A critical role for OX40 in T cell-mediated immunopathology during lung viral infection.
Respiratory infections are the third leading cause of death worldwide. Illness is caused by pathogen replication and disruption of airway homeostasis by excessive expansion of cell numbers. One strategy to prevent lung immune-mediated damage involves reducing the cellular burden. To date, antiinflammatory strategies have affected both antigen-specific and naive immune repertoires. Here we report a novel form of immune intervention that specifically targets recently activated T cells alone. OX40 (CD134) is absent on naive T cells but up-regulated 1-2 d after antigen activation. OX40-immunoglobulin fusion proteins block the interaction of OX40 with its ligand on antigen-presenting cells and eliminate weight loss and cachexia without preventing virus clearance. Reduced proliferation and enhanced apoptosis of lung cells accompanied the improved clinical phenotype. Manipulation of this late costimulatory pathway has clear therapeutic potential for the treatment of dysregulated lung immune responses.
Humphreys
Ian R
IR
Imperial College of Science, Technology and Medicine, Exhibition Road, London SW7 2AZ, United Kingdom.
Walzl
Gerhard
G
Edwards
Lorna
L
Rae
Aaron
A
Hill
Sue
S
Hussell
Tracy
T
D000818:Animals; D000943:Antigens, Differentiation / Q000494:pharmacology; D017209:Apoptosis; D005260:Female; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000276:immunology* / Q000517:prevention & control; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D012141:Respiratory Tract Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology*; D014777:Virus Diseases / Q000276:immunology*; D015431:Weight Loss
D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; C406562:OX40Ig; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7