Wang S Y, Yang M, Xu X P, Qiu G F, Ma J, Wang S J, Huang X X, Xu H X
Department of Pediatrics, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
J Investig Allergol Clin Immunol. 2008;18(5):357-65.
Allergic asthma is caused by aberrant helper T (T(H)) type 2 immune responses in susceptible individuals, characterized by airway hyperresponsiveness, chronic airway inflammation, and mucus hypersecretion. Its prevalence continues to increase, but optimal treatment remains a challenge. The transcription factor T-bet is a master regulator of T(H)1 lineage commitment and strongly promotes interferon gamma expression during T(H)1 cell differentiation.
The aim of this study was to explore the role of intranasal delivery of T-bet on the differentiation of T(H) cell subsets and airway inflammation in the ovalbumin (OVA)-induced mouse model of allergic airway inflammation.
BALB/c mice were sensitized by intraperitoneal injection of OVA and challenged with nebulized OVA. Four days before the inhalation challenge, the sensitized mice were subjected to intranasal delivery of a recombinant adeno-associated virus vector carrying murine T-bet gene (AAV-T-bet). Expression of the transcription factors T-bet, GATA3, and Foxp3 was then assayed in the lungs, and airway histology was analyzed along with other inflammatory parameters, such as eosinophils and cytokines in bronchoalveolar lavage (BAL) fluid, and total and OVA-specific immunoglobulin (Ig) E in serum.
Intranasal administration of AAV-T-bet efficiently balanced the T(H)1/T(H)2 transcription factor and cytokine profile and significantly decreased the number of eosinophils in BAL fluid. It also resulted in a reduction of peribronchial inflammation scores and serum IgE levels in OVA-sensitized and challenged mice during the effector phase.
Our data show that intranasal delivery of T-bet can promote a T(H)1 immune response, restore a balanced Th immune response, and inhibit airway inflammation during the challenge phase in a mouse model of allergic airway inflammation.
过敏性哮喘是由易感个体中异常的辅助性T（Th）2型免疫反应引起的，其特征为气道高反应性、慢性气道炎症和黏液分泌亢进。其患病率持续上升，但最佳治疗仍然是一项挑战。转录因子T-bet是Th1细胞谱系定向分化的主要调节因子，并在Th1细胞分化过程中强烈促进γ干扰素的表达。
本研究旨在探讨经鼻递送T-bet对卵清蛋白（OVA）诱导的变应性气道炎症小鼠模型中Th细胞亚群分化及气道炎症的作用。
通过腹腔注射OVA使BALB/c小鼠致敏，然后用雾化的OVA进行激发。在吸入激发前4天，对致敏小鼠经鼻递送携带小鼠T-bet基因的重组腺相关病毒载体（AAV-T-bet）。随后检测肺中转录因子T-bet、GATA3和Foxp3的表达，并分析气道组织学以及其他炎症参数，如支气管肺泡灌洗（BAL）液中的嗜酸性粒细胞和细胞因子，以及血清中的总免疫球蛋白（Ig）E和OVA特异性IgE。
经鼻给予AAV-T-bet可有效平衡Th1/Th2转录因子和细胞因子谱，并显著减少BAL液中嗜酸性粒细胞的数量。在效应期，它还能降低OVA致敏和激发小鼠的支气管周围炎症评分和血清IgE水平。
我们的数据表明，在变应性气道炎症小鼠模型的激发阶段，经鼻递送T-bet可促进Th1免疫反应，恢复Th免疫反应平衡，并抑制气道炎症。
