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辅助细胞在肺中引起过敏性气道炎症的机制的鉴定。过敏原屋尘螨引起的c-kit和它的配体，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，锯齿状蛋白-2的表达，但下调IL-12的生产。这反过来又促进了Th 2/Th 17的发育，但抑制了Th 1的分化。缺乏功能性c-kit的DC不能产生IL-6或表达Jagged-2。当过继转移到小鼠中时，与野生型对应物不同，表达突变c-kit的DC不能在受体小鼠中诱导稳健的Th 2/Th 17应答或过敏性气道炎症。由PI 3激酶缺陷的小鼠产生的DC在用粘膜佐剂刺激时分泌较低水平的IL-6。这些发现共同引导我们假设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Jagged-2的表达（其共同影响对过敏原的免疫应答）在促进过敏性气道疾病中起重要作用。在DCs中禁用c-kit将有助于控制哮喘，以响应促进这一途径的特定过敏原。为了解决这些假设，我们将：目的一。描述常见过敏原对肺DCs中c-kit/Jagged-2/IL-6表达的影响，以及使用改良形式的Gleevec阻断c-kit功能的结果。Aim II.建立可诱导表达c-kit显性阴性突变体的转基因小鼠，研究上述变应原对哮喘表型的影响。 公共卫生相关性：本研究的目的是利用小鼠过敏性哮喘模型，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应答中的作用。

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.