Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation.
BACKGROUND
As Th2 type lymphocytes orchestrate the cardinal features of allergic asthma, inhibiting their recruitment to the lungs could be of therapeutic benefit. Although human Th2 cells express the CCR4 chemokine receptor and increased production of CCR4 ligands has been found in asthmatic airways, studies in animals have reached contradictory conclusions on whether blocking this pathway would be beneficial.


OBJECTIVE
As a lack of efficacy might be due to differences between mouse and man, we readdressed this question using a humanized severe combined immunodeficiency model of asthma.


METHODS
Mice received peripheral blood mononuclear cells from house dust mite (HDM) allergic asthmatic patients and then underwent bronchial challenge with HDM.


RESULTS
This resulted in marked allergic inflammation and bronchial hyper-reactivity. Administration of CCR4 blocking antibody abolished the airway eosinophilia, goblet cell hyperplasia, IgE synthesis and bronchial hyper-reactivity. In this chimeric system, human CD11c+ dendritic cells (DCs) were the predominant source of CCR4 ligands, suggesting that DC-derived chemokines attract Th2 cells. In separate experiments using human DCs, in vitro exposure to HDM of DCs from HDM allergic patients but not healthy controls caused CCL17 and CCL22 release that resulted in chemoattraction of polarized human Th2 cells in a CCR4-dependent way.


CONCLUSIONS
Taken together, our data provide proof of concept that CCR4 blockade inhibits the salient features of asthma and justify further clinical development of CCR4 antagonists for this disease.
Perros
F
F
Laboratory of Immunoregulation, University Hospital of Ghent, De Pintelaan 185, Ghent, Belgium.
Hoogsteden
H C
HC
Coyle
A J
AJ
Lambrecht
B N
BN
Hammad
H
H
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D054414:Chemokine CCL17 / Q000276:immunology / Q000378:metabolism; D054422:Chemokine CCL22 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D039981:Pyroglyphidae / Q000276:immunology; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054398:Receptors, CCR4