Colonies of cells with distinctive dendritic appearance were observed in methylcellulose cultures of human bone marrow and peripheral blood mononuclear cells (PBMC). Such cells appeared alone in colonies of less than 50 cells, together with macrophages in mixed colonies and also within clusters of T lymphocytes at high culture cell numbers. The morphologic resemblance to lymphoid dendritic cells was confirmed by electron microscopy and the cells were distinguished from macrophages by immunoenzymatic and immunogold labeling with monoclonal antibodies (MoAbs). Like macrophages they were HLA-DR+ and CD4+. However, they lacked nonspecific esterase and the macrophage cytoplasmic marker Y1/82A. Most strikingly, cells were strongly HLA-DQ+ and expressed CD1a (T6), which is characteristic of skin Langerhans cells. Their functional similarity to lymphoid dendritic cells was demonstrated by their ability to stimulate allogeneic mixed leukocyte reactions. Dendritic cell colony numbers were estimated in both bone marrow and peripheral blood of controls and in leukemia and lymphoma patients before and after chemotherapy. Colony numbers were low in control blood and in patients before treatment (less than 1.0 to 3.7/10(5) cells). However, during hematopoietic recovery the mean value increased to 37.5/10(5) cells and this increase correlated closely with the observed increase in circulating colony forming unit-granulocyte macrophage (CFU- GM) in individual patients. Autoradiographic studies demonstrated mitotic activity within CD1a+ colonies and a linear relationship between cultured cells and both pure and mixed colonies was consistent with their derivation from a single precursor. These data indicate that a novel hematopoietic progenitor of dendritic/Langerhans cells (DL-CFU) may now be identified in a clonal assay system and suggest a probable common progenitor for these cells and macrophages.
IntroductionThe intestinal microbiota drive inflammation associated with Crohn's disease.1 The composition of the intestinal microbiota can be influenced by prebiotic's such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS can increase colonic bifidobacteria and induce immunoregulatory dendritic cell (DC) epithelial responses.2MethodsTo assess the impact of a diet supplemented with FOS in patients with active Crohn's disease using an appropriately powered randomised, double-blind, placebo-controlled trial. Patients with active Crohn's disease (CDAI ≥ 220, plus one marker of inflammation) were randomised to receive 15 g/day FOS or placebo for 4 weeks. The primary endpoint was clinical response at week 4 (change in CDAI of −70 in the intention-to-treat (ITT) population). Multiple pre-specified secondary endpoints were analysed, including intracellular cytokine staining assessed by flow cytometry (n=27).ResultsIn total, 103 patients were randomised to receive FOS (n=54) or placebo (n=49). The mean (SD) baseline CDAI was 283 (61.1) and 286 (61.5) in the FOS and placebo groups, respectively (p=0.79). Significantly more patients receiving FOS (n=14.26%) than placebo (n=4.8%) withdrew before the 4-week endpoint (p=0.018). There was no significant clinical benefit of FOS compared to placebo (Abstract 003). Patients receiving FOS, but not placebo, had a reduced proportion of IL-6+ intestinal DC, and increased DC staining of IL-10 (both p<0.05). No effect on DC IL-12 was seen. Throughout the intervention patients receiving FOS had a significantly greater severity of flatulence (FOS mean 10.8, SD 5.7 vs placebo 7.3, 3.6, p=0.004) and rumbling gut (mean 8.3, SD 5.0 vs 6.1, 4.1, p=0.029) compared with placebo.ConclusionAn adequately powered trial of a diet supplemented with FOS in a well defined population of patients with active Crohn's disease showed no clinical benefit despite impacting on DC immunology. Patient withdrawal was greater in patients receiving FOS.
Abstract OC-003Clinical resultsFOSPlacebop ValueResponse, n (%) intention-to-treat12 (22)19 (39)0.067Per protocol, n (%)12 (30)19 (42)0.243Remission, n (%) intention-to-treat6 (11)10 (20)0.193Per protocol, n (%)6 (15)10 (22)0.395Change in calprotectin, mean (SD)62 (301)296 (494)0.092
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