CC chemokine receptor 4 (CCR4) in human allergen-induced late nasal responses.
BACKGROUND
CC Chemokine receptor 4 (CCR4) is preferentially expressed on Th2 lymphocytes. CCR4-mediated inflammation may be important in the pathology of allergic rhinitis. Disruption of CCR4 - ligand interaction may abrogate allergen-induced inflammation.


METHODS
Sixteen allergic rhinitics and six nonatopic individuals underwent both allergen and control (diluent) nasal challenges. Symptom scores and peak nasal inspiratory flow were recorded. Nasal biopsies were taken at 8 h post challenge. Sections were immunostained and examined by light or dual immunofluorescence microscopy for eosinophils, T-lymphocytes, CCR4(+)CD3(+) and CXCR3(+)CD3(+) cells and examined by in situ hybridization for CCR4, IL-4 and IFN-gamma mRNA(+) cells. Peripheral blood mononuclear cells were obtained from peripheral blood of nine normal donors and the CCR4(+)CD4(+) cells assessed for actin polymerization in response to the CCR4 ligand macrophage-derived chemokine (MDC/CCL22) and the influence of a CCR4 antagonist tested.


RESULTS
Allergic rhinitics had increased early and late phase symptoms after allergen challenge compared to diluent; nonatopics did not respond to either challenge. Eosinophils, but not total numbers of CD3(+) T cells, were increased in rhinitics following allergen challenge. In rhinitics, there was an increase in CCR4(+)CD3(+) protein-positive cells relative to CXCR3(+)CD3(+) cells; CCR4 mRNA+ cells were increased and IL-4 increased to a greater extent than IFN-gamma. CCR4(+)CD4(+) T cells responded to MDC in vitro, and this response was inhibited by the selective CCR4 antagonist.


CONCLUSIONS
Lymphocyte CCR4 expression is closely associated with induction of human allergen-induced late nasal responses. Blocking CCR4-ligand interaction may provide a novel therapeutic approach in allergic disease.
Department of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College London, London, UK.
G
G
Banfield
H
H
Watanabe
G
G
Scadding
M R
MR
Jacobson
S J
SJ
Till
D A
DA
Hall
D S
DS
Robinson
C M
CM
Lloyd
K T
KT
Nouri-Aria
S R
SR
Durham
D000281:Administration, Intranasal; D000328:Adult; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D001706:Biopsy; D005260:Female; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology* / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D008297:Male; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism*; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology* / Q000503:physiopathology; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology* / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
D000485:Allergens; D054398:Receptors, CCR4