Regulation of T-cell activation in the airway mucosa of rats expressing low versus high IgE responder phenotype

我们建立了一种模拟人类哮喘的实验性大鼠变应性气道炎症模型。气道粘膜树突状细胞和CD4+ Th2（效应）细胞群之间发生的相互作用是哮喘加重的晚期反应（LPR）成分的原因，包括气道高反应（AHR）。我们之前已经证明，面对持续的空气过敏原挑战，LPR的终止和防止其持续复发是通过诱导动态平衡状态建立的，由局部T调节细胞（Treg）介导，其作用是功能性沉默局部Th2记忆（效应）细胞。保护性Treg活性的维持依赖于持续的过敏原暴露，因为停止暴露会导致Treg数量和功能的减少以及粘膜过敏原特异性Th2细胞的释放。这些研究主要涉及低IgE反应（LR） PVG大鼠（正常或非特应性）。本研究将重点阐明高IgE应答（HR） BN大鼠（特应性）对吸入抗原的Th2依赖性免疫应答的控制。同时研究这两种菌株，可以比较气道中Th2免疫诱导和表达的易感性谱的极端情况。更详细地了解气道粘膜和引流淋巴结内发生的细胞相互作用以及负责维持气道内免疫稳态的机制将为炎性气道疾病（如特应性哮喘）的发病机制提供新的见解。这将促进进一步发展，并可能阐明其他干预途径，以更有效地控制哮喘的治疗策略，这是本研究的长期目标。

We have established an experimental rat model of allergic airways inflammation which mimics human asthma. Interactions occurring between airway mucosal dendritic cells and CD4+ Th2 (effector) cell populations are responsible for the late phase response (LPR) component of asthma exacerbations, including airways hyperresponsiveness (AHR). We have previously demonstrated that termination of the LPR and prevention of its continual recurrence in the face of ongoing aeroallergen challenge is established via the induction of a state of dynamic equilibrium, mediated by local T regulatory cells (Treg) which act to functionally silence local Th2 memory (effector) cells. Maintenance of protective Treg activity is dependent upon continuing allergen exposure as cessation of exposure leads to waning of Treg numbers and function and release of mucosal allergen specific Th2 cells from control. These studies have primarily involved low IgE responder (LR) PVG rats (normals or nonatopics). The present study will focus on elucidating the control of Th2 dependent immune responses to inhaled antigen in high IgE responder (HR) BN rats (atopics). Studying these two strains in parallel enables a comparison between the extremes of the spectrum of susceptibility to both the induction and the expression of Th2 immunity in the airways. A more detailed understanding of the cellular interactions occurring within the airway mucosa and draining lymph nodes and the mechanisms responsible for the maintenance of immunological homeostasis within the airways will provide new insights into the pathogenesis of inflammatory airway diseases such as atopic asthma. This will enable further development and possibly illuminate other avenues of intervention for more effective therapeutic strategies used in the control of asthma, which is the long term goal of this research.