IL-35依赖的免疫调节T细胞iT(R)35对抗原特异性记忆T细胞的抑制在过敏性哮喘特异性免疫治疗中的作用和机制研究

Allergic asthma is a hard-to-cure airway disease and usually caused by the repeated allergen exposure. The typically pathological change is characterized by pulmonary inflammation and reversible airway obstruction caused by the type 2 T helper (Th2) cells. Allergen-specific immunotherapy (AIT) is the only causative therapy aimed to establish the immunological tolerance, which is based on the repeated allergen treatment. However, this kind of treatment is non-effective to quite a number of patients for unrevealed reasons. Besides, the lack of clinical parameters that could precisely reflect the symptom remission is still a bottle neck for physicians to adjust the treatment prescription in time. It is impending to elucidate the molecular mechanisms involved in the AIT and develop a potential biomarker for monitoring the therapeutic effect. In this study, we intent to explore the role of the antigen specific iT(R)35 and IL-35 in AIT-induced immune tolerance and clarify the underlying molecular mechanisms. We will employ a novel murine model with improved clinical association to reveal the effect of AIT induced iT(R)35 and IL-35 on the key immune cell subpopulation----antigen specific memory T cells----that are responsible for the development of airway allergic inflammation. Our study would provide a theoretical basis and experimental evidences for AIT, and be beneficial for the optimization of dosage and time schedule in clinical treatment.

过敏性哮喘是II型T辅助细胞（Th2）及其相关细胞因子介导的呼吸道疾病。过敏原特异性免疫治疗是一种基于过敏原对机体的多次刺激，最终使机体产生免疫耐受的具有潜在治愈性的治疗方法。但临床上仍有相当一部分患者治疗后症状得不到显著改善，且缺乏特异的疗效监测指标。因此亟需进一步阐明特异性免疫治疗的分子机制，并寻找灵敏、特异的疗效监测生物标志物。本课题拟用小鼠慢性哮喘模型，研究过敏原特异性免疫治疗中诱导产生的抗原特异性免疫调节T细胞iT(R)35和抑制型细胞因子IL-35，在机体对过敏原耐受过程中所扮演的角色以及相关机制。并进一步阐明抗原特异性iT(R)35和IL-35对过敏性哮喘发病至关重要的过敏原特异性记忆T细胞的调节机制。本课题的开展有望探明过敏原特异性免疫治疗的机理，并明确机体产生免疫耐受所需的关键分子和细胞亚群，有助于临床制定更合理的用药剂量和治疗周期，最终提高过敏原免疫治疗的临床疗效。

哮喘是一种常见且难以治愈的呼吸道疾病，被列为十大死亡原因之一，严重威胁人类健康。过敏性哮喘主要是由Th2型炎症因子介导的气道粘膜增厚，粘膜固有层胶原沉积，平滑肌增生肥大，肌成纤维细胞生成增多等病理性变化，最终导致气道结构发生严重改变以及气道通气能力显著下降，严重者甚至因窒息而死亡。过敏原特异性免疫治疗是一种基于过敏原对机体的多次刺激，最终使机体产生免疫耐受的具有潜在治愈性的治疗方法。本研究分析了过敏性哮喘的患者在过敏原特异性免疫治疗前和治疗后的血清IL-35的变化以及表达IL-35的iTreg的变化。并利用小鼠模型评估了IL-35和iTreg在过敏性哮喘中的作用。结果发现过敏原特异性免疫治疗可以引起过敏儿童血浆IL-35表达升高，且调节型T细胞增加，并伴随着过敏症状的改善。过敏原脱敏治疗能够抑制过敏小鼠肺组织炎症并够诱导IL-35的表达升高。抑制IL-35的功能，能够降低过敏原特异性免疫治疗的疗效。过敏原脱敏治疗诱导产生的分泌IL-35的iTreg细胞，在过敏症状改善中起至关重要的作用。本课题阐明了调节型免疫因子IL-35以及相关调节型T淋巴细胞在过敏原脱敏治疗中发挥了至关重要的作用，为临床疗效监测提供了潜在生物标志物。同时也进一步揭示了IL-35在过敏性疾病中的作用机理。