Using combination adjuvants to direct and control immune responses at the intestinal mucosa

使用组合佐剂指导和控制肠粘膜的免疫反应

基本信息

批准号：
9247816
负责人：
James B McLachlan
金额：
$ 54.66万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247816
关键词：
Address Adjuvant Affect Agonist Alpha Cell Antibodies Antibody Formation Antigen Presentation Antigens Automobile Driving B-Lymphocytes Bacteria CD4 Positive T Lymphocytes Cells Cellular Immunity Communicable Diseases Data Dendritic Cells Enteral Enterotoxins Epitopes Escherichia coli Goals Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Homing Human Humoral Immunities Immune Immune response Immunity Immunization Immunize Immunoglobulin A In Vitro Infection Injectable Injection of therapeutic agent Intervention Intestinal Mucosa Intestines Intramuscular Investigation Knowledge Lead Lymphoid Tissue MHC Class II Genes Mediating Medical Memory Mission Modeling Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Oral Outcome Phenotype Play Recording of previous events Research Role Salmonella Salmonella infections Salmonella typhimurium Signal Pathway Site Skin Surface T memory cell T-Lymphocyte T-Lymphocyte Epitopes Testing Th1 Cells United States National Institutes of Health Vaccines Vibrio cholerae Work aluminum sulfate burden of illness cell motility cell type enteric pathogen experimental study human disease in vivo insight interest lymph nodes mouse model mucosal vaccine mutant novel pathogen pathogenic Escherichia coli public health relevance response tool trafficking uptake weapons

项目摘要

DESCRIPTION (provided by applicant): 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 immunization may be manipulated to elicit mucosal immune responses and how such knowledge might be exploited to create better vaccines for 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 preliminary experiments using major histocompatibility complex class II (MHCII) 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 Th17 CD4 T cells and B cell IgA immune responses to the intestinal mucosa possibly by engagement of CD103+ skin dendritic cells. We also show intradermal immunization with dmLT plus a single CD4 T cell epitope can significantly reduce bacterial burden in a mouse model of Salmonella infection. These combined results, in addition to our past work, lead us to hypothesize that intradermal immunization with dmLT engages CD103+ dendritic cells, which prime antigen-specific B cells and CD4 T cells to upregulate gut- homing markers and mucosal trafficking. We further posit that when this is combined with adjuvants acting via different signaling pathways, both cellular and humoral immunity can be tuned to adapt to a mucosal pathogen of interest. We propose to: 1) assess antigen uptake and presentation when intradermal immunization with dmLT is combined with Th1 or Th2 driving adjuvants, determine how this immunization directs 2) T cells and 3) B cells to mucosal tissue, and 4) determine if this immunization is protective against a lethal enteric infection with Salmonella bacteria. This investigation should provide novel insights into how adjuvants regulate immunity at the mucosa and allow us to guide the response in favor of pathogen elimination.

描述（由适用提供）：大多数病原体以粘膜表面输入身体，但是迄今为止，大多数许可的疫苗被育儿注射，主要是肌肉内。尽管擅长引起全身免疫力，但它们并不总是诱导所需的粘膜免疫反应。这突出了我们对如何操纵免疫的理解以引起粘膜免疫反应以及如何利用这种知识来为粘膜病原体创造更好的疫苗。定义调整在此响应中发挥的作用是开发这种疫苗的关键。但是，尚不清楚决定可调式驱动粘膜抗体和细胞免疫复杂的机制。我们使用主要的组织相容性复合物II类（MHCII）四聚体进行初步实验检查，以检查粘膜免疫复杂，并使用新型解毒细菌抗核糖毒素（称为DMLT）在皮内免疫抑制后，称为DMLT，表明我们可以将内源性th17 cd4 th17 cd4 th17 cd4 th17 cd4 th17 cd4 t cd4 t iiga恢复活力。通过CD103+皮肤树突状细胞参与可能。我们还用DMLT和单个CD4 T细胞表位显示了皮内免疫抑制，可以在沙门氏菌感染的小鼠模型中显着降低细菌性。除了过去的工作外，这些结合的结果还使我们假设使用DMLT的皮内免疫抑制与CD103+树突状细胞接合，这些细胞会引起抗原特异性的B细胞和CD4 T细胞，以上调肠道肠道粘结标记和粘膜运输。我们进一步说明，当它与通过不同信号通路作用的调节器结合在一起时，可以调节细胞和体液免疫组织切口，以适应感兴趣的粘膜病原体。我们提出：1）当用DMLT与TH1或TH2驾驶调节器结合处皮内免疫抑制时，评估抗原摄取和表现，确定该免疫抑制如何指导2）T细胞和3）B细胞对粘膜组织，以及4）确定这种免疫抑制是否会抗salmane salmane salmane salmane salmane salmane salmane salmane salmane salmane salmane selmane salmane selmane salmane selmane selmane selmane selmane。这项投资应提供有关调节器如何调节粘膜免疫史的新见解，并使我们能够指导反应以消除病原体。