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Gastroenterology Research and Practice
Volume 2018, Article ID 5962624, 22 pages
https://doi.org/10.1155/2018/5962624
Research Article

Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease

1Global Research, Novo Nordisk A/S, Maaloev, Denmark
2Novo Nordisk LIFE In Vivo Pharmacology Centre, Frederiksberg, Denmark

Correspondence should be addressed to Thomas Lindebo Holm; moc.ksidronovon@hlht

Received 9 August 2017; Revised 5 February 2018; Accepted 13 February 2018; Published 10 April 2018

Academic Editor: Paul Enck

Copyright © 2018 Thomas Lindebo Holm et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background and Aim. Interleukin-21 (IL-21) is primarily a T cell-derived cytokine; it is upregulated in patients with Crohn’s Disease (CD) and could be a potential new therapeutic target in CD. Methods. In human material, IL-21 and IL-21R expression was investigated by in situ hybridization (ISH) and immunohistochemistry (IHC) in noninflammatory bowel disease (non-IBD) controls and patients with CD. The pathologic role of IL-21 was examined in murine models of T cell-dependent and T cell-independent colitis, either with a neutralizing monoclonal antibody against IL-21 or with the transfer of CD4+CD45RBhighIL-21R−/− T cells. Colonic pathology was examined by endoscopy, histopathology, IHC, ELISA, and Luminex. Results. In the human intestine, IL-21 and IL-21R mRNA and protein-expressing cells were observed in the mucosa, in lymphoid aggregates of submucosa in non-IBD controls, and in lymphoid aggregates of muscularis externa in patients with CD. IL-21 expression was most abundant in germinal centers (GCs) of the lymphoid aggregates, and IL-21R expression assessed semiquantitatively, was significantly higher in patients with CD compared to non-IBD controls. Following prophylactic and interventive anti-IL-21 mAb treatment in the adoptive transfer (AdTr) model, clinical and pathological parameters were significantly reduced. The most persistent finding was a reduction in colonic infiltrating neutrophils. As well, Rag2−/− mice receiving CD4+CD45RBhighIL-21R−/− T cells developed less severe colitis compared to Rag2−/− mice receiving CD4+CD45RBhighIL-21R+/+ T cells. No effect of reduced IL-21 signalling was observed in T cell-independent colitis. Conclusion. Our study shows that patients with CD have significant expression of IL-21 and IL-21R in the gut. As well, we show that neutralization of IL-21 in experimental T cell-driven colitis is associated with a reduction in clinical and pathological findings. This amelioration seems to be associated with a reduction in colon-infiltrating neutrophils.