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: 10186460
• 负责人: James J Kobie
• 金额: $ 63.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186460
• 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; Interleukin-9; Intestinal Mucosa; Intestines; Kinetics; 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; Rhesus; SIV; Sampling; Serology; Site; Stimulus; Structure of germinal center of lymph node; System; Testing; Tonsil; Vaccinated; Vaccines; Virus; Work; base; conditioning; env Gene Products; gp160; insight; integrin alpha4beta7; lymph nodes; lymphoid structures; mucosal site; neutralizing antibody; novel strategies; novel vaccines; pathogen; peripheral blood; plasmid DNA; preservation; prevent; rectal; response; simian human immunodeficiency virus; trafficking; transmission process; vaccine development; vaccine response; vaginal mucosa

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.

项目概要/摘要 有效的 HIV 疫苗可能取决于足够数量和质量的 HIV 包膜 (Env) 特异性疫苗 直肠和阴道粘膜有抗体。口腔粘膜的启动被认为是产生 HIV 进入位点的粘膜抗体，但是对介导这一过程的机制的理解尚不清楚 不太了解。我们的项目旨在精确定义诱导肠粘膜浆细胞的动力学 通过直接扁桃体内（i.t）免疫，并根据经验测试策略来调整该过程以获得 最佳粘膜抗体谱（定位、广度、功能和耐久性）以实现保护性 HIV 疫苗 战略。诱导 HIV 特异性 B 细胞反应的一个主要重点是评估佐剂/刺激物 针对常规 B 细胞反应；留下非常规 B 细胞反应的诱导，包括那些 与粘膜抗体产生的直接相关性很大程度上尚未得到充分探索。 IgM 记忆，一种非常规 B 细胞 群体，是 IgM 记忆，对抗粘膜病原体的主要第一道防线，包括异源 边缘区和 B-1 B 细胞等亚群，它们是粘膜 IgA 浆细胞的主要前体细胞。我们的 研究表明，IgM 记忆 B 细胞对急性 HIV 感染高度敏感，并且其 维持与 Env 特异性抗体的产生高度相关。诱导强效 IgM 的机制 尽管我们最近的工作已经证明了IL- 9 和 IL-33 是已知的粘膜免疫调节因子，可促进 HIV 包膜特异性的强劲发展 IgM，除了增加 Env 特异性 IgG 和 IgA 反应的广度、强度和持久性之外 当与有前景的 DNA/蛋白质 HIV Env 免疫原平台 VC10014 结合使用时，可引发 Tier 2 恒河猴中的中和抗体。我们的中心假设是调节扁桃体 含有 IL-9 或 IL-33 的微环境将能够快速诱导持久有效的粘膜体液 VC10014 HIV 疫苗平台的免疫力。该假设将通过以下具体目标进行检验：1） 定义扁桃体微环境对诱导粘膜体液免疫的影响，2）评估 IL-9 或 IL-33 佐剂 VC10014 HIV 疫苗平台的保护能力，以及 3) 确定策略 增强人扁桃体原代 B 细胞对免疫的反应。该项目将显着推进我们的 深入了解预防艾滋病毒传播以及控制保护性发展的机制 HIV 的体液粘膜反应。