Cyclosporin A attenuates genetic airway hyperresponsiveness in mice but not through inhibition of CD4+ or CD8+ T cells.
We examined the influence of T lymphocytes on genetically determined airway hyperresponsiveness to acetylcholine (ACh) in mice. A/J and C3H/HeJ mice were treated with the T-cell suppressant cyclosporin A [(CsA) 25 to 100 mg/kg, intraperitoneally (i.p.), for 5 to 10 days], whereas control animals received the vehicle or remained untreated. CsA treatment induced a dose-dependent suppression of mitogen-stimulated spleen cell proliferation which was equivalent between the two strains. A/J control animals demonstrated approximately 8-fold greater ACh-stimulated airway responsiveness, assessed by the time-integrated peak inspiratory pressure (APTI) compared with C3H/HeJ control mice. ACh-induced APTI was attenuated by CsA in a dose- and time-dependent manner in the A/J strain; no significant changes occurred in the C3H/HeJ strain. To determine whether lymphocyte subtypes mediated this response, we depleted T-cell subsets with either rat anti-mouse CD4+ (L3T4) monoclonal antibody (GK1.5, 500 micrograms, i.p.) or anti-CD8+ monoclonal antibody (J1.2, 500 micrograms; or YTS169.4, 150 micrograms, i.p.) and assessed airway responsiveness. No significant change in airway responsiveness was detected in either strain after CD4+ or CD8+ T-cell depletion. Thus, although CsA administration attenuated spleen cell activation and was associated with a marked attenuation of airway responsiveness in mice with genetically hyperresponsive airways, CD4+ and CD8+ T cells do not appear to mediate this response.
Ewart
S L
SL
Department of Anesthesiology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Gavett
S H
SH
Margolick
J
J
Wills-Karp
M
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D007958:Leukocyte Count; D008168:Lung / Q000166:cytology / Q000276:immunology; D016131:Lymphocyte Subsets / Q000166:cytology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013997:Time Factors
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016572:Cyclosporine; D000109:Acetylcholine