Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease
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) an...
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| Format: | Article |
| Language: | English |
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Wiley
2018-01-01
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| Series: | Gastroenterology Research and Practice |
| Online Access: | http://dx.doi.org/10.1155/2018/5962624 |
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| author | Thomas Lindebo Holm Ditte Tornehave Henrik Søndergaard Peter Helding Kvist Bodil-Cecilie Sondergaard Lene Hansen Mette Brunsgaard Hermit Kristine Holgersen Sandra Vergo Klaus Stensgaard Frederiksen Claus Haase Dorthe Lundsgaard |
| author_facet | Thomas Lindebo Holm Ditte Tornehave Henrik Søndergaard Peter Helding Kvist Bodil-Cecilie Sondergaard Lene Hansen Mette Brunsgaard Hermit Kristine Holgersen Sandra Vergo Klaus Stensgaard Frederiksen Claus Haase Dorthe Lundsgaard |
| author_sort | Thomas Lindebo Holm |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-754172b7ee274a7ea49e758f08ef3c8d |
| institution | OA Journals |
| issn | 1687-6121 1687-630X |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
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| series | Gastroenterology Research and Practice |
| spelling | doaj-art-754172b7ee274a7ea49e758f08ef3c8d2025-08-20T02:07:13ZengWileyGastroenterology Research and Practice1687-61211687-630X2018-01-01201810.1155/2018/59626245962624Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s DiseaseThomas Lindebo Holm0Ditte Tornehave1Henrik Søndergaard2Peter Helding Kvist3Bodil-Cecilie Sondergaard4Lene Hansen5Mette Brunsgaard Hermit6Kristine Holgersen7Sandra Vergo8Klaus Stensgaard Frederiksen9Claus Haase10Dorthe Lundsgaard11Global Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkNovo Nordisk LIFE In Vivo Pharmacology Centre, Frederiksberg, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkGlobal Research, Novo Nordisk A/S, Maaloev, DenmarkBackground 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.http://dx.doi.org/10.1155/2018/5962624 |
| spellingShingle | Thomas Lindebo Holm Ditte Tornehave Henrik Søndergaard Peter Helding Kvist Bodil-Cecilie Sondergaard Lene Hansen Mette Brunsgaard Hermit Kristine Holgersen Sandra Vergo Klaus Stensgaard Frederiksen Claus Haase Dorthe Lundsgaard Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease Gastroenterology Research and Practice |
| title | Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease |
| title_full | Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease |
| title_fullStr | Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease |
| title_full_unstemmed | Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease |
| title_short | Evaluating IL-21 as a Potential Therapeutic Target in Crohn’s Disease |
| title_sort | evaluating il 21 as a potential therapeutic target in crohn s disease |
| url | http://dx.doi.org/10.1155/2018/5962624 |
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