Honjo Akifumi, Ogawa Hirohisa, Azuma Masahiko, Tezuka Toshifumi, Sone Saburo, Biragyn Arya, Nishioka Yasuhiko
Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Respir Investig. 2013 Dec;51(4):241-9. doi: 10.1016/j.resinv.2013.04.007. Epub 2013 Jun 22.
Bronchial asthma is characterized by allergic airway inflammation involving C-C chemokine receptor type 4 (CCR4)-positive Th2 cells. As such, we hypothesize that the disease can be alleviated by targeted-elimination of CCR4⁺ cells. Thymus and activation-regulated chemokine (TARC)-PE38, a TARC fused the exotoxin fragment PE38 from Pseudomonas aeruginosa, has been shown to efficiently kill CCR4⁺ cells by delivering the exotoxin fragment PE38 into CCR4⁺ cells. To test our hypothesis, we examined whether TARC-PE38 could suppress allergic airway inflammation in a mouse model of house dust mite (HDM)-induced allergic airway inflammation.
We evaluated the effect of TARC-PE38 on the major characteristics of HDM-induced allergic airway inflammation. Airway hyperresponsiveness, lung histopathology, lung Th1/Th2 cell populations, and concentrations of Th1/Th2 cytokines in the lungs were assessed in HDM-sensitized and challenged mice in the presence and absence of TARC-PE38.
TARC-PE38 efficiently suppressed allergic airway inflammation by significantly reducing airway hyperresponsiveness, the overall area of inflammation, and goblet cell hyperplasia. In HDM-sensitized and challenged mice, TARC-PE38 specifically reduced the numbers of CCR4⁺ cells. This reduction was associated with a significant decrease in the production of Th2 cytokines in the airway,and a decrease in the number of leukocytes, including macrophages, eosinophils and lymphocytes, within the subepithelial area of the lungs and airway lumen. TARC-PE38 had noeffect on Th1 cells.
Our data suggest that the elimination of CCR4⁺ cells via TARC-PE38 treatment is sufficient to control allergic airway inflammation and airway hyperresponsiveness.
支气管哮喘的特征是涉及C-C趋化因子受体4（CCR4）阳性Th2细胞的过敏性气道炎症。因此，我们推测通过靶向清除CCR4⁺细胞可以缓解该疾病。胸腺和激活调节趋化因子（TARC）-PE38是一种将铜绿假单胞菌外毒素片段PE38与TARC融合的产物，已证明它能通过将外毒素片段PE38递送至CCR4⁺细胞来有效杀死这些细胞。为了验证我们的假设，我们研究了TARC-PE38是否能在屋尘螨（HDM）诱导的过敏性气道炎症小鼠模型中抑制过敏性气道炎症。
我们评估了TARC-PE38对HDM诱导的过敏性气道炎症主要特征的影响。在有和没有TARC-PE38的情况下，对HDM致敏和激发的小鼠评估气道高反应性、肺组织病理学、肺Th1/Th2细胞群体以及肺中Th1/Th2细胞因子的浓度。
TARC-PE38通过显著降低气道高反应性、炎症总面积和杯状细胞增生，有效抑制了过敏性气道炎症。在HDM致敏和激发的小鼠中，TARC-PE38特异性减少了CCR4⁺细胞的数量。这种减少与气道中Th2细胞因子产生的显著减少以及肺和气道腔上皮下区域中包括巨噬细胞、嗜酸性粒细胞和淋巴细胞在内的白细胞数量减少有关。TARC-PE38对Th1细胞没有影响。
我们的数据表明，通过TARC-PE38治疗清除CCR4⁺细胞足以控制过敏性气道炎症和气道高反应性。
