B cell based protection against recurrent herpes

基于 B 细胞的针对复发性疱疹的保护

• 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
• 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

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.

项目摘要 单纯疱疹病毒-2（HSV-2）是最常见的性传播感染（stis）之一 美国的患病率为4500万。 HSV-2主要通过在生殖器粘膜处暴露传播 表面，导致在s骨神经节中建立潜伏期。虽然药理 存在与HSV-2相关症状的干预措施，没有预防疫苗或治疗性测量值 可用于这种疾病。旨在开发疫苗以防止HSV-2传播，这是一种清晰的理解 需要在相关粘膜部位中介导免疫反应的机制。 目前，女性生殖器粘膜内保护的免疫力学知识较低。我们的 先前的研究导致人们了解到记忆T细胞向阴道循环受到稳定的限制 州（Nakanishi等人，自然，2009年）。基于这种见解，我们制定了一种新的疫苗策略， “ Prime和Pult”，肠胃外疫苗接种后趋化因子的局部应用建立了本地 记忆CD8 T细胞可极大地改善肠胃外疫苗提供的保护（Shin和Iwasaki， 大自然，2012年）。我们还表明，用TK-HSV-2局部的阴道内（IVAG）免疫提供了局部 基于机构CD4组织居民记忆T（TRM）细胞（IIJIMA和IWASAKI，科学，科学， 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）为了重新刺激CD4 TRM。令人惊讶的是，与T细胞不同，B细胞不会成为组织居民，而是 相反，以组成型输入FRT并响应HSV-2感染为“访客”或B宾客记忆（BGM） 细胞。 TRM的记忆B细胞接合导致它们分泌抗病毒细胞因子IFN-γ和B助手 细胞因子，IL-21。因此，在TRM存在的情况下，BGM被诱导为秘密病毒特异性IgG frt。该赠款申请的目的是了解保护性免疫的机制 HSV-2由BGM在女性生殖道中精心策划，并应用此理解来设计强大 通过以下特定目的，针对复发生殖器疱疹的疫苗。我们建议剖析 在病毒挑战之后，B细胞募集到局部免疫的宿主中的FRT机制（AIM 1）， 确定刺激CD4 TRM（AIM 2）的内存B细胞子集的身份，并确定 CD4的帮助为记忆B细胞提供了将它们转化为分泌浆细胞的抗体（AIM 3）。经过 提供对迁移记忆B细胞和CD4如何介导针对HSV-的保护的基本了解 2生殖器感染，并应用此类知识设计更好的疫苗方法，这些研究将有助于 建立重要的基础，以设计免疫学干预和预防测量 针对人类的生殖器疱疹和其他有害性的性传播性传播疾病。