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P063. IL-21 and IL-21 receptor expression in the intestine from patients with Crohn's disease

D. Tornehave1, S. Zahn2, F. Matthiesen3, B. Olsen Krogh4, D. Lundsgaard5, 1Histology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark, 2Antibody Technology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark, 3Protein Purification, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark, 4Mammalian Cell Technology, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark, 5Inflammation Sciences, Biopharmaceuticals Research Unit, Novo Nordisk A/S, Maaloev, Denmark

Background

IL-21 is a proinflammatory cytokine produced by activated T cells and the IL-21R is expressed by multiple cell types. IL-21 has pleiotropic actions and has been suggested to have a role in the pathogenesis of Crohn's disease (CD). The aim of our study was to investigate expression of IL-21 and IL-21R and to characterize IL-21R+ cells in the intestine from patients with CD.

Methods

IL-21 and IL-21R expression was investigated by in-situ hybridization and immunohistochemistry in normal intestine and from patients with CD. Characterization of IL-21R+ cells was performed by double immunofluorescence staining with markers for T cells (CD3), B cells (CD20), plasma cells (CD138), and macrophages (CD68).

Results

IL-21 and IL-21R mRNA expressing cells were observed in mucosa (M) and lymphoid aggregates of submucosa (SM) in normal intestine. In patients with CD, additionally expression localized to lymphoid aggregates of SM and muscularis (Mu), with abundant expression in germinal centres (GCs). IL-21+ and IL-21R+ expressing immune cells were present in M and lymphoid aggregates of SM and Mu from patients with CD. The number of intestinal IL-21+ cells seemed increased with disease activity in CD patients. The extent of intestinal IL-21R+ expressing cells assessed semi-quantitatively was significantly higher (P < 0.05) in patients with CD compared to normal. The intestinal IL-21 and IL-21R mRNA and protein expression patterns were similar. IL-21R+CD3+ T cells were present in M, SM and Mu in lymphoid aggregates from patients with CD. IL-21R+CD20+ B cells were found in M, lymphoid aggregates, in particular in GCs, of SM and Mu from patients with CD. IL-21R+CD138+ plasma cells were observed only in M in normal intestine, whereas in patients with CD IL-21R+ plasma cells were also present in lymphoid aggregates of SM and Mu. IL-21R+CD68+ macrophages were present in M, lymphoid aggregates of SM and Mu from patients with CD.

Conclusion

We found IL-21 and IL-21R expression present in normal and diseased intestine. IL-21 expression seemed more pronounced in CD patients with severe disease activity, and IL-21R expression was significantly up-regulated in CD patients. IL-21R+ cells were identified as T cells, B cells, plasma cells and macrophages. Our data suggest that locally produced IL-21 can activate IL-21R+ T cells, B cells, plasma cells and macrophages, suggesting a role of this cytokine-receptor interaction in the pathogenesis of CD. Thus, IL-21 may represent a promising target for treatment of CD.