Involvement of alpha-4 integrins in allergic airway responses and mast cell degranulation in vivo.
Antibodies against integrins have been shown to inhibit allergic airway responses. The purpose of this study was to test the hypothesis that the beta1 integrin, very late antigen-4 (VLA-4), is involved in mast cell activation triggered by allergen exposure in sensitized animals. To do this we studied Brown Norway rats that were sensitized to ovalbumin (OA; 1 mg subcutaneously) using Bordetella pertussis as an adjuvant. Two weeks later rats were challenged with OA, pulmonary resistance (RL) was determined, and the concentrations of histamine and tryptase in bronchoalveolar lavage fluid and N-acetyl-leukotriene (LT)E4 in bile were measured. Pretreatment with a monoclonal antibody against VLA-4 (TA-2) attenuated the early response after OA challenge (342.9 +/- 24.4% baseline RL versus 153.3 +/- 19.4%; p < 0.01). There were significantly lower concentrations of histamine (67.11 +/- 11.90 microgram/ml versus 26.69 +/- 1.84; p < 0.01) and tryptase (0.143 +/- 0. 035 microgram/ml versus 0.053 +/- 0.022 microgram/ml; p < 0.01) in TA-2-treated animals. The increases in the concentrations of biliary N-acetyl-LTE4 after OA challenge were also significantly lower in TA-2-treated animals. These data suggest that a selective anti-VLA-4 monoclonal antibody prevents early responses through inhibition of mast cell activation.
Meakins-Christie Laboratories, McGill University, Montreal, Quebec; and the Izaak Walton Killam Children's Hospital, Grace Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
M
M
Hojo
K
K
Maghni
T B
TB
Issekutz
J G
JG
Martin
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000403:Airway Resistance / Q000276:immunology; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D018926:Anti-Allergic Agents / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D001646:Bile / Q000737:chemistry; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology*; D053818:Chymases; D006632:Histamine / Q000032:analysis; D007114:Immunization; D039441:Integrin alpha4; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000276:immunology; D016023:Integrins / Q000276:immunology*; D017999:Leukotriene E4 / Q000031:analogs & derivatives / Q000032:analysis; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*; D016029:Receptors, Very Late Antigen / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D012697:Serine Endopeptidases / Q000032:analysis; D053802:Tryptases; D010566:Virulence Factors, Bordetella / Q000008:administration & dosage
D000276:Adjuvants, Immunologic; D000485:Allergens; D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D016029:Receptors, Very Late Antigen; D010566:Virulence Factors, Bordetella; D039441:Integrin alpha4; D017999:Leukotriene E4; C047630:N-acetylleukotriene E4; D006632:Histamine; D010047:Ovalbumin; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases