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


METHODS
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.


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 noeffect on Th1 cells.


CONCLUSIONS
Our data suggest that the elimination of CCR4⁺ cells via TARC-PE38 treatment is sufficient to control allergic airway inflammation and airway hyperresponsiveness.
Department of Respiratory Medicine & Rheumatology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Electronic address: aki1078@ceres.ocn.ne.jp.
Akifumi
A
Honjo
Hirohisa
H
Ogawa
Masahiko
M
Azuma
Toshifumi
T
Tezuka
Saburo
S
Sone
Arya
A
Biragyn
Yasuhiko
Y
Nishioka
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000209:etiology; D054414:Chemokine CCL17 / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005098:Exotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D039981:Pyroglyphidae / Q000276:immunology; D054398:Receptors, CCR4; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D054414:Chemokine CCL17; D005098:Exotoxins; D054398:Receptors, CCR4; D011993:Recombinant Fusion Proteins; C000592234:TARC-PE38 fusion protein; D007073:Immunoglobulin E
Airway hyperresponsiveness; Allergic inflammation; BALF; BSA; Bronchial asthma; C-C chemokine receptor type 4; CCR4; CKLF1; Dermatophagoides pteronyssinus; Dp; H&E; HDM; IFN; Lung resistance; MDC; Mch; PAS; R(L); TARC; TARC-PE38; bovine serum albumin; bronchial alveolar lavage fluid; chemokine-like factor 1; hematoxylin and eosin; house dust mite; interferon; macrophage-derived chemokine; methacholine; periodic acid Schiff; thymus and activation-regulated chemokine