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

描述(由申请人提供)：我们最近报告了一种树突状细胞(DC)影响T辅助细胞在肺内安装过敏性呼吸道炎症的机制。变应原屋尘螨致DC c-kit及其配体干细胞因子(SCF)双重上调，刺激IL-6的产生和Notch配体Jagge-2的表达，但下调IL-12的产生。这反过来促进了Th2/Th17的发展，但抑制了Th1的分化。缺乏功能c-kit的DC不能产生IL-6或表达Jagge-2。与野生型DC不同，当过继转移到小鼠体内时，表达突变c-kit的DC不能在受体小鼠中诱导强大的Th2/Th17反应或过敏性呼吸道炎症。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。这些发现使我们推测，DC中的c-kit/Jagge-2/IL-6途径通过调节细胞因子(IL-6/IL-12)平衡和Jagge-2的表达，共同影响对变应原的免疫反应，在促进过敏性呼吸道疾病的发生中发挥重要作用。在DC中禁用c-kit将有助于控制哮喘，以应对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1.表征常见变应原对肺树突状细胞c-kit/Jagge-2/IL-6表达的影响，以及用改良的格列卫阻断c-kit功能的后果。目的II.在树突状细胞中诱导表达显性-负性c-kit突变体的转基因小鼠，观察上述变应原对哮喘表型的影响。 公共卫生相关性：该项目的目标是通过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。

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.