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T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's disease
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery Östergötland.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

Keyword [en]
Blood, E.coli LF82, FACS, IBD, ileum, mixed lymphhocyte reaction
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-52228OAI: oai:DiVA.org:liu-52228DiVA: diva2:280708
Available from: 2009-12-11 Created: 2009-12-11 Last updated: 2009-12-11Bibliographically approved
In thesis
1. Mucosal dendritic cells in inflammatory bowel disease
Open this publication in new window or tab >>Mucosal dendritic cells in inflammatory bowel disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crohn's disease, a chronic inflammation of the bowel, is a multi-factorial condition where uncontrolled immune responses to luminal bacteria occur in genetically predisposed individuals. The first observable clinical signs are small ulcers that form at a specialised form of epithelium, follicle-associated epithelium (FAB). The FAB covers immune inductive sites, Peyer's patches, which function primarily as sensory areas that sample the externaI gut environment. Dendritic cells are one of the key cells that are involved in sensing luminal contents and orchestrating the gut immune system.

The main aim of this thesis was to determine whether the barrier of the FAB is breached in Crohn's disease and if dysfunctional immune regulators, namely dendritic cells, playaroIe in initiating and/or maintaining the chronic intestinal inflammation.

Using biopsies and surgical specimens, we were able to show that in Crohn's disease, there was an increased transmucosaI transport of Escherichia coli compared to specimens from ulcerative colitis and non-inflammatory bowel disease (IBD) controIs. Dendritic cells internalised a higher percentage of bacteria that had translocated across the FAB in the Crohn's samples. Furthermore, significantly higher concentrations of TNF-u was released upon bacterial stimulation by tissues from patients with Crohn's disease than in controIs.

We went on to characterise the dendritic cells present in the Peyer's patches of patients with Crohn's disease. We found an accumulation of both immature and mature dendritic cells beneath the FAB, in the sub-epithelial dome (SED). Normally, mature dendritic cells migrate towards T cell-rich areas. However, we observed mature dendritic cells accumulating in the SED because they lacked the CCR7 migratory receptor. Furthermore, they were more prone to take-up bacteria, and produced TNF.

To study the function of mucosal dendritic cells, we performed isolation experiments and mixed Iymphocyte reactions. Dendritic cells from both the ileum and blood of patients with active Crohn's had reduced capacity for inducing T cell proliferation than non-IBD controIs. Blood dendritic cells of patients in remission had normalised function that was similar to dendritic cells from healthy controls.

The SAMPl/YitFc mice, considered an appropriate murine model for Crohn's disease, had an inherent permeability defect that increased with the chronicity of intestinaI inflammation. However unlike in human Crohn's disease, dendritic cells did not seem to playaroIe in murine ileitis.

This thesis highlights the accumulation of the actively surveying dendritic cells that are prone to bacterial internalisation, and points to their possible different functional roles in active versus in-active disease; thereby confirming dendritic cells as one ofthe key components in the pathogenesis ofCrohn's disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1129
Keyword
Blood, Crohn's disease, dendritic cells, E. coli, FACS, follicle-associated, epithelium, human, ileum, mixed lymphocyte reaction, permeability, Peyer's patches, SAMP1/YitFc, Ussing chambers, villous epithelium
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-52234 (URN)978-91-7393-625-5 (ISBN)
Public defence
2009-05-19, Berzeliussalen, Hälsouniversitetet, Campus Valla, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2009-12-11 Created: 2009-12-11 Last updated: 2009-12-11Bibliographically approved

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Salim, Sa'ad YislamLarsson, MarieSöderholm, Johan

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