B cell based protection against recurrent herpes

基于 B 细胞的针对复发性疱疹的保护

基本信息

批准号：
9380483
负责人：
AKIKO IWASAKI
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9380483
关键词：
Antibodies Antigen-Presenting Cells Antigens Antiviral Agents Applications Grants B-Lymphocytes Blood Circulation Bone Marrow CD8-Positive T-Lymphocytes Cells Dendritic Cells Disease Female Foundations Ganglia Genital system Goals High Prevalence Human Human Herpesvirus 2 Immune Immune response Immunity Immunization Immunize Immunoglobulin G Immunoglobulin-Secreting Cells Infection Interferon Type II Intervention Knowledge Lamina Propria Life Measures Mediating Memory Memory B-Lymphocyte Mucous Membrane Mus Nature Peptides Pharmacology Phenotype Plasma Cells Population Preventive measure Preventive vaccine Recruitment Activity Recurrence Recurrent disease Residencies Science Seeds Sexually Transmitted Diseases Signal Transduction Source Surface Symptoms System T memory cell T-Lymphocyte Thymidine Kinase Tissues Topical application Vaccination Vaccines Vagina Viral Virus base chemokine cytokine design genital herpes genital infection immunological intervention improved insight mucosal site mutant novel vaccines prevent reproductive tract response secondary infection transmission process

项目摘要

Project Summary Herpes simplex virus-2 (HSV-2) is one of the most common sexually transmitted infections (STIs) with a high prevalence of 45 million in the USA. HSV-2 is primarily transmitted via exposure at the genital mucosal surfaces, which leads to the establishment of latency in the sacral ganglia. Although pharmacological interventions exist for HSV-2-related symptoms, there are no preventative vaccines or curative measures available for this disease. Towards developing vaccines to prevent HSV-2 transmission, a clear understanding of the mechanism by which immune responses are mediated within the relevant mucosal sites is necessary. Currently, the immune mechanisms of protection within the female genital mucosa are poorly understood. Our previous studies led to the understanding that memory T cell circulation to the vagina is restricted at steady state (Nakanishi et al, Nature, 2009). Based on this insight, we developed a new vaccine strategy we call, “Prime and Pull”, in which topical application of chemokines following parenteral vaccination establishes local memory CD8 T cells to dramatically improve protection afforded by parenteral vaccines (Shin and Iwasaki, Nature, 2012). We have also shown that intravaginal (ivag) immunization with TK- HSV-2 provides local protection based on establishment CD4 tissue resident memory T (TRM) cells (Iijima and Iwasaki, Science, 2014). Our Preliminary Studies reveal that memory B cells must migrate into the female reproductive tract (FRT) in order to restimulate the CD4 TRM. Strikingly, unlike T cells, B cells do not become tissue-resident, but rather, enter the FRT constitutively and in response to HSV-2 infection as “guest”, or B guest memory (BGM) cells. Memory B cell engagement of TRM results in their secretion of antiviral cytokine IFN-γ as well as B helper cytokine, IL-21. Consequently, BGM are induced to secrete virus-specific IgG in the presence of TRM within the FRT. The goal of this grant application is to understand the mechanism by which protective immunity against HSV-2 is orchestrated by BGM in the female genital tract, and to apply this understanding to design a robust vaccine against recurrent genital herpes through the following Specific Aims. We propose to dissect the mechanism of B cell recruitment to the FRT in locally immunized host following viral challenge (Aim 1), to determine the identity of memory B cell subset that stimulates CD4 TRM (Aim 2), and to determine the nature of CD4 help provided to memory B cells that converts them into antibody secreting plasma cells (Aim 3). By providing basic understanding of how migrating memory B cells and CD4 TRM mediate protection against HSV- 2 genital infection, and applying such knowledge to design a better vaccine approach, these studies will help to establish important foundation with which to design immunological interventions and preventative measures against genital herpes and other deleterious STI diseases in humans.

项目概要单纯疱疹病毒 2 (HSV-2) 是最常见的性传播感染 (STI) 之一，发病率很高在美国，HSV-2 的流行率为 4500 万，主要通过生殖器粘膜传播。表面，这导致在骶神经节中建立潜伏期，尽管具有药理学作用。针对 HSV-2 相关症状存在干预措施，但没有预防性疫苗或治疗措施对于开发疫苗来预防 HSV-2 传播，我们有一个清晰的认识。有必要了解相关粘膜部位内介导免疫反应的机制。目前，我们对女性生殖器粘膜内的免疫保护机制知之甚少。之前的研究表明，记忆 T 细胞在稳定状态下的阴道循环受到限制。（Nakanishi 等人，Nature，2009）基于这一见解，我们开发了一种新的疫苗策略，我们称之为： “Prime and Pull”，其中肠外疫苗接种后局部应用趋化因子建立了局部记忆 CD8 T 细胞可显着改善肠外疫苗提供的保护（Shin 和 Iwasaki， Nature，2012）我们还表明，TK-HSV-2 阴道内（ivag）免疫可提供局部效果。基于建立 CD4 组织驻留记忆 T (TRM) 细胞的保护（Iijima 和 Iwasaki，Science， 2014）我们的初步研究表明，记忆 B 细胞必须迁移到女性生殖道中。 (FRT) 以重新刺激 CD4 TRM 引人注目的是，与 T 细胞不同，B 细胞不会成为组织驻留细胞，但相反，作为“访客”或 B 访客记忆（BGM），组成性地进入 FRT 并响应 HSV-2 感染记忆 B 细胞与 TRM 的结合导致其分泌抗病毒细胞因子 IFN-γ 以及 B 辅助细胞。细胞因子、IL-21 被检测，BGM 在 TRM 存在的情况下被诱导分泌病毒特异性 IgG。这项拨款申请的目的是了解针对 FRT 的保护性免疫的机制。 HSV-2 是由 BGM 在女性生殖道中精心策划的，并应用这种理解来设计一个强大的我们建议通过以下具体目标来预防复发性生殖器疱疹疫苗。病毒攻击后局部免疫宿主中 B 细胞招募至 FRT 的机制（目标 1），确定刺激 CD4 TRM 的记忆 B 细胞亚群的身份（目标 2），并确定其性质 CD4 帮助记忆 B 细胞将其转化为分泌抗体的浆细胞（目标 3）。提供对迁移记忆 B 细胞和 CD4 TRM 如何介导针对 HSV 的保护的基本了解 2 生殖器感染，并应用这些知识来设计更好的疫苗方法，这些研究将有助于为设计免疫干预和预防措施奠定重要基础对抗人类生殖器疱疹和其他有害的性传播感染疾病。