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。具体地说，这项提议将定义黏附分子在调节过敏性哮喘模型中T辅助细胞1型(Th1)和Th2细胞归巢中的作用。只有Th2细胞介导变态反应性肺部疾病，但定义不同调节Th1和Th2归巢的黏附分子提供了有选择地排除与疾病有关的亚群的机会。归巢在这里被定义为效应的CD4+T细胞离开血管空间进入实质组织的能力，将通过比较脾(它们起源的地方)和肺(它们迁移的地方)中存在的细胞数量来评估。我们假设，Th1和Th2细胞不同地需要整合素及其受体来归巢到肺。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d1)，T细胞表达的CD18(形成白细胞功能抗原1；LFA-1)的异二聚体伙伴，以及相关的整合素家族成员在Th2依赖的过敏性肺病模型中的作用。CD18缺陷小鼠在鼻内过敏原攻击后产生功能正常的Th1和Th2细胞，但未能发展为类似哮喘的过敏性疾病，如野生型对照小鼠所见。Th2，而不是Th1，细胞仍然局限在CD18-/-小鼠的脾内，无法回到肺中。总之，我们的数据表明CD18协调Th2细胞到肺的归巢，而不是Th1细胞到肺的归巢，揭示了一种新的范式，其中T辅助效应亚群不同地依赖于整合素来进行组织归巢。目的1探讨CD18、CD11a和CD11b两个分子伴侣在同一哮喘模型中T细胞效应分子发育和归巢过程中的作用。具体目标2将研究LFA-1-CD54(细胞间黏附分子1；ICAM-1)相互作用在利用基因缺陷小鼠和具有潜在临床应用的新型LFA-1抑制剂进行肺Th1和Th2归巢的差异协调中的要求。最后，特异靶3将利用归巢的体外趋化模型确定LFA-1对Th2归巢的选择性要求的基础。这项工作将为过敏性肺病的发病机制提供机制方面的见解，并为基于整合素的治疗药物的开发提供合理的基础，以阻断Th2驱动的过敏过程。

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.