Pulmonary Interactions with Innate Immunity

描述(由申请人提供)：哮喘发病率正在增加，需要研究不同的免疫机制。先天的、非抗原依赖的免疫已被证明在过敏反应中发挥作用。我们的数据表明，先天免疫凝集素，表面活性物质(SP-)-D，可以作为过敏反应的内源性抗炎调节因子发挥作用。我们分析了T细胞和SP-D的相互作用，并重点研究了T辅助(Th)17T细胞。此外，我们还调查了T细胞的抑制物细胞毒性T淋巴细胞抗原4(CTLA4)介导SP-D效应的证据。我们的数据表明，SP-D降低了IL-17的反应，而增加了CTLA4。我们的总体假设是，SP-D是一种内源性免疫调节剂，通过诱导T细胞内的免疫抑制途径来减少过敏性炎症。目的1研究SP-D对T细胞亚群的调节机制。目的2将分析SP-D与T细胞结合的生化和细胞机制。目的3将重点介绍SP-D依赖的分子调控CTLA4表达的分子机制。目的研究哮喘患者T细胞亚群对SP-D的反应。SP-D的抗炎作用，特别是在T细胞激活方面，为T细胞介导的疾病的潜在治疗干预揭示了一条独特的途径。这项提案将研究可能导致开发哮喘治疗干预候选药物的生化和生物途径。公共卫生相关性：过敏性哮喘已成为世界许多地区的流行病，并迫使研究替代策略。我们将关注与哮喘没有经典联系的免疫途径，但可能会发现预防或治疗哮喘的新见解。我们将在哮喘动物模型和人类哮喘患者样本中研究免疫分子在减少免疫反应中的作用，包括免疫(T细胞)激活。

DESCRIPTION (provided by applicant): Asthma incidence is increasing and warrants investigation of distinct immune mechanisms. Innate, non- antigen-dependent immunity has been shown to play a role in allergic responses. Our data suggest that the innate immune collectin, surfactant (SP-)-D, can function as an endogenous, anti-inflammatory regulator of allergic responses. We analyze T cell and SP-D interactions, and focus on T helper (Th) 17 T cells. Also, we investigate evidence that cytotoxic t-lymphocyte antigen 4 (CTLA4), an inhibitor of T cells, mediates SP-D effects. Our data indicate that SP-D diminishes IL-17 responses while increasing CTLA4. Our overall hypothesis is that SP-D is an endogenous regulator of immunity that decreases allergic inflammation by inducing immunosuppressive pathways within T cells. Aim 1 will investigate the mechanisms of SP-D modulation of T cell subsets. Aim 2 will analyze the biochemical and cellular mechanisms of SP-D binding to T cells. Aim 3 will focus on SP-D-dependent molecular mechanisms regulating CTLA4 expression. Aim 4 will investigate the response of T cell subsets to SP-D in cells obtained from asthmatic subjects. An anti-inflammatory role for SP-D, specifically in T cell activation, reveals a distinct pathway for potential therapeutic intervention in T cell mediated disorders. This proposal will examine biochemical and biological pathways that may lead to the development of candidates for therapeutic intervention for asthma. PUBLIC HEALTH RELEVANCE: Allergic asthma has become an epidemic in many parts of the world, and compels investigation of alternative strategies. We will focus on immune pathways that are not classically associated with asthma, but may uncover new insights into the prevention or treatment of asthma. We will examine the roles of immune molecule in decreasing immune responses, including immune (T cell) activation in an animal model of asthma and with samples from human asthmatics.