Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4+ T-cell responses in murine colitis

Abstract

Background: The efficacy of anti-tumor necrosis factor monoclonal antibody (anti-TNF mAb) for Crohn's disease (CD) is well established, and anti-interleukin-6 receptor (anti-IL-6R) mAb has also been reported to be effective in CD. It is, however, unclear if the efficacy and mechanisms of both agents are different in CD therapy. Methods: Using an adoptive transfer colitis model, we compared the efficacy of anti-IL-6R mAb, anti-TNF mAb, and TNF receptor-Fc fusion protein (TNFR-Fc), and their modes of action on CD4 + T cells. We also investigated the role of Th1 and Th17 cells in colitis using the same model. Results: The histological scores for the anti-IL-6R mAb and anti-TNF mAb groups but not for TNFR-Fc group were much lower than that for the control group, and the score was the lowest for the anti-IL-6R mAb group. The frequency of proliferating CD4+ T cells was reduced in anti-IL-6R mAb and anti-TNF mAb groups, but not in the TNFR-Fc group, whereas the frequency of apoptotic CD4+ T cells was similar in all groups. Anti-IL-6R mAb suppressed the induction of Th17 cells and increased the frequency of lamina propria regulatory T cells, whereas anti-TNF mAb exerted no influence on CD4+ T-cell differentiation. A deficiency in interferon-γ and/or IL-17 in CD4+ T cells reduced the severity of colitis. Conclusions: Our findings suggest that suppression of the proliferation of pathogenic CD4+ T cells is the major mode of action of biological agents for colitis therapy. Anti-IL-6R mAb might have benefits in CD patients with Th17 dominance and impaired Treg frequency. (Inflamm Bowel Dis 2011) Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.