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Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease
Thomas Lindebo Holm1, Ditte Tornehave1, Henrik Søndergaard1
1Global Research, Novo Nordisk A/S, Maaloev, Denmark.
Gastroenterology Research and Practice
|June 1, 2018
Summary
Interleukin-21 (IL-21) is elevated in Crohn's Disease (CD). Neutralizing IL-21 reduced inflammation and colon-infiltrating neutrophils in experimental colitis, suggesting IL-21 as a therapeutic target for CD.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Interleukin-21 (IL-21) is a T cell-derived cytokine.
- IL-21 is upregulated in patients with Crohn's Disease (CD).
- IL-21 presents a potential therapeutic target for CD.
Purpose of the Study:
- To investigate the expression of IL-21 and its receptor (IL-21R) in human CD.
- To examine the pathological role of IL-21 in murine models of colitis.
- To evaluate the therapeutic potential of neutralizing IL-21 in T cell-driven colitis.
Main Methods:
- In situ hybridization (ISH) and immunohistochemistry (IHC) were used to assess IL-21 and IL-21R expression in human intestinal tissue.
- Murine models of T cell-dependent and T cell-independent colitis were employed.
- Neutralizing monoclonal antibodies against IL-21 and adoptive transfer of IL-21R-/- T cells were utilized.
Main Results:
- IL-21 and IL-21R expression was significantly higher in the gut mucosa and lymphoid aggregates of CD patients compared to controls.
- Anti-IL-21 monoclonal antibody treatment significantly reduced clinical and pathological parameters in an adoptive transfer model of colitis.
- Mice receiving IL-21R-/- T cells developed less severe colitis, and a reduction in colonic infiltrating neutrophils was observed.
- No effect of reduced IL-21 signaling was noted in T cell-independent colitis.
Conclusions:
- Patients with CD exhibit significant expression of IL-21 and IL-21R in the gut.
- Neutralization of IL-21 ameliorates experimental T cell-driven colitis, reducing clinical and pathological findings.
- The therapeutic benefit of IL-21 neutralization appears linked to a decrease in colon-infiltrating neutrophils.
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