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Using parenteral combination adjuvants to induce pan-mucosal cellular and humoral immunity

使用肠外组合佐剂诱导全粘膜细胞和体液免疫

基本信息

批准号：
10650818
负责人：
LISA A MORICI
金额：
$ 66.04万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-21 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650818
关键词：
ADP ribosylation Address Adjuvant Affect Antibodies Antibody Formation Antibody-mediated protection Antigens B-Lymphocytes Bacterial Infections CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Communication Cell Count Cells Cellular Immunity Chlamydia Citrobacter Communicable Diseases Data Drug Metabolic Detoxication Enterotoxins Escherichia coli heat-labile toxin Female Future Gastrointestinal tract structure Goals Humoral Immunities Immune Immune response Immunity Immunization Immunoglobulin Class Switching Individual Infection Influenza Injections Intervention Intestinal Mucosa Intramuscular Investigation Knowledge Licensing Lung Lymphoid Tissue Major Histocompatibility Complex Medical Membrane Memory Memory B-Lymphocyte Mission Modeling Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Outcome Parabiosis Persons Phenotype Play Program Development Publishing Recording of previous events Research Role Site Structure of parenchyma of lung Surface T-Cell Activation T-Lymphocyte Testing Tissues United States National Institutes of Health Vaccination Vaccine Adjuvant Vaccine Antigen Vaccine Design Vaccines Vesicle Virus Diseases Work aluminum sulfate cell motility combat draining lymph node experimental study human disease innovation insight migration mucosal site mutant novel parenteral administration pathogen pathogenic bacteria pathogenic virus protective efficacy reproductive tract response tissue resident memory T cell tool trafficking vaccine development

项目摘要

PROJECT SUMMARY Most pathogens enter the body at mucosal surfaces, yet, to date, the majority of licensed vaccines are injected parenterally, predominantly intramuscularly. While excellent at eliciting systemic immunity, they do not always induce the required mucosal immune responses. This highlights a gap in our understanding of how non-mucosal immunization might be manipulated to elicit mucosal immune responses and how such knowledge could be exploited to create better vaccines against mucosal pathogens. Defining the role that adjuvants play in this response is key to developing such vaccines; however, the mechanisms that dictate adjuvant driven mucosal antibody and cellular immune responses are not well understood. Our published work and preliminary experiments using major histocompatibility complex class I (MHCI) and II (MHCII) and B cell tetramers to examine mucosal immune responses after intradermal immunization with a novel detoxified bacterial ADP- ribosylating enterotoxin, called dmLT, demonstrate that we can retarget the endogenous T and B cell immune responses to the lung, intestinal mucosa, and female reproductive tract (FRT). When dmLT is combined with a safe, bacterial-derived outer membrane vesicle (OMV) adjuvant, CD4 T cell numbers and vaccine-specific antibodies and B cells are even further increased. Simultaneously, OMV adjuvant induces significant expansion of vaccine-specific CD8 T cells. Furthermore, immunization with dmLT- or OMV-adjuvanted vaccines elicits protection against bacterial infections in the lung and gut. These results lead us to hypothesize that intradermal immunization with combined dmLT plus OMVs will drive antigen-specific B cells and T cells to the mucosa and enhance vaccine protection against mucosal pathogens. We propose to: 1) determine how intradermal immunization with dmLT combined with OMV adjuvant directs 1) T cells and 2) B cells to mucosal tissue and whether these cells are bona fide tissue resident memory cells. In parallel, we will 3) examine if immunization with dmLT-OMV adjuvanted vaccines is protective against mucosal viral and bacterial infections in the lung, gut and FRT. This investigation will provide novel insights into how adjuvants regulate immunity at the mucosa and allow us to guide the response in favor of pathogen elimination.

项目摘要大多数病原体从粘膜表面进入人体，然而，迄今为止，大多数许可的疫苗都是注射的胃肠外，主要是肌内。虽然它们在引发全身免疫方面很出色，但它们并不总是诱导所需的粘膜免疫应答。这突出了我们对非粘膜上皮细胞如何免疫可能被操纵以引起粘膜免疫应答，以及这些知识如何被利用它来制造针对粘膜病原体的更好疫苗。确定佐剂在这一过程中的作用免疫应答是开发此类疫苗的关键;然而，抗体和细胞免疫应答还没有被很好地理解。我们已发表的工作和初步的使用主要组织相容性复合体I类（MHCI）和II类（MHCII）以及B细胞四聚体进行的实验检查用新型解毒细菌ADP皮内免疫后的粘膜免疫应答，核糖基化肠毒素，称为dmLT，证明我们可以重新靶向内源性T和B细胞免疫对肺、肠粘膜和女性生殖道（FRT）的反应。当dmLT与安全、细菌衍生的外膜囊泡（OMV）佐剂、CD4 T细胞数量和疫苗特异性抗体和B细胞甚至进一步增加。同时，OMV佐剂诱导显著扩增疫苗特异性CD8 T细胞。此外，用dmLT或OMV佐剂疫苗免疫会引发保护肺部和肠道免受细菌感染。这些结果使我们假设皮内用组合的dmLT加OMV免疫将驱使抗原特异性B细胞和T细胞到达粘膜，增强疫苗对粘膜病原体的保护。我们建议：1）确定皮内如何用与OMV佐剂组合的dmLT免疫将1）T细胞和2）B细胞导向粘膜组织，这些细胞是否是真正的组织驻留记忆细胞。与此同时，我们将检查免疫接种是否与dmLT-OMV佐剂疫苗联合使用，的FRT。这项研究将为佐剂如何调节粘膜免疫提供新的见解，使我们能够引导反应有利于病原体的消除。