似 (3) TG 驻留 CD8+ TRM 细胞与 HLA Tg 小鼠的 ASYMP 疱疹感染相关。角膜和 TG 中耗竭（功能失调）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发现，我们的中心假设是， TG 和角膜驻留 CD8+ T 细胞的特定亚群和病毒因子决定了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 细胞大多是 TEM/TRM，而在 SYMP HLA Tg 小鼠（一次或多次 UV-B 诱发的复发性疾病），它们主要是 TCM 目标 2：测试。假设使用 ASYMP CD8+ TEM/TRM 细胞表位进行治疗性疫苗接种，但不使用 SYMP CD8+ 中药表位将减少 HLA Tg 小鼠的病毒再激活并减少疱疹疾病的复发。转化研究项目聚集了一个多学科团队，解决当前的 NEI Audacious 目标倡议：“通过小分子方法开发新疗法来治疗眼部疾病并该项目的成功完成将为开发有效的视力奠定基础。免疫治疗干预可预防致盲性复发性疱疹病。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

Focal ischemic stroke leads to lung injury and reduces alveolar macrophage phagocytic capability in rats.

局灶性缺血性中风导致大鼠肺损伤并降低肺泡巨噬细胞的吞噬能力。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Samary, Cynthia S;Ramos, Alane B;Maia, Lígia A;Rocha, Nazareth N;Santos, Cíntia L;Magalhães, Raquel F;Clevelario, Amanda L;Pimentel;Mendez;Cruz, Fernanda F;Capelozzi, Vera L;Ferreira, Tatiana P T;Koch, Thea;de A
通讯作者：
de A

Imaginological characterization of multiple myeloma lesions of the jaws through cone-beam computed tomography.

通过锥形束计算机断层扫描对颌骨多发性骨髓瘤病变进行影像学表征。

DOI：
发表时间：
2020-04
期刊：
影响因子：
2.2
作者：
Rocha, Thaiza Gonçalves;Feitosa, Édila Figuerêdo;Maiolino, Ângelo;de Magalhães Filho, Roberto José Pessoa;Guedes, Fábio Ribeiro;Torres, Sandra Regina;Visconti, Maria Augusta
通讯作者：
Visconti, Maria Augusta

Role of western blot assay for the diagnosis of histoplasmosis in AIDS patients from a National Institute of Infectious Diseases in Rio de Janeiro, Brazil.

巴西里约热内卢国家传染病研究所采用蛋白质印迹法诊断艾滋病患者组织胞浆菌病的作用。

DOI：
发表时间：
2019-03
期刊：
影响因子：
4.9
作者：
Almeida, Marcos Abreu;Damasceno, Lisandra Serra;Pizzini, Cláudia Vera;Muniz, Mauro de Medeiros;Almeida;Zancopé
通讯作者：
Zancopé

Interaction with Pantoea agglomerans Modulates Growth and Melanization of Sporothrix brasiliensis and Sporothrix schenckii.

与成团泛菌相互作用调节巴西孢子丝菌和申克孢子丝菌的生长和黑化。

DOI：
发表时间：
2019-06
期刊：
影响因子：
5.5
作者：
Almeida;Brito;Oliveira, Manoel Marques Evangelista;Bailão, Alexandre Melo;Borges, Clayton Luiz;Araújo, Glauber Ribeiro de Souza;Frases, Susana;Soares, Célia Maria de Almeida;Zancopé
通讯作者：
Zancopé

Glutamine Therapy Reduces Inflammation and Extracellular Trap Release in Experimental Acute Respiratory Distress Syndrome of Pulmonary Origin.

谷氨酰胺疗法可减少实验性肺源性急性呼吸窘迫综合征中的炎症和细胞外捕获物释放。

DOI：
发表时间：
2019-04-12
期刊：
影响因子：
5.9
作者：
de Oliveira, Gisele Pena;Kitoko, Jamil Zola;de Souza Lima;Rochael, Natália Cadaxo;de Araújo, Carla Cristina;Lugon, Pâmella Nowaski;Dos Santos, Heloísa Lopes;Martins, Eduarda Gabrielle Lopes;Ornellas, Felipe Mateus;de Oliveira, Hel
通讯作者：
de Oliveira, Hel