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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 prior to the onset of arthritis on individual limb involvement. Data are from the experiment in Fig. 1 where mice were treated intraperitoneally with either 300 ?g anti-GM-CSF or 300 ?g isotype control every second day from days 21 to 31. (a) The number of mice that developed arthritis in a given number of limbs is presented. Anti-GM-CSF (n = 9) versus isotype control mice (n = 10) (P = 0.048; multiway chi-squared). There were no anti-GM-CSF-treated mice with all four limbs affected. (b) The number of individual limbs from arthritic mice only with a particular clinical score (severity) is presented. For the anti-GM-CSF-treated group, n = 20 limbs (5 mice); for the isotype control-treated group, n = 36 limbs (9 mice). There were no limbs from anti-GM-CSF-treated mice with a clinical score of 3. GM-CSF, Granulocyte macrophage-colony stimulating factor.
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Figure 2: Effect of anti-GM-CSF treatment prior to the onset of arthritis on individual limb involvement. Data are from the experiment in Fig. 1 where mice were treated intraperitoneally with either 300 ?g anti-GM-CSF or 300 ?g isotype control every second day from days 21 to 31. (a) The number of mice that developed arthritis in a given number of limbs is presented. Anti-GM-CSF (n = 9) versus isotype control mice (n = 10) (P = 0.048; multiway chi-squared). There were no anti-GM-CSF-treated mice with all four limbs affected. (b) The number of individual limbs from arthritic mice only with a particular clinical score (severity) is presented. For the anti-GM-CSF-treated group, n = 20 limbs (5 mice); for the isotype control-treated group, n = 36 limbs (9 mice). There were no limbs from anti-GM-CSF-treated mice with a clinical score of 3. GM-CSF, Granulocyte macrophage-colony stimulating factor.

Mentions: Mice were treated i.p. with increasing doses of anti-GM-CSF (30, 100, and 300 ?g) beginning at day 21, and then every second day until day 31. Control mice received the highest dose (300 ?g) of control mAb. There was a dose-related suppression of the clinical score, with mice receiving 300 ?g anti-GM-CSF mAb showing a marked reduction of disease (Fig. 1a). This decrease in severity was seen both as a reduction in the number of affected limbs per mouse and as lower clinical scores for these affected limbs (see Supplementary Fig. 1). However, while there was a trend towards a lower incidence of arthritis with increasing doses of anti-GM-CSF mAb, this did not reach significance (Fig. 1b).


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 prior to the onset of arthritis on individual limb involvement. Data are from the experiment in Fig. 1 where mice were treated intraperitoneally with either 300 ?g anti-GM-CSF or 300 ?g isotype control every second day from days 21 to 31. (a) The number of mice that developed arthritis in a given number of limbs is presented. Anti-GM-CSF (n = 9) versus isotype control mice (n = 10) (P = 0.048; multiway chi-squared). There were no anti-GM-CSF-treated mice with all four limbs affected. (b) The number of individual limbs from arthritic mice only with a particular clinical score (severity) is presented. For the anti-GM-CSF-treated group, n = 20 limbs (5 mice); for the isotype control-treated group, n = 36 limbs (9 mice). There were no limbs from anti-GM-CSF-treated mice with a clinical score of 3. GM-CSF, Granulocyte macrophage-colony stimulating factor.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Effect of anti-GM-CSF treatment prior to the onset of arthritis on individual limb involvement. Data are from the experiment in Fig. 1 where mice were treated intraperitoneally with either 300 ?g anti-GM-CSF or 300 ?g isotype control every second day from days 21 to 31. (a) The number of mice that developed arthritis in a given number of limbs is presented. Anti-GM-CSF (n = 9) versus isotype control mice (n = 10) (P = 0.048; multiway chi-squared). There were no anti-GM-CSF-treated mice with all four limbs affected. (b) The number of individual limbs from arthritic mice only with a particular clinical score (severity) is presented. For the anti-GM-CSF-treated group, n = 20 limbs (5 mice); for the isotype control-treated group, n = 36 limbs (9 mice). There were no limbs from anti-GM-CSF-treated mice with a clinical score of 3. GM-CSF, Granulocyte macrophage-colony stimulating factor.
Mentions: Mice were treated i.p. with increasing doses of anti-GM-CSF (30, 100, and 300 ?g) beginning at day 21, and then every second day until day 31. Control mice received the highest dose (300 ?g) of control mAb. There was a dose-related suppression of the clinical score, with mice receiving 300 ?g anti-GM-CSF mAb showing a marked reduction of disease (Fig. 1a). This decrease in severity was seen both as a reduction in the number of affected limbs per mouse and as lower clinical scores for these affected limbs (see Supplementary Fig. 1). However, while there was a trend towards a lower incidence of arthritis with increasing doses of anti-GM-CSF mAb, this did not reach significance (Fig. 1b).

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