Alpha 4-integrins mediate antigen-induced late bronchial responses and prolonged airway hyperresponsiveness in sheep.
Eosinophils and T lymphocytes are thought to be involved in allergic airway inflammation. Both cells express the alpha 4 beta 1-integrin, very late antigen-4 (VLA-4, CD49d/CD29); alpha 4-integrins can promote cellular adhesion and activation. Therefore, we examined the in vivo effects of a blocking anti-alpha 4 monoclonal antibody, HP 1/2, on antigen-induced early and late bronchial responses, airway hyperresponsiveness, inflammatory cell influx, and peripheral leukocyte counts in allergic sheep. Sheep blood lymphocytes, monocytes, and eosinophils expressed alpha 4 and bound HP 1/2. In control sheep, Ascaris antigen challenge produced early and late increases in specific lung resistance of 380 +/- 42% and 175 +/- 16% over baseline immediately and 7 h after challenge, respectively, as well as airway hyperresponsiveness continuing for 14 d after antigen challenge. Treatment with HP 1/2 (1 mg/kg, i.v.) 30 min before antigen challenge did not affect the early increase in specific lung resistance but inhibited the late-phase increase at 5-8 h by 75% (P < 0.05) and inhibited the post-antigen-induced airway hyperresponsiveness at 1, 2, 7, and 14 d (P < 0.05, for each time). Intravenous HP 1/2 given 2 h after antigen challenge likewise blocked late-phase airway changes and postchallenge airway hyperresponsiveness. Airway administration of HP 1/2 (16-mg dose) was also effective in blocking these antigen-induced changes. Response to HP 1/2 was specific since an isotypic monoclonal antibody, 1E6, was ineffective by intravenous and aerosol administration. Inhibition of leukocyte recruitment did not totally account for the activity of anti-alpha 4 antibody since HP 1/2 neither diminished the eosinopenia or lymphopenia that followed antigen challenge nor consistently altered the composition of leukocytes recovered by bronchoalveolar lavage. Because airway administration of HP 1/2 was also active, HP 1/2 may have inhibited cell activation. Reduction of platelet-activating factor-induced eosinophil peroxidase release from HP 1/2-treated eosinophils supports such a mechanism. These findings indicate a role for alpha 4-integrins in processes that lead to airway late phase responses and persisting airway hyperresponsiveness after antigen challenge.
Abraham
W M
WM
Department of Medicine, University of Miami, Mount Sinai Medical Center, Florida 33140.
Sielczak
M W
MW
Ahmed
A
A
Cortes
A
A
Lauredo
I T
IT
Kim
J
J
Pepinsky
B
B
Benjamin
C D
CD
Leone
D R
DR
Lobb
R R
RR
D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000276:immunology*; D001200:Ascaris / Q000276:immunology; D001980:Bronchi / Q000276:immunology / Q000502:physiology*; D004804:Eosinophils / Q000276:immunology / Q000502:physiology; D005434:Flow Cytometry; D006967:Hypersensitivity / Q000276:immunology / Q000503:physiopathology; D007275:Injections, Intravenous; D039441:Integrin alpha4; D016023:Integrins / Q000276:immunology / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology; D008214:Lymphocytes / Q000276:immunology / Q000502:physiology*; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000276:immunology / Q000503:physiopathology; D012756:Sheep; D013997:Time Factors
D000336:Aerosols; D000911:Antibodies, Monoclonal; D000947:Antigens, Helminth; D016023:Integrins; D039441:Integrin alpha4