Targeting myeloid cells for regulation of alum-based immunity

靶向骨髓细胞调节明矾免疫

基本信息

批准号：
10333230
负责人：
Prosper N Boyaka
金额：
$ 62.36万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10333230
关键词：
Address Adjuvant Affect Affinity Animal Model Antibodies Antibody Formation Antibody Response Antigen-Presenting Cells Antigens B-Lymphocytes Binding Blood Blood Circulation Cells Data Dendritic Cells Development Dose Ebola Edema Elastases Enteral Enzymes Epithelial Cells Family Family suidae Fees Future Genes Germ Germ-Free Goals Growth Factor Human Immune Immune response Immunity Immunization Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Isotypes Immunoglobulin Switch Recombination Infection Infectious Agent Injections Kinetics Leukocyte Elastase Measures Memory B-Lymphocyte Modeling Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Myeloid Cells Neutrophil Infiltration Nose Oral Outcome Pathway interactions Pharmacology Play Prevention Production Regulation Research Role Rotavirus Rotavirus Infections Route Secretory Immunoglobulin A Seminal Serine Protease Serum Signal Pathway Signal Transduction Specificity Subunit Vaccines Supplementation Surface Symptoms T cell response Testing Toxin Transcript Tretinoin Vaccine Adjuvant Vaccines Virus Vitamins Wild Type Mouse Work ZIKA alpha Toxin aluminum sulfate base chemokine cytokine enteric virus infection germ free condition improved in vivo innovation mucosa-associated lymphoid tissue mucosal vaccine neutrophil neutrophil elastase inhibitor novel oral vaccine pathogen prevent protective effect rectal response stem transcriptome sequencing vaccine delivery

项目摘要

Alum is the most widely used adjuvant in current subunit vaccines against infectious agents. Mucosal tissues represent the main portal of entry of pathogens. In contrast with the general bloodstream in the systemic compartment, mucosal tissues contain a large number of IgA producing cells. This immunoglobulin isotype contributes to the protection of exposed mucosal surfaces via a number of mechanisms including prevention of pathogen binding to host cells (epithelial cells and dendritic cells), neutralization of toxins in the lumen, and neutralization of viruses within epithelial cells. Injected vaccines can induce high levels of IgG responses in the bloodstream, but they are not effective at inducing secretory IgA responses which are needed for optimal protection of mucosal surfaces. In contrast with injected vaccines, mucosal vaccines delivered through the oral, rectal, nasal or sublingual routes target Mucosal-Associated Lymphoid Tissues where they can induce innate signals necessary for induction of secretory IgA responses. Despite decades of research on mucosal vaccines, to date, only two oral vaccines and one intranasal vaccine are licensed for use in the US. This proposal will address the overall hypothesis that the adjuvant alum triggers innate signals that restrict the breath of antibody responses and prevent the production of IgA. Our newly generated data suggest that a family of molecules produced by myeloid cells plays a central role in preventing IgA production by alum-based injected vaccines and targeting those molecules will improve protection by increasing IgA production. Aim 1 will focus on the mechanisms underlying innate suppression of IgA responses by myeloid cells in non-mucosal sites. Aim 2 will identify the cells and signaling pathways targeted by pharmacological agents inhibiting this family of molecules to regulate induction of systemic and mucosal immune responses after systemic immunization. Aim 3 will establish whether strategies targeting the innate suppressors of IgA responses promote broad systemic and mucosal immunity and can protect a relevant animal model against infection with an enteric virus.

明矾是当前亚基疫苗对感染剂的最广泛使用的佐剂。粘膜组织代表病原体进入的主要门户。与全身性的一般血液相反隔室，粘膜组织包含大量IgA产生的细胞。这种免疫球蛋白同种型通过多种机制有助于保护裸露的粘膜表面病原体与宿主细胞（上皮细胞和树突状细胞）结合，管腔中的毒素中和，以及上皮细胞中病毒的中和。注射的疫苗可以诱导高水平的IgG反应血液，但它们在诱导最佳所需的分泌IgA响应方面无效保护粘膜表面。与注射的疫苗相反，通过口服输送的粘膜疫苗，直肠，鼻或舌下路线靶向粘膜相关的淋巴组织，它们可以诱导先天性诱导分泌IgA响应所需的信号。尽管有数十年的粘膜疫苗研究，但迄今为止，只有两种口服疫苗和一种鼻内疫苗在美国使用。该提议将解决了总体假设，即辅助校友会触发限制抗体呼吸的先天信号响应并防止IgA的产生。我们新生成的数据表明一个分子家族由髓样细胞产生的靶向这些分子将通过增加IGA产生来改善保护。 AIM 1将重点放在髓样细胞在非粘膜位点对IgA反应的先天抑制的基础机制。 AIM 2意志确定由抑制该分子家族的药理学剂靶向的细胞和信号通路调节全身免疫后全身和粘膜免疫反应的诱导。目标3意志确定针对IGA响应的先天抑制器的策略是否促进了广泛的系统性和粘膜免疫，可以保护相关的动物模型免受肠道病毒感染。