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

Autor: Holm TL; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Tornehave D; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Søndergaard H; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Kvist PH; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Sondergaard BC; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Hansen L; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Hermit MB; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Holgersen K; Novo Nordisk LIFE In Vivo Pharmacology Centre, Frederiksberg, Denmark., Vergo S; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Frederiksen KS; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Haase C; Global Research, Novo Nordisk A/S, Maaloev, Denmark., Lundsgaard D; Global Research, Novo Nordisk A/S, Maaloev, Denmark.
Jazyk: angličtina
Zdroj: Gastroenterology research and practice [Gastroenterol Res Pract] 2018 Apr 10; Vol. 2018, pp. 5962624. Date of Electronic Publication: 2018 Apr 10 (Print Publication: 2018).
DOI: 10.1155/2018/5962624
Abstrakt: 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 + CD45RB high IL-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 + CD45RB high IL-21R -/- T cells developed less severe colitis compared to Rag2 -/- mice receiving CD4 + CD45RB high IL-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.
Databáze: MEDLINE
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