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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘