Targeting c-kit in Dendritic Cells to Control allergic Immune Responses

靶向树突状细胞中的 c-kit 控制过敏性免疫反应

基本信息

批准号：
8135015
负责人：
Prabir Ray
金额：
$ 18.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8135015
关键词：
1-Phosphatidylinositol 3-Kinase Academy Address Adjuvant Allergens Allergic Ambrosia Antigen-Presenting Cells Asthma Biological Assay CD4 Positive T Lymphocytes Cardiotoxicity Cell Separation Cell surface Cells Cellular biology Characteristics Cholera Toxin Defect Dendritic Cells Development Dominant-Negative Mutation Ensure Enzyme-Linked Immunosorbent Assay Epithelial Cells Equilibrium Experimental Models Extrinsic asthma Felis catus Flow Cytometry Generations Gleevec Goals Helper-Inducer T-Lymphocyte House Dust Mite Allergens ITGAM gene ITGAX gene Immune response Immune system Immunology In Vitro Interleukin-12 Interleukin-17 Interleukin-4 Interleukin-6 Lead Ligands Literature Lung Medicine Modeling Molecular Mus Mutant Strains Mice Nature New York Outcome Ovalbumin Pathway interactions Phenotype Play Pollen Production Proto-Oncogene Protein c-kit Publications Pyroglyphidae Relative (related person)Reporting Role Science Signal Transduction Specificity Stem Cell Factor T cell differentiation T-Lymphocyte T-bet protein Time Transgenic Mice Tumor Necrosis Factor-alpha Up-Regulation airway hyperresponsiveness airway inflammation allergic airway disease allergic airway inflammation allergic response base cockroach allergen cytokine enzyme linked immunospot assay human TSLP protein in vivo interest lymph nodes mast cell member mutant news notch protein novel prevent promoter public health relevance response

项目摘要

DESCRIPTION (provided by applicant): We recently reported the identification of a mechanism by which dendritic cells (DCs) influence T helper cells to mount allergic airway inflammation in the lung. The allergen house dust mite caused dual upregulation of c-kit and its ligand, stem cell factor (SCF), on DCs stimulating production of interleukin-6 (IL-6) and expression of the Notch ligand, Jagged-2, but downregulated IL-12 production. This, in turn, promoted Th2/Th17 development but inhibited Th1 differentiation. DCs lacking functional c-kit were unable to produce IL-6 or express Jagged-2. When adoptively transferred into mice, unlike their wild-type counterparts, DCs expressing mutant c-kit were unable to induce a robust Th2/Th17 response or allergic airway inflammation in the recipient mice. DCs generated from mice with defects in PI3 kinase secreted lower levels of IL-6 upon stimulation with a mucosal adjuvant. These findings collectively lead us to hypothesize that the c-kit/Jagged-2/IL-6 pathway in DCs plays an important role in the promotion of allergic airways disease by regulating cytokine (IL-6/IL-12) balance and expression of Jagged-2 that together influence the immune response to allergens. Disabling c-kit in DCs would help control asthma in response to particular allergens that promote this pathway. To address these hypotheses we will: Aim I. Characterize the effect of common allergens on c-kit/Jagged-2/IL-6 expression in lung DCs and the consequence of blockade of c-kit function with a modified form of Gleevec. Aim II. Generate transgenic mice inducibly expressing a dominant-negative mutant of c-kit in DCs to investigate effects on the asthma phenotype in response to the above allergens. PUBLIC HEALTH RELEVANCE: The goal of this project is to understand the role of a cell surface molecule, c-kit, in promoting allergic immune response to various common allergens using murine models of allergic asthma.

描述（由申请人提供）：我们最近报告了树突状细胞（DC）影响T辅助细胞在肺部引发过敏性气道炎症的机制的鉴定。过敏原屋尘螨引起 DC 上 c-kit 及其配体干细胞因子 (SCF) 的双重上调，刺激白细胞介素 6 (IL-6) 的产生和 Notch 配体 Jagged-2 的表达，但 IL 下调-12生产。这反过来促进了 Th2/Th17 的发育，但抑制了 Th1 的分化。缺乏功能性 c-kit 的 DC 无法产生 IL-6 或表达 Jagged-2。当过继转移到小鼠体内时，与野生型对应物不同，表达突变 c-kit 的 DC 无法在受体小鼠中诱导强烈的 Th2/Th17 反应或过敏性气道炎症。 PI3激酶缺陷小鼠产生的DC在用粘膜佐剂刺激后分泌较低水平的IL-6。这些发现共同使我们假设 DC 中的 c-kit/Jagged-2/IL-6 通路通过调节细胞因子 (IL-6/IL-12) 平衡和表达，在促进过敏性气道疾病中发挥重要作用。 Jagged-2 共同影响对过敏原的免疫反应。禁用 DC 中的 c-kit 将有助于控制哮喘，以应对促进该途径的特定过敏原。为了解决这些假设，我们将：目标 I. 表征常见过敏原对肺 DC 中 c-kit/Jagged-2/IL-6 表达的影响，以及使用改良形式的格列卫阻断 c-kit 功能的后果。目标二。生成在 DC 中诱导表达 c-kit 显性失活突变体的转基因小鼠，以研究对上述过敏原反应对哮喘表型的影响。公共健康相关性：该项目的目标是利用过敏性哮喘小鼠模型了解细胞表面分子 c-kit 在促进对各种常见过敏原的过敏性免疫反应中的作用。