Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease

• Published in: Immunology letters 2010-06, Vol.131 (1), p.49-58
• Main Authors: Laverny, Gilles, Penna, Giuseppe, Vetrano, Stefania, Correale, Carmen, Nebuloni, Manuela, Danese, Silvio, Adorini, Luciano
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Allergy and Immunology; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antiinflammatory agents; Calcitriol - analogs & derivatives; Calcitriol - chemistry; Calcitriol - pharmacology; Calcitriol - therapeutic use; Cells, Cultured; Colitis; Colitis, Ulcerative - drug therapy; Colon - drug effects; Colon - pathology; Crohn Disease - drug therapy; Female; Humans; Ileum - drug effects; Ileum - pathology; Inflammatory bowel disease; Inflammatory Bowel Diseases - drug therapy; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; LPMC; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mucous Membrane - drug effects; Mucous Membrane - pathology; Receptors, Calcitriol - agonists; TLR; Treatment Outcome; VDR; Vitamin D; Young Adult
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2010.03.006

Abstract Deficiency in 1α,25-dihydroxyvitamin D3 (1,25D3 ) has been suggested as an important environmental factor for immuno-mediated disorders including inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, both characterized by chronic intestinal inflammation. Administration of vitamin D receptor (VDR) agonists can ameliorate spontaneous and induced animal models of colitis, but hypercalcemia is a dose-limiting adverse event. Previous work in our laboratory has identified 1α,25(OH)2 -16-ene-20-cyclopropyl-vitamin D3 (BXL-62) as a potent anti-inflammatory VDR agonist with a low calcemic activity. In the present study, we confirm the marked anti-inflammatory properties of BXL-62 and show its capacity to induce VDR primary response genes, like CYP24A1 and CAMP , at lower concentrations than 1,25D3 , in PBMCs from IBD patients. Its higher anti-inflammatory potency compared to 1,25D3 was demonstrated by the significantly more potent inhibition in PBMCs and in lymphocyte-enriched lamina propria mononuclear cells of the pro-inflammatory cytokines TNF-α, IL-12/23p40, IL-6 and IFN-γ, both at mRNA and protein level. The therapeutic efficacy of intra-rectal administration of BXL-62 in experimental IBD is shown by its beneficial effects, significantly higher than 1,25D3 , to induce recovery of clinical symptoms of colitis at normocalcemic doses in mice undergoing dextran sodium sulfate-induced colitis. These results confirm the therapeutic efficacy of VDR agonists in experimental colitis, and suggest BXL-62 as a promising compound for IBD treatment.