Arachidonic Acid Mediated Regulation of Secretory IgA Levels in the Airways

描述（由申请人提供）：分泌IgA （SIgA）是粘膜免疫的重要介质。促进气道中SIgA产生的策略将使易受空气传播病原体感染的患者受益。我们的研究指出了一种新的分子途径，通过这种途径花生四烯酸代谢调节气道中SIgA产生的基础速率。因此，我们的研究可能会支持一种药物的开发，这种药物可以作为粘膜疫苗的联合疗法，永久性地提高气道中SIgA的水平；从而提供了一种非常持久的病原体特异性保护。然而，由于先天SIgA的多反应性及其寡糖侧链直接与细菌结合的能力，我们的研究也可能支持开发一种单独的治疗方法，以增强SIgA提供的一般保护性粘膜免疫。我们的初步研究支持一个工作模型，其中气道中SIgA产生的大小在很大程度上取决于气道上皮细胞产生的12/15-脂氧合酶（LO）和5-LO代谢物的组成生成水平及其下游诱导树突状细胞产生一氧化氮（NO）的能力。我们将通过完成两个具体目标来检验这一假设。具体目标目的：确定半胱氨酸白三烯（cyyslts）是否介导野生型小鼠气道中NO和SIgA的基线生成，以及CysLTs的增加是否介导12/15-LO-/-小鼠气道中NO和SIgA的增加。具体目标2。为了确定NO是否介导野生型小鼠气道中基线SIgA的产生，以及是否增加NO介导12/15-LO-/-小鼠气道中SIgA产生的增加。我们估计我们提出的研究将在大约两年内完成，我们预计它们将导致更多关于气道中SIgA调节的基本机制的问题。我们提出的小鼠研究将利用非常明确的遗传和药理学方法。针对LO和NO途径的药物已经开发或正在出现。因此，我们相信我们提出的研究将揭示一种新的机制途径，可以很容易地操纵来显著提高气道中的SIgA水平。我们的研究表明，花生四烯酸代谢酶、12/15-脂氧合酶和5-脂氧合酶调节传导气道的一线防御分子分泌IgA。我们推测这是由于它们产生半胱氨酸白三烯的能力，而半胱氨酸白三烯的作用是由一氧化氮介导的。操纵这一途径将导致诱导分泌IgA和降低对肺部感染的易感性。我们的研究将为美国国立卫生研究院预防疾病和促进健康的目标提供有价值的信息。

DESCRIPTION (provided by applicant): Secretory IgA (SIgA) is an important mediator of mucosal immunity. Strategies that boost SIgA production in the airways will confer benefit to patients that have become susceptible to infections caused by airborne pathogens. Our studies point to a novel molecular pathway by which arachidonic acid metabolism regulates the basal rate of SIgA production in the airways. As such our studies might support the development of a medicine that can be used as a co-therapy with mucosal vaccines to permanently boost the levels of SIgA in the airways; thus providing a very long-lived pathogen-specific protection. However, because of the polyreactivity of innate SIgA and the ability of its oligosaccharide side-chains to bind directly to bacteria, our studies might also support the development of a stand-alone therapy to boost the generally protective mucosal immunity that is afforded by SIgA. Our preliminary studies support a working model in which the magnitude of SIgA production in the airways is largely dependent upon the levels of constitutive generation of 12/15- lipoxygenase (LO) and 5-LO metabolites produced by airway epithelial cells and their downstream ability to induce nitric oxide (NO) production by dendritic cells. We will test this hypothesis by completing two specific aims. Specific Aim 1. To determine if cysteinyl leukotrienes (CysLTs) mediate baseline NO and SIgA production in the airways of wild-type mice and if increased CysLTs mediate the increase of NO and SIgA observed in the airways of 12/15-LO-/- mice. Specific Aim 2. To determine if NO mediates baseline SIgA production in the airways of wild-type mice and if increased NO mediates the increase of SIgA production observed in the airways of 12/15-LO-/- mice. We estimate that our proposed studies will be complete in approximately two-years and we anticipate that they will lead to additional questions regarding the basic mechanisms by which SIgA is regulated in the airways. Our proposed mouse studies will utilize very well characterized genetic and pharmacologic approaches. Medicines that target the LO and NO pathways are already developed or emerging. Thus, we believe that our proposed studies will reveal a novel mechanistic pathway that can be readily manipulated to dramatically boost SIgA levels in the airways. Our studies indicate that the arachidonic acid metabolizing enzymes, 12/15-lipoxygenase and 5-lipoxygenase regulate the first-line defense molecule secretory IgA in the conducting airways. We hypothesize that this is due to their ability to produce cysteinyl leukotrienes and the effects of the cysteinyl leukotrienes are mediated by nitric oxide. Manipulation of this pathway would be predicted to result in induction of secretory IgA and decreased susceptibility to pulmonary infections. Our studies will provide valuable information supporting the goal of the National Institutes of Health to prevent disease and promote health.