Targeting tonsillar B cells for the induction of effective mucosal immunity to HIV

靶向扁桃体 B 细胞诱导针对 HIV 的有效粘膜免疫

• 批准号: 9390329
• 负责人: James J Kobie
• 金额: $ 77.52万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-12 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9390329
• 关键词: Acute; Adjuvant; Antibodies; Antibody Formation; Antigen Presentation; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; CCR9 gene; Cells; Complement Activation; DNA; Development; Dissection; Dose; Flow Cytometry; Genetic Transcription; HIV; HIV Infections; HIV envelope protein; HIV vaccine; HIV-1; Homing; Human; Humoral Immunities; Immunization; Immunize; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infection; Injectable; Interleukin-9; Intestines; Kinetics; Lymphoid; Macaca mulatta; Maintenance; Mediating; Memory; Memory B-Lymphocyte; Microbubbles; Monitor; Mucosal Immunity; Mucous Membrane; Needles; Oral mucous membrane structure; Palatine Tonsil; Phenotype; Plasma Cells; Population; Process; Proteins; Research; Resolution; SIV; Sampling; Serologic tests; Site; Stimulus; Structure; Structure of germinal center of lymph node; System; Testing; Tonsil; Vaccinated; Vaccines; Vagina; Virus; Work; base; conditioning; env Gene Products; gp160; insight; integrin alpha4beta7; lymph nodes; mucosal site; neutralizing antibody; novel strategies; novel vaccines; pathogen; peripheral blood; plasmid DNA; prevent; rectal; response; simian human immunodeficiency virus; trafficking; transmission process; vaccine development; vaccine response

Project Summary/Abstract An effective HIV vaccine is likely to be dependent on sufficient quantity and quality of HIV Envelope (Env)-specific antibody at the rectal and vaginal mucosa. Priming of the oral mucosa is viewed as a promising approach to generate mucosal antibody at HIV entry sites, however the understanding of the mechanisms that mediate this process are poorly understood. Our project seeks to precisely define the dynamics of inducing intestinal-mucosal plasma cells through direct intra-tonsillar (i.t.) immunization, and empirically test strategies to tune this process for obtaining an optimal mucosal antibody profile (localization, breadth, function, and durability) to achieve a protective HIV vaccine strategy. A main emphasis for inducing HIV-specific B cell responses has been to evaluate adjuvants/stimuli that target conventional B cell responses; leaving induction of non-conventional B cell responses, including those with direct relevance to mucosal antibody production largely under-explored. IgM memory, one such unconventional B cell population, is IgM memory, a major first line of defense against mucosal pathogens, and includes heterologous subsets such as marginal zone and B-1 B cells, which are major precursors of mucosal IgA plasma cells. Our research has demonstrated that IgM memory B cells are highly responsive to acute HIV infection and their maintenance is highly correlated with Env-specific antibody development. Mechanisms to induce robust IgM memory vaccine responses remain poorly defined, although our recent work has demonstrated the ability of IL- 9 and IL-33, known regulators of mucosal immunity, to promote the robust development of HIV Env-specific IgM, in addition to increasing the breadth, magnitude, and durability of the Env-specific IgG and IgA response when combined with the promising DNA/protein HIV Env immunogen platform VC10014 which elicits Tier 2 neutralizing antibody in rhesus macaques. Our central hypothesis is that conditioning the tonsil microenvironment with IL-9 or IL-33 will enable the rapid induction of durable and effective mucosal humoral immunity by the VC10014 HIV vaccine platform. This hypothesis will be tested by the following specific aims: 1) Define the effect of the tonsil microenvironment on the induction of mucosal humoral immunity, 2) Evaluate the protective ability of IL-9 or IL-33 adjuvanted VC10014 HIV vaccine platform, and 3) Identify strategies for enhancing human tonsil primary B cell responses to immunization. This project will significantly advance our insight into preventing HIV transmission and the mechanisms that control the development of protective humoral mucosal responses to HIV.

项目摘要/摘要 有效的艾滋病毒疫苗可能取决于艾滋病毒信封的足够数量和质量（特异性） 直肠和阴道粘膜处的抗体。口腔粘膜的启动被视为一种有希望的生成方法 艾滋病毒进入部位的粘膜抗体，但是对介导该过程的机制的理解是 理解不佳。我们的项目旨在精确定义诱导肠粘膜细胞的动力学 通过直接扁桃体内（I.T.）免疫，并经验测试策略，以调整此过程以获得 最佳粘膜抗体概况（本地化，广度，功能和耐用性）可获得保护性HIV疫苗 战略。诱导HIV特异性B细胞反应的主要重点是评估辅助/刺激 目标常规B细胞反应；留下非惯性B细胞反应的诱导，包括 与粘膜抗体产生的直接相关性在很大程度上不足。 IGM记忆，这样非常规B细胞 人口，是IgM记忆，是针对粘膜病原体的主要防御线，包括异源 边际区和B-1 B细胞等子集，它们是粘膜IgA浆细胞的主要前体。我们的 研究表明，IgM记忆B细胞对急性HIV感染及其 维护与ENV特异性抗体的开发高度相关。诱导鲁棒IgM的机制 记忆疫苗反应仍然很差，尽管我们最近的工作表明了IL-的能力 9和IL-33，已知的粘膜免疫调节剂，以促进HIV ENV特异性的稳健发展 IgM除了增加ENV特异性IgG和IgA响应的宽度，幅度和耐用性外 与有希望的DNA/蛋白质HIV INV免疫原平台VC10014结合使用时，它引起了2层 猕猴中和抗体中和抗体。我们的中心假设是调理扁桃体 使用IL-9或IL-33的微环境将使持久有效的粘膜体液迅速诱导 VC10014 HIV疫苗平台免疫。该假设将通过以下特定目的进行检验：1） 定义扁桃体微环境对粘膜体液免疫诱导的影响，2）评估 IL-9或IL-33辅助VC10014 HIV疫苗平台的保护能力，3）确定策略 增强人扁桃体原发性B细胞对免疫的反应。这个项目将大大推动我们的 深入了解防止艾滋病毒传播和控制保护发展的机制 对艾滋病毒的体液粘膜反应。