CCR3-blocking antibody inhibits allergen-induced eosinophil recruitment in human skin xenografts from allergic patients.
Eosinophil, basophil, and T helper 2 (TH2) cell recruitment into tissues is a characteristic feature of allergic diseases. These cells have in common the expression of the chemokine receptor CCR3, which may represent a specific pathway for their accumulation in vivo. Although animal models of allergic reactions are available, findings cannot always be extrapolated to man. To overcome these limitations, we have developed a humanized mouse model of allergic cutaneous reaction using severe combined immunodeficiency mice engrafted with skin and autologous peripheral blood mononuclear cells from allergic donors. Intradermal injection of the relevant allergen into human skin xenografts from allergic individuals induced a significant recruitment of human CD4(+) T cells, basophils, and TH2-type cytokine mRNA-expressing cells, as well as murine eosinophils. Human skin xenografts, atopic status, and autologous peripheral blood mononuclear cell reconstitution were all mandatory to induce the allergic reaction. Next, we addressed the role of CCR3 in the endogenous mechanisms involved in the inflammatory cell recruitment in this experimental model of allergic cutaneous reaction. In vivo administration of an anti-human CCR3-blocking antibody selectively reduced accumulation of eosinophils but not that of CD4(+) cells, basophils, or cells expressing mRNA for TH2-type cytokines. These findings establish a new in vivo model of humanized allergic reaction and suggest that eosinophil migration is mediated mainly through CCR3. Finally, these results suggest that this model might be useful to test human-specific antiallergic modulators.
INSERM U416, Institut Pasteur de Lille, France.
Stéphanie
S
Sénéchal
Olivier
O
Fahy
Thibaut
T
Gentina
Han
H
Vorng
Monique
M
Capron
Andrew F
AF
Walls
Alan R
AR
McEuen
Mark G
MG
Buckley
Qutayba
Q
Hamid
Benoît
B
Wallaert
André Bernard
AB
Tonnel
Anne
A
Tsicopoulos
D000485:Allergens / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D017403:In Situ Hybridization; D051379:Mice; D016513:Mice, SCID; D008925:Mites / Q000276:immunology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology
D000485:Allergens; D000906:Antibodies; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; D054397:Receptors, CCR3; D019707:Receptors, Chemokine