CTLA4-Ig inhibits allergic airway inflammation by a novel CD28-independent, nitric oxide synthase-dependent mechanism.
The T-cell response to antigen depends upon coordinate signaling between costimulatory and inhibitory receptors. Altered function of either may underlie the pathophysiology of autoimmune and/or chronic inflammatory diseases and manipulation of these pathways is an important emerging area of therapeutics. We report here that the immunosuppressant drug CTLA4-Ig inhibits the effector phase of allergic airway inflammation through a CD28-independent, nitric oxide synthase dependent mechanism. Using mice deficient in both B and T lymphocyte attenuator (BTLA) and CD28, we demonstrate that simultaneous deficiency of an inhibitory receptor can rescue the in vivo but not the in vitro CD28-deficient phenotype. Furthermore, we demonstrate that inflammation in the CD28/BTLA-double-deficient mice is suppressed by CTLA4-Ig. This suppression is reversed by treatment with the Nitric Oxide Synthase (NOS) inhibitor, N(6)-methyl-L-arginine acetate (L-NMMA). In addition CTLA4-Ig was ineffective at inhibiting inflammation in NOS2-deficient mice when given at the effector phase. Thus, CD28 and BTLA coordinately regulate the in vivo response to inhaled allergen, and CTLA4-Ig binding to B7-proteins inhibits the effector phase of inflammation by a CD28-independent, NOS-dependent mechanism.
Deppong
Christine M
CM
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
Parulekar
Amit
A
Boomer
Jonathan S
JS
Bricker
Traci L
TL
Green
Jonathan M
JM
D000069594:Abatacept; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology*; D018796:Immunoconjugates / Q000276:immunology* / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D019001:Nitric Oxide Synthase