B7-CD28/CTLA-4 costimulatory pathways are required for the development of T helper cell 2-mediated allergic airway responses to inhaled antigens.
We have previously demonstrated that the development of allergen-induced airway hyperresponsiveness in a murine model is CD4+ T cell dependent. In the present study, we examined the role of the B7/CD28-CTLA4 costimulatory T cell activation pathway in the pathogenesis of allergen-induced airway hyperresponsiveness in this murine model. Sensitized A/J mice develop significant increases in airway responsiveness, bronchoalveolar lavage eosinophils, serum IgE levels, and Th2-associated cytokine production following aspiration challenge with OVA. Administration of CTLA4-Ig either before Ag sensitization or before pulmonary Ag challenge abolished Ag-induced airway hyperresponsiveness and pulmonary eosinophilia. Examination of cytokine protein levels in the bronchoalveolar lavage showed a significant decrease in the level of the Th2 cytokine, IL-4, after CTLA4-Ig treatment either before sensitization or before challenge, with no significant change in the concentration of the Th1 cytokine, IFN-gamma. Further, the Ag-specific Ab isotypes IgG1 and IgE were significantly decreased in animals treated with CTLA4-Ig before challenge, while there was no significant change in the IgG2a Ab isotype. These data demonstrate that administration of CTLA4-Ig is effective in ablating allergen-induced airway dysfunction concomitant with a significant reduction in the Th2 response. We conclude that B7/CD28-CTLA-4 costimulation is required for the development of many of the immunologic and physiologic features of asthma, possibly by promoting a pathologic type 2-associated response.
Keane-Myers
A
A
School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Gause
W C
WC
Linsley
P S
PS
Chen
S J
SJ
Wills-Karp
M
M
D000069594:Abatacept; D000280:Administration, Inhalation; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000517:prevention & control; D018106:CD28 Antigens / Q000502:physiology*; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000187:drug effects; D007141:Immunoglobulin Fc Fragments / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000502:physiology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D010047:Ovalbumin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D007073:Immunoglobulin E; D000069594:Abatacept; D010047:Ovalbumin