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：
9897437
负责人：
Prosper N Boyaka
金额：
$ 65.83万
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/9897437
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 Virus Diseases Vitamins Wild Type Mouse Work ZIKA alpha Toxin aluminum sulfate base chemokine cytokine 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

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.

明矾是目前针对传染原的亚单位疫苗中使用最广泛的佐剂。粘膜组织代表病原体进入的主要门户。与全身的一般血流相反粘膜组织含有大量 IgA 产生细胞。这种免疫球蛋白同种型通过多种机制有助于保护暴露的粘膜表面，包括预防病原体与宿主细胞（上皮细胞和树突状细胞）结合，中和管腔中的毒素，以及中和上皮细胞内的病毒。注射疫苗可在体内诱导高水平的 IgG 反应血流，但它们不能有效诱导最佳分泌型 IgA 反应所需的分泌型 IgA 反应。保护粘膜表面。与注射疫苗相比，粘膜疫苗通过口服、直肠、鼻腔或舌下途径以粘膜相关淋巴组织为目标，可诱导先天性诱导分泌型 IgA 反应所必需的信号。尽管对粘膜疫苗进行了数十年的研究，迄今为止，只有两种口服疫苗和一种鼻内疫苗获准在美国使用。该提案将解决了佐剂明矾触发限制抗体呼吸的先天信号的总体假设反应并阻止 IgA 的产生。我们新生成的数据表明，一个分子家族骨髓细胞产生的 IgA 在防止明矾注射疫苗产生 IgA 方面发挥着核心作用针对这些分子将通过增加 IgA 的产生来改善保护。目标 1 将重点关注非粘膜部位的骨髓细胞先天性抑制 IgA 反应的机制。目标2将识别抑制该分子家族的药物所针对的细胞和信号通路调节全身免疫后诱导全身和粘膜免疫反应。目标3将确定针对 IgA 反应先天抑制因子的策略是否能促进广泛的系统性和粘膜免疫，可以保护相关动物模型免受肠道病毒感染。