CCR9 Antagonists in the Treatment of Ulcerative Colitis

Figure 4

Pharmacological CCR9 inhibition results in a significant reduction in severity of colitis symptoms in mdr1^−/− mice. (a) CCX025 treatment, starting at 11 weeks of age, resulted in a significant inhibition of the growth retardation associated with disease. Mice treated with CCX025 () gained weight in an identical fashion to wild-type controls (); vehicle-treated mdr1a^−/− mice () failed to gain weight after week 22. (b) CCX025 treatment resulted in a significant reduction in mortality compared to vehicle in mdr1a^−/− mice. (c) CCX025 treatment resulted in a significant reduction in the percentage of mdr1a^−/− mice that developed established diarrhea (score of ≥3 out of 5). (d) CCX025 treatment resulted in a significant inhibition of the disease-induced increase in CCR9⁺CD4⁺ PBMC frequencies in mdr1a^−/− mice, measured at 17 weeks of age. (e) CCX282-B treatment (), starting at 10 weeks of age, resulted in a significant inhibition of the growth retardation associated with disease, compared to controls (). (f) Therapeutic treatment with CCX282-B ( per treatment group) resulted in a significant reduction in the weight loss associated with active disease. Animals were randomized at 16 weeks of age to either CCX282-B or vehicle treatment. All panels: < 0.05; < 0.01.

(a)

(b)

(c)

(d)

(e)

(f)