A specific CCR3 chemokine receptor antagonist inhibits both early and late phase allergic inflammation in the conjunctiva.
Allergic inflammation manifests as one of a number of diseases, including asthma, dermatitis, food allergy, vernal keratoconjunctivitis, and systemic anaphylaxis. Together these diseases affect nearly 25% of the Western world and are a leading health-care problem. The diseases are often biphasic, with an early phase driven primarily by mast cell degranulation and a late phase characterized by leukocyte recruitment. While chemokines are well known to be critical for leukocyte recruitment, their importance in early-phase reactions is poorly defined. We show here that administration of a single oral dose of a high affinity and highly selective CCR3 antagonist ablates both the early and late phase reactions in a mouse model of allergic conjunctivitis. A direct analysis of mast cells in the conjunctiva demonstrates that antagonism of the CCR3 receptor stabilizes the mast cell in vivo, thereby leading to the impaired early phase reaction. The late phase reaction is also strongly inhibited as characterized by both reduced eosinophilia and neutrophilia. These results constitute the first direct evidence that antagonism of CCR3 has clear potential for the treatment of allergic diseases.
Nakamura
Takao
T
Department of Immunology University College London University of London Institutes of Ophthalmology and Child Health and Moorfields Eye Hospital London, EC1V 9EL, United Kingdom.
Ohbayashi
Masaharu
M
Toda
Masako
M
Hall
David A
DA
Horgan
Carmel M
CM
Ono
Santa Jeremy
SJ
D000284:Administration, Oral; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003233:Conjunctivitis, Allergic / Q000188:drug therapy* / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D009025:Morpholines / Q000008:administration & dosage / Q000627:therapeutic use*; D009504:Neutrophils / Q000187:drug effects; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*
C515351:Ccr3 protein, mouse; C511196:GW78415X; D009025:Morpholines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D013777:Tetrazoles