CTLA4-Ig inhibits allergic airway inflammation by a novel CD28-independent, nitric oxide synthase-dependent mechanism

• Published in: European journal of immunology Vol. 40; no. 7; pp. 1985 - 1994
• Main Authors: Deppong, Christine M, Parulekar, Amit, Boomer, Jonathan S, Bricker, Traci L, Green, Jonathan M
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH Verlag 01.07.2010; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Abatacept; Allergic lung inflammation; Animals; Asthma - drug therapy; Asthma - immunology; CD28 Antigens - immunology; Costimulation; CTLA-4 Antigen - immunology; CTLA4‐Ig; Hypersensitivity - drug therapy; Hypersensitivity - immunology; Immunoconjugates - immunology; Immunoconjugates - pharmacology; Immunosuppressive Agents - immunology; Immunosuppressive Agents - pharmacology; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Mice; Mice, Inbred C57BL; Nitric oxide; Nitric Oxide Synthase - immunology; Respiratory Hypersensitivity - drug therapy; Respiratory Hypersensitivity - immunology; Respiratory System - drug effects; Respiratory System - immunology; Rodents; T cell receptors; T-Lymphocytes - immunology; T‐cell activation
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200940282

The T-cell response to antigen depends on coordinate signaling between costimulatory and inhibitory receptors. The 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 (NOS)-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 CD28/BTLA-double-deficient mice is suppressed by CTLA4-Ig. This suppression is reversed by treatment with the NOS inhibitor, N⁶-methyl-L-arginine acetate (L-NMMA). In addition, CTLA4-Ig is 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.