P021. Glucagon-like peptide‑2 modulates the production of proinflammatory cytokine interferon-γ in human blood and intestinal dendritic cells a potential new therapy for Crohn's disease
C.T. Tee1, S. Peake2, D. Bernardo1, E. Mann1, J. Landy2, N. Daulatzai2, K. Wallis3, S.M. Gabe2, S. Knight1, H.O. Al-Hassi1
1Antigen Presentation Research Group, Imperial College, London, United Kingdom; 2St Mark's Hospital, London, United Kingdom; 3Watford Hospital, London, United Kingdom
Background: Glucagon-like peptide‑2 (GLP2), an intestinotrophic growth hormone plays an important role in intestinal adaptation and repair during inflammatory events. Rodent models of intestinal injury have shown that GLP2 ameliorates mucosal damage, intestinal lesions, and inflammation  by reducing production of proinflammatory cytokines. Early clinical trial data of its use in Crohn's disease are promising . Dendritic cells (DC), commanders-in-chief of the immune system, determine development of either immunogenic or tolerogenic immune responses. Dysregulation of this balance of immune responses contribute to inflammatory bowel disease pathogenesis. We hypothesize that DC mediates the immunomodulatory function of GLP2 in humans.
Methods: Human blood enriched DC and colonic biopsy migratory intestinal DC from healthy volunteers were cultured in-vitro for 24 hours with GLP2. Ongoing intracellular cytokine production was measured after 4‑hour monensin incubation and analysed for statistical significance. DC were identified by flow cytometry as HLA-DR +ve and lineage −ve cells (CD3-CD14-CD19-CD34-CD16−). Stimulatory and cytokine priming capacity of blood GLP2-conditioned DC were studied on allogeneic CFSE-labelled T cells.
Results: GLP‑2 conditioning of blood and intestinal DC significantly reduce the ongoing production of inflammatory cytokine IFNγ (blood DC, p = 0.003, n = 5; gut DC, p = 0.004, n = 8). Inflammatory IL12 production was also significantly reduced in blood DC (p = 0.043, n = 5). There was no change in the production of IL‑10 or IL17a in blood or gut DC. GLP2 conditioning modulated blood DC function by significantly reducing the production of IFNγ by allogeneic T‑cell stimulated by those DC, compared to untreated DC (p = 0.045, n = 5).
Conclusions: Effects of GLP2 on human DC have not been previously investigated. Our novel data suggests that the reported therapeutic effects of GLP2 in rodent models may be due to induction of immunoregulatory properties in DC and the T‑cells that they stimulate. Manipulating immunity via modulating characteristics of DC may provide tools to generate DC-specific immunotherapy in T‑cell dominated inflammatory bowel diseases such as IBD.
1. Sigalet et al. (2007), Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2, Am J Physio Gastrointest Liver Physiol, 293: G21121.
2. Buchman et al. (2010), Teduglutide, a novel mucosally active analog of glucagon-like peptide‑2 (GLP‑2) for the treatment of moderate to severe Crohn's disease, Inflammatory bowel diseases, 16(6): 96273.