Regulation of mucosal IgA and allergic inflammation by intestinal epithelial cells

肠上皮细胞对粘膜IgA和过敏性炎症的调节

基本信息

批准号：
9473042
负责人：
Prosper N Boyaka
金额：
$ 34.61万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9473042
关键词：
Address Affect Allergens Allergic Allergic Disease Allergic inflammation American Americas Antibodies Antigen-Presenting Cells Antigens Asthma Attenuated B-Lymphocytes Binding Cell Shape Cells Country Development Digestion Distant Dose Eosinophilia Epithelial Cells Epithelium Equilibrium Event Exhibits Extrinsic asthma Food Food Hypersensitivity Foundations Gastrointestinal tract structure Grant Histamine Agents Hypersensitivity IgE Immunoglobulin A Immunoglobulin Isotypes Incidence Inflammation Inflammatory disease of the intestine Injections Interferon Type II Interleukin-13 Interleukin-17 Interleukin-4 Interleukin-5 Intestines Knowledge Lead Lung Inflammation Lymphocyte antigen CD50 Mediating Modeling Molecular Mucous Membrane Mucous body substance Mus Myeloid Cells Neutrophil Infiltration Nose Oral Pathway interactions Persons Pharmacologic Substance Pharmacology Phenotype Play Polymeric Immunoglobulin Receptors Process Production Public Health Regulation Role Secretory Immunoglobulin A Shapes Signal Pathway Signal Transduction Site Surface Testing Th1 Cells Work absorption adaptive immune response airway hyperresponsiveness allergic airway inflammation allergic response anti-IgE antigen challenge cell type cost cytokine desensitization food allergen inhibitor/antagonist insight mucosal site novel therapeutic intervention pathogen polymeric IgA prevent protective effect public health relevance receptor response stem

项目摘要

DESCRIPTION (provided by applicant): Epithelial cells lining mucosal surfaces represent the first barrier of the host against exogenous products and pathogens. Intestinal epithelial cells (IEC) have been extensively studied for their role in the digestion and selective absorption of ingested food molecules. IEC produce cytokines that influence the differentiation of classical antigen presenting and other innate cells and subsequently, shape adaptive immune responses. These cells also express the receptor for polymeric immunoglobulins, which allows the transport of polymeric IgA across the epithelium and their secretion as secretory IgA antibodies in the lumen. However, the role of IEC in allergic responses remains poorly understood and it remains unclear how specific signaling pathways in IEC affect allergic sensitization in the GI tract and impact allergic responses at distant mucosal sites such as the airways. We will address the overall hypothesis that selected innate signaling pathway in intestinal epithelial cells shape allergen-specific antibody isotype responses and promote IgA antibodies, which can prevent the development, or reduce the magnitude of allergic inflammation at distant sites. Using genetically modified mice and pharmaceutical inhibitors of the selected innate signaling pathway we propose to 1) address how activation of the non-canonical NFB signaling in intestinal epithelial cells regulate adaptive immune response during allergic sensitization; 2) Establish mechanisms of protection against allergic inflammation by IgA and IgA+ B cells.

描述（由申请人提供）：粘膜表面的上皮细胞代表了宿主抵抗外源性产物和病原体的第一道屏障肠上皮细胞（IEC）已主要研究其在消化和选择性吸收摄入的食物分子中的作用。产生影响经典抗原呈递细胞和其他先天细胞分化的细胞因子，随后形成适应性免疫反应，这些细胞还表达聚合免疫球蛋白的受体，从而允许转运。跨上皮的聚合 IgA 及其在管腔中作为分泌性 IgA 抗体的分泌然而，IEC 在过敏反应中的作用仍然知之甚少，而且还不清楚 IEC 中的特定信号通路如何影响胃肠道的过敏致敏并影响过敏反应。我们将讨论肠上皮细胞中选择的先天信号通路形成过敏原特异性抗体同种型反应并促进 IgA 的总体假设。我们建议使用转基因小鼠和选定先天信号通路的药物抑制剂来防止远处部位过敏性炎症的发展或减轻其程度。肠上皮细胞在过敏致敏过程中调节适应性免疫反应；2) 建立 IgA 和 IgA+ B 细胞对抗过敏性炎症的保护机制。