Andrew N. Milestone

Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer

Over the past 5 years, there has been a rapid resurgence of interest in vitamin D outside of its traditional role in metabolic bone disease. Some nontraditional roles ascribed to vitamin D include anti-inflammatory and immune-modulating effects. These effects have led to possible implications in the pathophysiology of immune-mediated diseases including multiple sclerosis and inflammatory bowel disease (IBD). In addition, vitamin D insufficiency has been linked to higher rates of cancers including colon, prostate and breast cancers. Given these diverse associations of vitamin D and disease states, this review describes recent advances with regard to vitamin D and gastrointestinal diseases, in particular IBD and colorectal cancer.

Human gut‐specific homeostatic dendritic cells are generated from blood precursors by the gut microenvironment

Background: Dendritic cells (DC) dictate not only the type of T‐cell immunity, but also homing patterns of T cells in mice. In humans, we characterized normal human gut DC and tested whether gut‐specific homeostatic DC could be generated from blood precursors by factors in the gut microenvironment. Methods: We characterized the phenotype and function of healthy human gut DC compared with blood and skin DC, and studied whether conditioning of blood DC in the presence of colonic biopsy supernatants (Bx‐SN) induced gut‐like phenotype and functions. Results: Blood DC mostly expressed both gut and skin homing markers, indicating potential to migrate to both major immune surface organs, and induced multi‐homing T cells. However, DC within gut or skin did not demonstrate this multi‐homing phenotype, were tissue‐specific, and induced tissue‐specific T cells. Human gut DC were less stimulatory for allogeneic T cells than their dermal and blood counterparts. Human blood DC cultured in vitro lost homing marker expression. Conditioning of human enriched blood DC with colonic Bx‐SN from healthy controls induced a gut‐homing phenotype and a homeostatic profile. Moreover, Bx‐SN‐conditioned DC demonstrated a restricted T‐cell stimulatory capacity and preferentially induced gut‐specific T cells. Retinoic acid and transforming growth factor beta (TGF‐&bgr;) mediated the acquisition of the gut‐homing and homeostatic properties, respectively, induced by colonic Bx‐SN on blood enriched DC. Conclusions: Tissue‐specific factors manipulate immunity via modulating characteristics of DC and may provide tools to generate tissue‐specific immunotherapy. (Inflamm Bowel Dis 2011;)

Skin‐ and gut‐homing molecules on human circulating γδ T cells and their dysregulation in inflammatory bowel disease

Changes in phenotype and function of γδ T cells have been reported in inflammatory bowel disease (IBD), including Crohns disease (CD) and ulcerative colitis (UC). Dysregulation of lymphocyte migration plays a key role in IBD pathogenesis; however, data on migratory properties of γδ T cells are scarce. Human circulating γδ T cells from healthy controls (n = 27), patients with active CD (n = 15), active UC (n = 14) or cutaneous manifestations of IBD (n = 2) were characterized by flow cytometry. Circulating γδ T cells in healthy controls were CD3hi and expressed CD45RO. They expressed gut‐homing molecule β7 but not gut‐homing molecule corresponding chemokine receptors (CCR)9, or skin‐homing molecules cutaneous lymphocyte‐associated antigen (CLA) and CCR4, despite conventional T cells containing populations expressing these molecules. CCR9 expression was increased on γδ T cells in CD and UC, while skin‐homing CLA was expressed aberrantly on γδ T cells in patients with cutaneous manifestations of IBD. Lower levels of CD3 expression were found on γδ T cells in CD but not in UC, and a lower proportion of γδ T cells expressed CD45RO in CD and UC. Enhanced expression of gut‐homing molecules on circulating γδ T cells in IBD and skin‐homing molecules in cutaneous manifestations of IBD may be of clinical relevance.

Is rosiglitazone a promising treatment for ulcerative colitis

In this Practice Point commentary, we discuss the findings and limitations of a randomized, placebo-controlled trial conducted by Lewis and colleagues that examined the efficacy of rosiglitazone for the treatment of patients with mild-to-moderately active ulcerative colitis. The results show that rosiglitazone had superior efficacy to placebo for inducing clinical response and remission. However, the efficacy of rosiglitazone in this setting was modest. We believe that this finding might be attributable to the high numbers of patients included in the trial who were refractory to conventional therapy. Rosiglitazone might be more effective if combined with 5-aminosalicylic acid therapy and used in patients with less-refractory disease. We highlight the issues to consider when interpreting and generalizing these findings to clinical practice.

PTU-036 The immunomodulatory effects of vitamin d on low-density cells and monocyte-derived dendritic cells from human peripheral blood in vitro

Introduction Emerging evidence suggests Vitamin D (VD) possesses a wide range of immunomodulatory properties. Epidemiological evidence also implicates VD insufficiency in Inflammatory Bowel Disease (IBD).1 Dendritic Cells (DC) are conductors of the immune system, uniquely capable of primary antigen presentation to naïve T cells, determining either immune response or tolerance. Studies on laboratory-generated monocyte-derived dendritic cells (MoDC) demonstrate 1,25-dihydroxyvitaminD3 (1,25(OH)2D3), the biologically active form of VD, induces an immature and tolerogenic DC phenotype.2 In vivo studies on murine models of IBD suggest therapeutic potential for VD.3 Methods We determined the immunomodulatory effects of 1,25(OH)2D3 on maturation and functional phenotype of blood DC, in particular DC-enriched Low-Density Cells (LDC). Peripheral blood mononuclear cells (PBMC) were isolated on Ficoll gradients from blood of healthy volunteers. LDC enriched for DC were isolated on a NycoPrep gradient from non-adherent cells after overnight PBMC culture. MoDC were obtained from magnetically sorted CD14+ monocytes of PBMC, incubated for 5 days with IL-4 and GM-CSF. LDC and MoDC were cultured for another 24 h in complete medium with and without 1,25(OH)2D3 and/or LPS. LDC and MoDC maturation was determined by flow cytometry using monoclonal antibodies to maturation markers including CD14, CD40, HLA-DR and ILT-3, which is an inhibitory receptor and a marker of DC immaturity. MoDC functional phenotype was determined by phagocytotic capacity (FITC-Dextran uptake) which is reduced in mature DC. Cell morphology was also assessed by electron microscopy (EM). Results VD-conditioned LDC demonstrated an immature phenotype compared with controls with significantly increased expression of monocyte marker CD14 (<0.01, n=10) and ILT-3 (p<0.02, n=10), but significantly decreased CD40 (p<0.001, n=14) and HLA-DR (p<0.03, n=7), even when co-cultured with the antigen LPS for 4 or 24 h. Furthermore, FITC-Dextran uptake by VD-conditioned MoDC was enhanced dose dependently, correlating with increased CD14 expression, suggesting reversion to a monocyte-like state (p<0.001). EM revealed a greater proportion of morphologically immature LDC cells in the VD groups compared with controls. Conclusion 1,25(OH)2D3 promotes an immature phenotype in both LDC and MoDC in vitro inducing a tolerogenic-type phenotype and monocyte-like state. These immunomodulatory effects suggest a potential therapeutic role for VD in IBD possibly by promotion of oral tolerance.