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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.

Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA - Arthritis Res. (2001)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Arthritis and Inflammation Research Centre, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. adcook@unimelb.edu.au

ABSTRACT
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.

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Effect of anti-GM-CSF treatment post-onset on individual limb involvement. Data are from the experiment in Fig. 2 where mice were treated intraperitoneally with 300 ?g anti-GM-CSF (n = 20 mice) or isotype control (n = 19 mice) daily from the day of disease onset (day 0) until day 9 (total, 10 times). (a) The progression of arthritis in limbs already affected prior to the commencement of treatment is presented: improvement, decrease in clinical score of individual limbs following treatment; no change, clinical score of individual limbs remained the same following treatment; mild progression, clinical score of individual limbs progressed from 1 initially to 2 at the end of treatment; progression, clinical score of individual limbs progressed from 1 or 2 initially to 3 at the end of treatment (n = 33 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 31 limbs [from 19 mice], isotype control-treated group) (P = 0.01; multiway chi-squared). (b) The number of limbs, initially unaffected (clinical score 0, day 0), that developed a particular score at the end of the experiment is presented (n = 47 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 45 limbs [from 19 mice], control-treated group) (P = 0.0007; multiway chi-squared). There were no limbs recruited in anti-GM-CSF-treated mice that developed a clinical score > 1. GM-CSF, Granulocyte macrophage-colony stimulating factor.
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Figure 5: Effect of anti-GM-CSF treatment post-onset on individual limb involvement. Data are from the experiment in Fig. 2 where mice were treated intraperitoneally with 300 ?g anti-GM-CSF (n = 20 mice) or isotype control (n = 19 mice) daily from the day of disease onset (day 0) until day 9 (total, 10 times). (a) The progression of arthritis in limbs already affected prior to the commencement of treatment is presented: improvement, decrease in clinical score of individual limbs following treatment; no change, clinical score of individual limbs remained the same following treatment; mild progression, clinical score of individual limbs progressed from 1 initially to 2 at the end of treatment; progression, clinical score of individual limbs progressed from 1 or 2 initially to 3 at the end of treatment (n = 33 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 31 limbs [from 19 mice], isotype control-treated group) (P = 0.01; multiway chi-squared). (b) The number of limbs, initially unaffected (clinical score 0, day 0), that developed a particular score at the end of the experiment is presented (n = 47 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 45 limbs [from 19 mice], control-treated group) (P = 0.0007; multiway chi-squared). There were no limbs recruited in anti-GM-CSF-treated mice that developed a clinical score > 1. GM-CSF, Granulocyte macrophage-colony stimulating factor.

Mentions: This absence of disease progression was seen as a relative lack of an increase in the clinical score of initially affected limbs following anti-GM-CSF treatment. Furthermore, anti-GM-CSF-treated mice showed a diminished recruitment of additional limbs that were normal at the commencement of treatment (see Supplementary Fig. 3).


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.

Cook AD, Braine EL, Campbell IK, Rich MJ, Hamilton JA - Arthritis Res. (2001)

Effect of anti-GM-CSF treatment post-onset on individual limb involvement. Data are from the experiment in Fig. 2 where mice were treated intraperitoneally with 300 ?g anti-GM-CSF (n = 20 mice) or isotype control (n = 19 mice) daily from the day of disease onset (day 0) until day 9 (total, 10 times). (a) The progression of arthritis in limbs already affected prior to the commencement of treatment is presented: improvement, decrease in clinical score of individual limbs following treatment; no change, clinical score of individual limbs remained the same following treatment; mild progression, clinical score of individual limbs progressed from 1 initially to 2 at the end of treatment; progression, clinical score of individual limbs progressed from 1 or 2 initially to 3 at the end of treatment (n = 33 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 31 limbs [from 19 mice], isotype control-treated group) (P = 0.01; multiway chi-squared). (b) The number of limbs, initially unaffected (clinical score 0, day 0), that developed a particular score at the end of the experiment is presented (n = 47 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 45 limbs [from 19 mice], control-treated group) (P = 0.0007; multiway chi-squared). There were no limbs recruited in anti-GM-CSF-treated mice that developed a clinical score > 1. GM-CSF, Granulocyte macrophage-colony stimulating factor.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC64841&req=5

Figure 5: Effect of anti-GM-CSF treatment post-onset on individual limb involvement. Data are from the experiment in Fig. 2 where mice were treated intraperitoneally with 300 ?g anti-GM-CSF (n = 20 mice) or isotype control (n = 19 mice) daily from the day of disease onset (day 0) until day 9 (total, 10 times). (a) The progression of arthritis in limbs already affected prior to the commencement of treatment is presented: improvement, decrease in clinical score of individual limbs following treatment; no change, clinical score of individual limbs remained the same following treatment; mild progression, clinical score of individual limbs progressed from 1 initially to 2 at the end of treatment; progression, clinical score of individual limbs progressed from 1 or 2 initially to 3 at the end of treatment (n = 33 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 31 limbs [from 19 mice], isotype control-treated group) (P = 0.01; multiway chi-squared). (b) The number of limbs, initially unaffected (clinical score 0, day 0), that developed a particular score at the end of the experiment is presented (n = 47 limbs [from 20 mice], anti-GM-CSF-treated group; and n = 45 limbs [from 19 mice], control-treated group) (P = 0.0007; multiway chi-squared). There were no limbs recruited in anti-GM-CSF-treated mice that developed a clinical score > 1. GM-CSF, Granulocyte macrophage-colony stimulating factor.
Mentions: This absence of disease progression was seen as a relative lack of an increase in the clinical score of initially affected limbs following anti-GM-CSF treatment. Furthermore, anti-GM-CSF-treated mice showed a diminished recruitment of additional limbs that were normal at the commencement of treatment (see Supplementary Fig. 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Arthritis and Inflammation Research Centre, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. adcook@unimelb.edu.au

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus