Targeted reduction of CCR4+ cells is sufficient to suppress allergic airway inflammation

Back ground: 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 PE38into CCR4+ cells. To test our hypothesis, we examined whether TARC-PE38could suppress allergic airway inflammation in a mouse model of house dust mite (HDM)-induced allergic airway inflammation.
Methods: We evaluated the effect of TARC-PE38 on the major characteristics of HDM-induced allergic airway inflammation. Airway hyper responsiveness, 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.
Results: 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 no effect on Th1 cells.
Conclusion: Our data suggest that the elimination of CCR4+ cells viaTARC-PE38 treatment is sufficient to control allergic airway inflammation and airway hyperresponsiveness.

内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨 : LID201312091001.pdf
論文本文 : LID201405271002.pdf
本論文は, 著者Akifumi Honjoの学位論文として提出され, 学位審査・授与の対象となっている。