期刊
INFLAMMATORY BOWEL DISEASES
卷 17, 期 2, 页码 491-502出版社
WILEY-BLACKWELL
DOI: 10.1002/ibd.21384
关键词
interleukin-6; tumor necrosis factor; colitis; Th17 cells; Treg cells
资金
- National Institute of Biomedical Innovation
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Grants-in-Aid for Scientific Research [21591276, 22591101] Funding Source: KAKEN
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-gamma 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.
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