TY - JOUR
T1 - CTLA4-Ig inhibits allergic airway inflammation by a novel CD28-independent, nitric oxide synthase-dependent mechanism
AU - Deppong, Christine M.
AU - Parulekar, Amit
AU - Boomer, Jonathan S.
AU - Bricker, Traci L.
AU - Green, Jonathan M.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
KW - Allergic lung inflammation
KW - CTLA4-Ig
KW - Costimulation
KW - T-cell activation
UR - http://www.scopus.com/inward/record.url?scp=77954122076&partnerID=8YFLogxK
U2 - 10.1002/eji.200940282
DO - 10.1002/eji.200940282
M3 - Article
C2 - 20443189
AN - SCOPUS:77954122076
SN - 0014-2980
VL - 40
SP - 1985
EP - 1994
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 7
ER -