Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease.
There is mounting evidence for a role of the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in inflammatory disease, including arthritis. In the present study, we examined the effectiveness of treatment of collagen-induced arthritis (CIA) with a neutralizing mAb to GM-CSF. DBA/1 mice were immunized for the development of CIA and treated at different times, and with different doses, with neutralizing mAb to GM-CSF or isotype control mAb. Anti-GM-CSF mAb treatment prior to the onset of arthritis, at the time of antigen challenge, was effective at ameliorating the ensuing disease. Modulation of arthritis was seen predominantly as a reduction in overall disease severity, both in terms of the number of limbs affected per mouse and the clinical score of affected limbs. Importantly, anti-GM-CSF mAb treatment ameliorated existing disease, seen both as a reduction in the number of initially affected limbs progressing and lower numbers of additional limbs becoming affected. By histology, both inflammation and cartilage destruction were reduced in anti-GM-CSF-treated mice, and the levels of tumor necrosis factor-a and IL-1beta were also reduced in joint tissue washouts of these mice. Neither humoral nor cellular immunity to type II collagen, however, was affected by anti-GM-CSF mAb treatment. These results suggest that the major effect of GM-CSF in CIA is on mediating the effector phase of the inflammatory reaction to type II collagen. The results also highlight the essential role of GM-CSF in the ongoing development of inflammation and arthritis in CIA, with possible therapeutic implications for rheumatoid arthritis.
Cook
A D
AD
Arthritis and Inflammation Research Centre, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. adcook@unimelb.edu.au
Braine
E L
EL
Campbell
I K
IK
Rich
M J
MJ
Hamilton
J A
JA
D000818:Animals; D000843:Ankle Joint / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D003094:Collagen / Q000276:immunology*; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D007114:Immunization; D007375:Interleukin-1 / Q000378:metabolism; D023441:Local Lymph Node Assay; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003094:Collagen