An antibody to colony stimulating factor-1 (CSF-1) inhibits DSS-induced colitis

D. Marshall, J. Cameron, D. Lightwood, A.D.G. Lawson & R. Foulkes, Celltech Antibody Centre of Excellence, UCB Group, 216 Bath Road, Slough, Berks. SL1 4EN. UK

The cytokine colony stimulating factor–1 (CSF-1) mediates macrophage recruitment, proliferation, differentiation and activation. Mucosal macrophages have been implicated in the pathogenesis of inflammatory bowel disease, and patients have raised serum CSF-1 with increased expression of CSF-1 in intestinal lesions (Klebl et al., 2001), however the role of CSF-1 in mucosal inflammation is unknown. Oral administration of dextran sulfate sodium (DSS) induces colitis in rodents (Okayasu et al., 1990), bearing some resemblance to ulcerative colitis, with crypt destruction and infiltration of inflammatory cells, including macrophages, into the colon. We investigated whether a blocking antibody to CSF-1 would inhibit DSS-induced colonic mucosal inflammation in mice.

DSS (1%) was added to the drinking water of male Balb/c mice (24.1 +0.3 g, n = 10/group) continuously for 8 days. The mice were treated with either Ab33 (chimeric mouse anti-mouse CSF-1 antibody) or 101.4 (isotype matched negative control antibody) at 10 mg/kg s.c. one day prior to DSS administration and weekly thereafter. An additional group of age-matched normal mice (n = 10) received drinking water only. Body weight and the appearance and severity of clinical signs of bowel disease were monitored daily. On day 8, mice were killed with an overdose of halothane, the length of the colon from the rectum to the caecum was measured and 2 cm of the distal colon was placed in formalin for histological assessment. Data are presented as mean + sem and analysed by one-way ANOVA with Bonferroni’s multiple comparison post test.

Addition of DSS to drinking water results in a significant reduction in body weight. Compared with normal animals, DSS animals receiving 101.4 had lower body weights (20.1 +0.7 g vs 25.8 +0.5 g) and ended the study at 85% of their starting weights. In contrast, DSS animals receiving Ab33 maintained their bodyweights and ended the study at 24.4 +0.8 g. Colon length in normal mice was 9.5 +0.1 cm and was reduced to 6.2 +0.2 cm in mice receiving DSS and treated with 101.4. Treatment with Ab33 protected against colon shortening (8.2 +0.4 cm p<0.001). Ab33 also inhibited incidence and severity of bowel disease. Only 2/10 Ab33 treated mice had clinical signs of disease, with a low clinical score of 1 or 2, whereas 9/10 101.4 treated mice had clinical signs of disease and included mice which scored a maximum clinical score of 4. Histological damage to the crypts was also reduced by treatment with Ab33 and the number of CD3+ cells in the colonic lamina propria of DSS colitis mice was reduced from 27.5 +2.0 to 10.0 +1.3 cells per 250 m m x 250 m m (p<0.001). The number of F4/80+ macrophages in the colon was also reduced by Ab33 to 12.9 +1.4 cells per 250 m m x 250 m m compared with 30.5 +2.4 cells (p<0.001) in mice receiving control antibody.

These results indicate that an antibody to CSF-1 can inhibit DSS-induced colitis and supports CSF-1 as a potential therapeutic target for inhibiting intestinal inflammation.

Klebl et al., (2001) Journal of Pathology 195 609-615.
Okayasu et al., (1990) Gastroenterology 98 694-702.