THERAPEUTIC POTENTIAL OF ANTI-IL-6 RECEPTOR MONOCLONAL ANTIBODY FOR MURINE MODEL OF CROHN'S DISEASE

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To examine therapeutic potential of blocking IL-6 signaling for Crohn's disease, we introduced anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb) to a murine model of colitis. Colitis was induced in CB17-scid mice transferred CD45RBィイD1highィエD1 CD4ィイD1+ィエD1 T cells from normal Balb/c mice. Anti-IL-6R mAb or control rat IgG was administered intraperitoneally soon after T cell transfer, followed by weekly injection. Body weight was monitored weekly. Colons were removed at 8 weeks and colitis was graded histologically as 0 (minimal) to 3 (severe). ICAM-1 and VCAM-1 expression was analyzed by immunofluolescence staining and FACS, apoptotic cells were determined by TUNEL method. Mice treated with anti-IL-6R mAb showed normal growth while controls lost weight. Average colitis score was 0.64 for mAb treated mice, and 1.80 for controls. CD4ィイD1+ィエD1 T cells in the colon were apparently reduced by mAb as compared to massive infiltration in the controls. Colonic ICAM-1 and VCAM-1 expression was markedly suppressed by the treatment. In mice with colitis, ICAM-1 was expressed mainly in lamina propria, which was more remarkable in the luminal portion. ICAM-1ィイD1+ィエD1 cells were mostly Mac-1ィイD1+ィエD1 but not CD4ィイD1+ィエD1 cells. VCAM-1 was most strongly expressed by submucosal vascular endothelial cells. TUNELィイD1+ィエD1 apoptotic cells were very sparse despite massive infiltration of CD4ィイD1+ィエD1 T cells in colitic mice, while increased apoptosis was seen in mAb treated mice with reduced number of CD4ィイD1+ィエD1 T cells. These results suggest the therapeutic potential of anti-IL-6R mAb for human Crohn's disease.