Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice.
The involvement of granulocyte-macrophage CSF (GM-CSF) in collagen-induced arthritis (CIA) was examined using GM-CSF-deficient mice. Although CIA is generally considered to be restricted to mice of the H-2q or H-2r haplotypes, we examined the role of GM-CSF in the CIA model using GM-CSF-deficient (-/-) and wild-type (+/+) mice on a C57BL/6 (H-2b) background. Mice were immunized by intradermal injection at the base of the tail with chick type II collagen followed by a repeat injection 21 days later. We found, based on both clinical and histologic assessments, that wild-type mice on this background developed severe CIA, while the GM-CSF-deficient mice had virtually no disease. Mice that were heterozygous for the GM-CSF gene (+/-) collectively displayed an intermediate response between those of the GM-CSF(+/+) and GM-CSF(-/-) groups, suggesting a gene dosage effect. GM-CSF(+/+) and GM-CSF(+/-) mice exhibited CIA responses ranging from mild (single digits) to severe swelling of all four paws, while in the few GM-CSF(-/-) mice that developed CIA the disease was confined to single digits. Despite the putative role of GM-CSF in dendritic cell development, GM-CSF-deficient mice exhibited both humoral and cellular (delayed-type hypersensitivity) responses to type II collagen; however, the cellular response was significantly reduced in the GM-CSF-deficient mice compared with the wild-type controls. These findings suggest that GM-CSF is required for CIA development in mice and support the idea that GM-CSF is a key cytokine in inflammatory joint disease.
Campbell
I K
IK
Department of Medicine, Inflammation Research Center, University of Melbourne, Victoria, Australia. campbell@wehi.edu.au
Rich
M J
MJ
Bischof
R J
RJ
Dunn
A R
AR
Grail
D
D
Hamilton
J A
JA
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D003094:Collagen / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000235:genetics*; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D007074:Immunoglobulin G; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen