title: Role of very late activation antigen-4 in the antigen-induced accumulation of eosinophils and lymphocytes in the lungs and airway lumen of sensitized brown Norway rats.
abstract: We used flow cytometry and treatment in vivo with a monoclonal antibody (mAb), TA-2, to the alpha 4 integrin to investigate the role of alpha 4 beta 1, CD49d/CD29 (VLA-4) in antigen-induced lung inflammation in Brown Norway (BN) rats. Ovalbumin (OVA) inhalation induced an accumulation of eosinophils and lymphocytes in the lungs and bronchoalveolar lavage (BAL) fluid of sensitized BN rats at 24 h after challenge. Phenotypic analyses demonstrated that the percentages of T cells expressing detectable alpha 4 and CD25 in the bronchial lumen after antigen challenge were dramatically increased compared with blood and lymph node T cells. The mean channel fluorescence values of alpha 4 expression were also increased on BAL T cells compared with blood or lymph node T cells. Treatment of OVA-sensitized rats in vivo with total cumulative doses of 0.75 to 6 mg/kg TA-2 mAb intraperitoneally produced dose-related increases in circulating TA-2 and a peripheral blood lymphocytosis, basophilia, and eosinophilia. Flow cytometric analysis of the peripheral blood T cells after in vivo TA-2 mAb administration showed decreases in detectable alpha 4 when these cells were examined ex vivo. Treatment with TA-2, but not an isotype-matched control mouse immunoglobulin G1 mAb, markedly inhibited the OVA-induced recruitment of lymphocytes and eosinophils into the airway lumen. Very few CD3+CD49d+ cells migrated into BAL fluid following anti-alpha 4 mAb treatment in vivo. Treatment with TA-2 also significantly attenuated OVA-induced inflammatory histopathology. We conclude that VLA-4 is a critically important adhesion molecule involved in antigen-specific lung inflammation in sensitized BN rats.
authors.affiliation: Pharmacia and Upjohn, Inc., Kalamazoo, Michigan 49001, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Richards
authors.forename: K P
authors.initials: KP
authors.lastname: Kolbasa
authors.forename: C A
authors.initials: CA
authors.lastname: Hatfield
authors.forename: G E
authors.initials: GE
authors.lastname: Winterrowd
authors.forename: S L
authors.initials: SL
authors.lastname: Vonderfecht
authors.forename: S F
authors.initials: SF
authors.lastname: Fidler
authors.forename: R L
authors.initials: RL
authors.lastname: Griffin
authors.forename: J R
authors.initials: JR
authors.lastname: Brashler
authors.forename: R F
authors.initials: RF
authors.lastname: Krzesicki
authors.forename: L M
authors.initials: LM
authors.lastname: Sly
authors.forename: K A
authors.initials: KA
authors.lastname: Ready
authors.forename: N D
authors.initials: ND
authors.lastname: Staite
authors.forename: J E
authors.initials: JE
authors.lastname: Chin
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004804:Eosinophils / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D016130:Immunophenotyping; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology*; D007958:Leukocyte Count; D008168:Lung / Q000166:cytology / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology; D008297:Male; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D010047:Ovalbumin