ABSTRACT
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-ß) 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.
Subject(s)
Dendritic Cells/immunology , Dendritic Cells/pathology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Skin/immunology , Skin/pathology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Adult , Aged , Cell Movement/drug effects , Cell Movement/immunology , Cell Proliferation , Cells, Cultured , Dendritic Cells/metabolism , Female , Flow Cytometry , Gastrointestinal Tract/metabolism , Humans , Male , Microscopy, Fluorescence , Middle Aged , Phenotype , Receptors, Lymphocyte Homing/immunology , Receptors, Lymphocyte Homing/metabolism , T-Lymphocytes/metabolism , Transforming Growth Factor beta/pharmacology , Tretinoin/pharmacologyABSTRACT
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.
ABSTRACT
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.
