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）：我们最近报道了树突状细胞（DCS）影响T辅助细胞以在肺中安装过敏性气道炎症的机制的鉴定。在DCS上引起了C-KIT及其配体干细胞因子（SCF）的双重上调，刺激了白介素-6（IL-6）的产生以及Notch配体的表达，Jagged-2，但下调IL-12的产生。反过来，这促进了TH2/TH17的发展，但抑制了Th1的分化。缺乏功能性C-KIT的DC无法产生IL-6或表达锯齿状-2。与野生型的同类产品不同时，表达突变体C-KIT的DC无法诱导受体小鼠中强大的TH2/TH17反应或过敏性气道炎症。由PI3激酶缺陷的小鼠产生的DC在用粘膜辅助刺激后分泌IL-6的较低水平。这些发现共同使我们假设DC中的C-KIT/JAGGED-2/IL-6途径通过调节细胞因子（IL-6/IL-12）（IL-6/IL-12）在促进过敏性气道疾病中起重要作用，从而共同影响对过敏原的免疫反应。在DC中禁用C-KIT将有助于控制促进该途径的特定过敏原。为了解决这些假设，我们将：AIMI。表征共同过敏原对肺DC中C-KIT/JAGGED-2/IL-6表达的影响，以及以修饰的Gleevec形式的C-KIT功能阻断的结果。目标II。产生的转基因小鼠在DC中表达C-KIT的显性阴性突变体，以研究对上述过敏原的响应对哮喘表型的影响。公共卫生相关性：该项目的目的是了解细胞表面分子C-KIT在使用过敏性哮喘的鼠模型中促进各种常见过敏原的过敏反应中的作用。