Development of Tolerance in a Murine Model of House Dust Mite-Induced Asthma

描述（由申请人提供）：免疫系统具有保护宿主免受有害生物侵害的能力，同时保持对自身蛋白质和无害抗原的免疫耐受或无反应性状态。免疫耐受的破坏可导致对常见的环境抗原过敏，如屋尘螨（HDM）。尽管过敏表现在多种情况下，但由于哮喘在发达国家和不发达国家的患病率越来越高，最近的注意力主要集中在哮喘上。不幸的是，哮喘的药物治疗只能提供短期的症状缓解，而不能特异性地改变对诱发过敏原的潜在免疫反应，因此在降低哮喘的总体发病率和经济负担方面效果甚微。因此，确定控制免疫耐受发展的机制以提高哮喘患者的护理标准变得至关重要。先前的研究通过建立T调节细胞（Treg）作为哮喘动物模型中耐受性发展的关键角色，极大地增加了我们对免疫耐受性的工作知识。在接受过敏原特异性免疫疗法（SIT）的人类受试者中进行的研究也表明，Tregs与免疫耐受性的发展（即症状的减轻）有关。SIT是一种改善疾病的疗法，可恢复过敏和哮喘患者的正常免疫力。然而，treg在哮喘和SIT环境中产生和维持的机制目前尚不清楚。ii型活化巨噬细胞（M h -II）是一种特异性巨噬细胞亚型，被怀疑在免疫调节和耐受性形成中发挥作用，可能是通过分泌激活Treg所需的可溶性抗炎介质（细胞因子）在肺室中产生Treg的潜在候选者。本研究假设，调节性M h s-II通过影响Treg活性来诱导对尘螨抗原的免疫耐受。该提案的总体目的是研究(1)慢性吸入暴露于HDM抗原后M h s-II的发展是否通过刺激Treg介导耐受性的形成(2)治疗HDM诱导的哮喘后SIT的耐受性形成是由M h s-II介导的Treg活性的影响引起的。总体影响：上述目标的成功实现将阐明肺巨噬细胞作为哮喘患者的一种新的治疗靶点。

DESCRIPTION (provided by applicant): The immune system has the capacity to protect the host from harmful organisms while maintaining a state of immunological tolerance, or non-reactivity, to self-proteins and innocuous antigens. Disruption of immunological tolerance can result in allergy to common, environmental antigens such as house dust mite (HDM). Although allergy manifests in a variety of conditions, recent attention has focused heavily on asthma due to its growing prevalence in developed and undeveloped nations alike. Unfortunately, pharmacologic therapies for asthma provide only short-term symptom relief without specifically altering the underlying immune response to the instigating allergen and thus have marginal effects on reducing the overall rate and economic burden of asthma. It has therefore become crucial to define the mechanisms that govern the development of immunological tolerance in order to improve upon the standards of care for patients with asthma. Previous studies have added tremendously to our working knowledge of immunological tolerance by establishing the T regulatory cell (Treg) as a key player in tolerance development in animal models of asthma. Studies in human subjects receiving allergen-specific immunotherapy (SIT), a disease-modifying treatment that restores normal immunity in patients with allergy and asthma, have also associated Tregs with development of immunological tolerance (i.e. reduction of symptoms). However, the mechanism by which Tregs are generated and maintained in the settings of asthma and SIT is currently unknown. The type II-activated macrophage (Mɸ-II), a specific macrophage subtype that is suspected of playing a role in immune regulation and tolerance formation, may be a potential candidate for generation of Tregs in the lung compartments through secretion of soluble, anti-inflammatory mediators (cytokines) required for Treg activation. This proposal hypothesizes that regulatory Mɸs-II drive the induction of immunological tolerance to house dust mite antigen through influences on Treg activity. The overall aims of the proposal center on investigating whether (1) development of Mɸs-II following chronic inhalational exposure to HDM antigen mediates tolerance formation through stimulatory effects on Tregs (2) tolerance formation following SIT for treatment of HDM- induced asthma results from Mɸ-II-mediated effects on Treg activity. Overall impact: Successful accomplishment of the aforementioned aims will elucidate pulmonary macrophages as a novel, therapeutic target for patients who suffer from asthma.