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

描述（由申请人提供）：我们最近报道了树突状细胞（dc）影响T辅助细胞在肺部产生过敏性气道炎症的机制。过敏原尘螨引起c-kit及其配体干细胞因子（SCF）对dc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，但下调IL-12的产生。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不能产生IL-6或表达Jagged-2。当过继转移到小鼠体内时，与野生型不同，表达突变c-kit的dc不能在受体小鼠中诱导强烈的Th2/Th17反应或过敏性气道炎症。由PI3激酶缺陷小鼠产生的dc在粘膜佐剂刺激下分泌较低水平的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）的平衡和Jagged-2的表达，共同影响对过敏原的免疫反应，在变应性气道疾病的促进中起重要作用。在dc中禁用c-kit将有助于控制哮喘对促进这一途径的特定过敏原的反应。为了解决这些假设，我们将：目的1：表征常见过敏原对肺dc中c-kit/Jagged-2/IL-6表达的影响，以及用改良形式的格列卫阻断c-kit功能的后果。目的二世。在dc中诱导表达c-kit显性阴性突变的转基因小鼠，研究上述过敏原对哮喘表型的影响。

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.