Adhesion Molecules in Allergic Lung Inflammation

描述（由申请人提供）：本实验室的长期目标是了解CD4+ T细胞介导过敏性肺部疾病的机制。具体来说，本提案将确定粘附分子在过敏性哮喘模型中调节辅助性T型1 （Th1）和Th2细胞归巢中的作用。只有Th2细胞介导过敏性肺部疾病，但定义粘附分子差异调节Th1和Th2归巢提供了一个机会，选择性地排除与疾病有关的亚群。归巢在这里被定义为效应CD4+ T细胞离开血管间隙进入实质组织的能力，并将通过比较脾脏（它们的起源）和肺（它们的迁移）中存在的细胞数量来评估。我们假设Th1和Th2细胞对整合素及其受体的要求是不同的。为了证明这一点，我们已经开始探索CD18（整合素a2）和cd11a（整合素DL）， T细胞表达CD18（形成白细胞功能抗原1；LFA-1）的异二聚体伴侣，以及相关整合素家族成员在th2依赖的变应性肺部疾病模型中的作用。CD18缺陷小鼠在鼻内过敏原刺激后产生功能性Th1和Th2细胞，但不像野生型对照小鼠那样发生哮喘样过敏性疾病。CD18-/-小鼠的Th2细胞，而不是Th1细胞，仍然局限于脾脏，不能回到肺部。总之，我们的数据表明CD18协调Th2细胞的归巢，而不是Th1细胞的归巢，揭示了一种新的模式，其中T辅助效应亚群不同地依赖于组织归巢的整合素。Specific Aim 1将探索CD18的两个分子伙伴，CD11a和cd11b在相同哮喘模型中使用基因缺陷小鼠的T细胞效应物发育和归巢中的作用。特异性目的2将研究LFA-1- cd54（细胞间粘附分子1；ICAM-1）相互作用在差异协调肺Th1和Th2归巢中的需求，使用基因缺陷小鼠和一种具有潜在临床适用性的新型LFA-1抑制剂。最后，Specific Aim 3将使用体外归巢趋化模型确定LFA-1对Th2归巢选择性需求的基础。所提出的工作将为变应性肺部疾病的发病机制提供深入的了解，并为开发基于整合素的治疗方法来中断th2驱动的过敏过程提供合理的基础。

DESCRIPTION (PROVIDED BY APPLICANT): The broad, long-term objectives of this laboratory are to understand the mechanisms by which CD4+ T cells mediate allergic lung disease. Specifically, this proposal will define the role of adhesion molecules in regulating the homing of T helper type 1 (Th1) and Th2 cells in an allergic asthma model. Only Th2 cells mediate allergic lung disease, but defining the adhesion molecules that differentially regulate Th1 and Th2 homing provides an opportunity to selectively exclude subsets implicated in disease. Homing is defined here as the ability of effector CD4+ T cells to exit the vascular space and enter parenchymal tissues and will be assessed by comparing numbers of cells present in spleens (where they originate) and the lung (where they immigrate). We hypothesize that integrins and their receptors are differentially required by Th1 and Th2 cells for homing to lung. To prove this, we have begun to explore the role of CD18 (integrin a2) and CD11 a (integrin DL), the heterodimeric partner of T cell-expressed CD18 (forming leukocyte function antigen 1; LFA-1), and related integrin family members in a Th2-dependent model of allergic lung disease. CD18- deficient mice generate functional Th1 and Th2 cells following intranasal allergen challenge but fail to develop asthma- like allergic disease as seen in wild type control mice. Th2, but not Th1, cells remained confined to the spleens of CD18-/- mice and were unable to home to lung. Together, our data indicate that CD18 coordinates the homing of Th2, but not Th1, cells to lung, revealing a new paradigm in which T helper effector subsets differentially depend on integrins for tissue homing. Specific Aim 1 will explore the role of two molecular partners of CD18, CD11a and CD11 b in T cell effector development and homing using gene deficient mice in the same asthma model. Specific Aim 2 will examine the requirement of the LFA-1-CD54 (intercellular adhesion molecule 1; ICAM-1) interaction in differentially coordinating lung Th1 and Th2 homing using gene deficient mice and a novel LFA-1 inhibitor with potential clinical applicability. Finally, Specific Aim 3 will determine the basis for the selective requirement of LFA-1 for Th2 homing using an in vitro chemotaxis model of homing. The work proposed will provide mechanistic insight into the pathogenesis of allergic lung disease and provide a rational basis for development of integrin-based therapeutics for interrupting Th2-driven allergic processes.