Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease
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Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease. / Lindebo Holm, Thomas; Tornehave, Ditte; Søndergaard, Henrik; Kvist, Peter Helding; Sondergaard, Bodil-Cecilie; Hansen, Lene; Hermit, Mette Brunsgaard ; Holgersen, Kristine; Vergo , Sandra; Frederiksen , Klaus Stensgaard ; Haase, Claus; Lundsgaard, Dorthe.
In: Gastroenterology Research and Practice, Vol. 2018, 5962624, 10.04.2018.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease
AU - Lindebo Holm, Thomas
AU - Tornehave, Ditte
AU - Søndergaard, Henrik
AU - Kvist, Peter Helding
AU - Sondergaard, Bodil-Cecilie
AU - Hansen, Lene
AU - Hermit, Mette Brunsgaard
AU - Holgersen, Kristine
AU - Vergo , Sandra
AU - Frederiksen , Klaus Stensgaard
AU - Haase, Claus
AU - Lundsgaard, Dorthe
PY - 2018/4/10
Y1 - 2018/4/10
N2 - 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.
AB - 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.
U2 - 10.1155/2018/5962624
DO - 10.1155/2018/5962624
M3 - Journal article
C2 - 29849593
VL - 2018
JO - Gastroenterology Research and Practice
JF - Gastroenterology Research and Practice
SN - 1687-6121
M1 - 5962624
ER -
ID: 213234761