Control of Airway Tolerance

描述(申请人提供)：哮喘是一种炎症性肺部疾病，常由吸入蛋白质过敏原引发。由于T细胞在哮喘和其他过敏性疾病中的核心作用，预防可能在于加强耐受机制的治疗。多年来，皮下注射过敏原一直被用作一种治疗方法，称为特异性过敏原免疫疗法(SIT或AIT)，目的是诱导长期耐受。然而，尽管SIT/AIT在一些患者中无疑是有效的，但它是一种漫长、低效且往往无效的治疗方法，需要新的方法，这种方法可能会迅速产生耐受状态，并随着时间的推移而保持。由于可诱导调节性T细胞(ITreg)的发展以及随之而来的记忆T细胞的缺失可能是耐受的关键，因此对这些细胞的分子控制的新见解可能会揭示与过敏原治疗相结合的治疗靶点。我们已经在哮喘小鼠模型中证明，吸入纯蛋白抗原可以诱导两种iTreg细胞群，Foxp3+LAP-和Foxp3-LAP+CD4细胞，这两种细胞都可以抑制Th2驱动的过敏性肺部炎症，并防止发生后续的肺部疾病。此外，我们还鉴定了一个肺抗原提呈细胞(APC)，它可能是诱导这些iTreg的原因。我们进一步证明，通过两种模式识别受体(PRR)，TLR4和NOD2，在肺中表达的信号，直接拮抗iTreg的发育，而有利于致病Th2细胞的发育。最重要的是，这些PRR通过两种细胞因子，TSLP和IL-25，以及TNFR超家族OX40L的共刺激成员来驱动肺反应。过敏原是否会引起相同的分子特征来反对耐受性尚不清楚，但我们发现，两种用于哮喘患者SIT的提取物(含有与哮喘相关的过敏原)可以抑制呼吸道iTreg的产生，这两种提取物分别来自屋尘螨(HDM)和烟曲霉菌(AspergillusFumigatus)。过敏和哮喘患者的耐受性也必须对抗原有记忆T细胞的活性。我们进一步确定OX40L和另一个肿瘤坏死因子共刺激家族配体LIGH是记忆T细胞的强大调节因子，推动其克隆性扩张和存活。因此，我们的假设是，只有当这些分子中的几个以及与这些分子协同作用的细胞因子被协同抑制时，才能在先前致敏的个体中实现对过敏原的长期有效耐受。这项提案将确定几种常见的人类过敏原引起的分子特征，并测试在过敏原免疫治疗期间操纵这些细胞因子和共刺激配体以及驱动iTreg诱导的APC是否将是促进致敏个体耐受性的关键。

DESCRIPTION (provided by applicant): Asthma is an inflammatory lung disease often triggered by inhalation of protein allergens. Because of the central role of T cells in asthma, as with other allergic diseases, prevention may lie in treatments that enhance tolerance mechanisms. Injection of allergens subcutaneously has been used for many years as a treatment, called specific-allergen immune therapy (SIT or AIT), with the goal of inducing long-term tolerance. However, although SIT/AIT can undoubtedly be efficacious in some patients, it is a lengthy, inefficient, and often ineffective treatment, warranting new approaches that may quickly induce a state of tolerance and one that is maintained over time. As the development of inducible regulatory T cells (iTreg) and the concomitant deletion of memory T cells may be key to tolerance, new insights into the molecular control of these cells may then reveal therapeutic targets that can be combined with allergen treatment. We have shown in a mouse model of asthma that inhalation of pure protein antigen induces two iTreg populations, Foxp3+LAP- and Foxp3-LAP+ CD4 cells, that both can suppress Th2-driven allergic lung inflammation and protect against developing subsequent lung disease. Moreover, we identified a lung antigen-presenting cell (APC) that may be responsible for inducing these iTreg. We have further shown that signals through two pattern recognition receptors (PRR), TLR4 and Nod2, expressed in the lung, directly antagonize development of the iTreg and instead favor the development of pathogenic Th2 cells. Most importantly, these PRR drive the lung response through two cytokines, TSLP and IL-25, and a costimulatory member of the TNFR superfamily OX40L. Whether allergens elicit the same molecular signature to oppose tolerance is unclear, but we have found that generation of airway iTreg is inhibited by two extracts that are used for SIT in asthmatics and contain allergens associated with asthma, from Dermatophagoides pteronyssinus, a house dust mite (HDM), and from Aspergillus fumigatus, a fungus. Tolerance in allergic and asthmatic individuals also has to counter activities of pre-existing memory T cells We have further identified OX40L and another TNF costimulatory family ligand, LIGHT, as strong regulators of memory T cells that drive their clonal expansion and survival. Our hypothesis is then that long-term and effective tolerance will only be achieved to allergens in previously sensitized individuals if several of these molecules, and cytokines that synergize with these molecules, are coordinately suppressed. This proposal will determine the molecular signature elicited by several common human allergens, and test whether manipulating these cytokines and costimulatory ligands, and APC that drive iTreg induction, will be key to promoting tolerance in sensitized individuals during allergen immunotherapy.