Murine CTLA4-IgG treatment inhibits airway eosinophilia and hyperresponsiveness and attenuates IgE upregulation in a murine model of allergic asthma.
Antigen-specific T-cell activation requires the engagement of the T-cell receptor (TCR) with antigen as well as the engagement of appropriate costimulatory molecules. One of the most important pathways of costimulation is the interaction of CD28 on the T cell with B7-1/B7-2 on antigen-presenting cells. In the present study, we have examined the in vivo effects of blocking the CD28:B7 T-cell costimulatory pathway by administration of mCTLA4-IgG in a murine model of allergic asthma. Mice were sensitized with ovalbumin and exposed to repeated ovalbumin inhalation challenges. In mice treated with a control antibody at the time of ovalbumin challenge a significant increase in the number of eosinophils (12.8 +/- 4.3 x 10(3) cells, P < 0.05) in the bronchoalveolar lavage (BAL) fluid and airway hyperresponsiveness to methacholine (49 +/- 15%, P < 0.05) was observed. In addition, serum levels of ovalbumin-specific IgE were significantly (P < 0.01) increased after ovalbumin challenge compared with saline challenge (1,133 +/- 261 experimental units [EU]/ml and 220 +/- 63 EU/ml, respectively). In mice treated with mCTLA4-IgG at the time of ovalbumin challenge, the infiltration of eosinophils into BAL fluid and the development of airway hyperresponsiveness to methacholine were completely inhibited. The upregulation of ovalbumin-specific IgE levels in serum was attenuated by mCTLA4-IgG treatment. Furthermore, addition of mCTLA4-IgG to cultures of parabronchial lymph node cells from sensitized mice inhibited the ovalbumin-induced interleukin-4 production. These data indicate the therapeutic potential of blocking T-lymphocyte costimulation by CTLA4-IgG as a possible immunosuppressive treatment for patients with allergic asthma.
Van Oosterhout
A J
AJ
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands. A.J.M.VanOosterhout@far.ruu.nl
Hofstra
C L
CL
Shields
R
R
Chan
B
B
Van Ark
I
I
Jardieu
P M
PM
Nijkamp
F P
FP
D000069594:Abatacept; D000280:Administration, Inhalation; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000517:prevention & control*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology*; D018796:Immunoconjugates; D007073:Immunoglobulin E / Q000502:physiology*; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D016085:Bronchoconstrictor Agents; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D000069594:Abatacept; D010047:Ovalbumin