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

描述（由申请人提供）：免疫系统有能力保护宿主免受有害生物的侵害，同时保持对自身蛋白质和无害抗原的免疫耐受性或无反应性状态。免疫耐受性的破坏可导致对常见的环境抗原如屋尘螨（HDM）的过敏。虽然过敏表现在各种条件下，最近的注意力集中在哮喘，由于其在发达国家和不发达国家的日益普遍。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应答，因此对降低哮喘的总体发病率和经济负担的作用甚微。因此，它已成为至关重要的，以确定的机制，管理免疫耐受的发展，以提高对哮喘患者的护理标准。以前的研究通过建立T调节细胞（Treg）作为哮喘动物模型耐受性发展的关键参与者，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，这是一种在过敏和哮喘患者中恢复正常免疫力的疾病修饰治疗，也将THBE与免疫耐受性的发展（即症状减轻）相关联。然而，在哮喘和SIT的情况下产生和维持TdR的机制目前尚不清楚。II型活化的巨噬细胞（M β-II），一种被怀疑在免疫调节和耐受形成中起作用的特定巨噬细胞亚型，可能是通过分泌Treg活化所需的可溶性抗炎介质（细胞因子）在肺隔室中产生Tcl 3的潜在候选者。该提议假设调节性M β-II通过影响Treg活性来驱动对屋尘螨抗原的免疫耐受的诱导。该提案的总体目标集中于研究（1）慢性吸入暴露于HDM抗原后M β-II的发展是否通过对T细胞的刺激作用介导耐受性形成（2）治疗HDM诱导的哮喘的SIT后的耐受性形成是否由M β-II介导的对Treg活性的作用引起。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.