[Show abstract][Hide abstract] ABSTRACT: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/- subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.
[Show abstract][Hide abstract] ABSTRACT: Introduction Multi-disciplinary team (MDT) working is an established part of cancer care. Limited data is available on their impact for benign complex colorectal polyps. Increased numbers of these polyps are referred to our tertiary centre for further management.
Method Polyp MDT comprising of gastroenterologists, colorectal surgeons and histopathologists was established in January 2013 to discuss the management of complex polyps (large or recurrent polyps or those where endoscopic access was difficult). Cases that were referred to individual consultants and had a provisional management plan made were then discussed at the MDT and a consensus management plan was agreed. The impact of MDT management plan was then evaluated.
Results 96 cases were discussed between January 2013 and October 2014. Of those 75 (78%) were tertiary referrals. The reasons for polyp complexity included large polyps 53 (55%), those with difficult access 52 (54%) and previous failed attempt 35 (36%). Majority of the polyps were in recto sigmoid, 49 (51%) or in caecum, 32 (32%). In 38 cases (40%) provisional management plan was changed after MDT discussion. This plan was then followed in 80/96 (82%) cases. Combined surgical-endoscopic approaches were proposed in 68 cases (65%).
25/96 patients had polypectomy during a single hospital visit. The remaining cases (71/96) needed further assessment before attempted polypectomy.
Complete polypectomy was achieved in 85/96 (89%) of patients: endoscopically in 75/96 cases (78%): 38 by endoscopic excision alone and 37 by combined endo-surgical approaches. Ten polyps were resected surgically.
Of the remaining 11 patients no polyps were found in 2 of those referred, 2 patients were referred back their local hospital for surgery, 5 were not fit for a polypectomy and are under surveillance, 1 had metastatic colorectal cancer and 1 declined any intervention.
Cancer was found in 7/96 polyps and 6/7 had surgical resection (the remaining patient had metastatic disease).
Conclusion The polyp MDT consensus management plan led to a change in the proposed management in almost half of the patients. This resulted in complete polypectomy for a large majority of patients referred to our service.
Disclosure of interest None Declared.
Gut 06/2015; 64(Suppl 1):A24.2-A24. DOI:10.1136/gutjnl-2015-309861.47 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: : The pathogenesis of inflammatory bowel disease is incompletely understood but results from a dysregulated intestinal immune response to the luminal microbiota. CD4 T cells mediate tissue injury in the inflammatory bowel disease-associated immune response. Dendritic cells (DC) generate primary T-cell responses and mediate intestinal immune tolerance to prevent overt inflammation in response to the gut microbiota. However, most information regarding function of intestinal DC has come from mouse models, and information in humans is scarce. We show here that intestinal DC subsets are skewed in ulcerative colitis (UC) in humans, with a loss of CD103 lymph-node homing DC; this intestinal DC subset preferentially generates regulatory T cells in mice. We show infiltrates of DC negative for myeloid marker CD11c, with enhanced expression of Toll-like receptors for bacterial recognition. After mixed leukocyte reaction, DC from the inflamed UC colon had an enhanced ability to generate gut-specific CD4 T cells with enhanced production of interleukin-4 but a loss of interferon γ and interleukin-22 production. Conditioning intestinal DC with probiotic strain Lactobacillus casei Shirota in UC partially restored their normal function indicated by reduced Toll-like receptor 2/4 expression and restoration of their ability to imprint homing molecules on T cells and to generate interleukin-22 production by stimulated T cells. This study suggests that T-cell dysfunction in UC is driven by DC. T-cell responses can be manipulated indirectly through effects of bacterial conditioning on gut DC with implications for immunomodulatory effects of the commensal microbiota in vivo. Manipulation of DC to allow generation of DC-specific therapy may be beneficial in inflammatory bowel disease.
[Show abstract][Hide abstract] ABSTRACT: The human/microbiota cross-talk is partially mediated by bacteria-derived peptides like Serine-Threonine peptide (STp), which is resistant to gut proteolysis, is found in the human healthy colon and induces regulatory properties on gut dendritic cells (DCs); here we characterized human gut DC in ulcerative colitis (UC) patients and studied the effect of STp on their properties.
Human colonic DC from healthy controls and UC patients were isolated, conditioned for 24 h +/- STp and characterized by flow cytometry, immunohistochemistry, and electron microscopy. Expression of immature DC markers DC-SIGN and ILT3, and Toll-like receptors were increased on gut UC-DC. Langerin (involved in phagocytosis), lymph node homing marker CCR7, and activation markers CD40/CD80/CD86 were decreased in UC. Gut DC had restricted stimulatory capacity for T-cells in UC. Conditioning of DC with STp in vitro reduced Toll-like receptor expression, increased CD40 and CD80 expression, and restored their stimulatory capacity.
Colonic DCs display an abnormal immature phenotype in UC, which was partially restored following STp treatment. Bacteria-derived metabolites, like STp, seem to have a role in gut homeostasis that is missing in UC so they might lead a new era of probiotic products setting the basis for nondrug dietary therapy in inflammatory bowel disease.
[Show abstract][Hide abstract] ABSTRACT: Diverticular disease (DD) and colonic cancer share common epidemiological characteristics, similar aetiological dietary factors and may present with bleeding.(1) The incidence of both disease entities has increased in parallel over the course of the last century. Additionally, DD of the colon is rare in developing populations where there is also a low incidence of colonic cancer.The association of DD and colonic cancer is unclear and not evidence based, although certain retrospective studies suggest a causal relationship between DD and left sided colorectal cancer.(2) This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Background:
Dendritic cells regulate immune responses to microbial products and play a key role in ulcerative colitis (UC) pathology. We determined the immunomodulatory effects of probiotic strain Lactobacillus casei Shirota (LcS) on human DC from healthy controls and active UC patients.
Human blood DC from healthy controls (control-DC) and UC patients (UC-DC) were conditioned with heat-killed LcS and used to stimulate allogeneic T cells in a 5-day mixed leucocyte reaction.
UC-DC displayed a reduced stimulatory capacity for T cells (P < 0.05) and enhanced expression of skin-homing markers CLA and CCR4 on stimulated T cells (P < 0.05) that were negative for gut-homing marker β7. LcS treatment restored the stimulatory capacity of UC-DC, reflecting that of control-DC. LcS treatment conditioned control-DC to induce CLA on T cells in conjunction with β7, generating a multihoming profile, but had no effects on UC-DC. Finally, LcS treatment enhanced DC ability to induce TGFβ production by T cells in controls but not UC patients.
We demonstrate a systemic, dysregulated DC function in UC that may account for the propensity of UC patients to develop cutaneous manifestations. LcS has multifunctional immunoregulatory activities depending on the inflammatory state; therapeutic effects reported in UC may be due to promotion of homeostasis.
Mediators of Inflammation 07/2013; 2013(2):573576. DOI:10.1155/2013/573576 · 3.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The medical management of refractory ulcerative colitis (UC) remains a significant challenge. Two randomised controlled studies have demonstrated tacrolimus therapy is effective for the induction of remission of moderate to severe UC. However, the long term outcomes of UC patients treated with tacrolimus as maintenance therapy are not certain.
Aims: This study aims to assess the efficacy of tacrolimus maintenance therapy for refractory UC.
Methods: A retrospective review of patients with UC treated with tacrolimus at two London tertiary centres was performed. Clinical outcomes were assessed at six months, at the end of tacrolimus treatment, or at the last follow-up for patients continuing tacrolimus treatment. Modified Truelove–Witts score (mTW) and Mayo endoscopy subscores were calculated.
Results: 25 patients with UC, treated with oral tacrolimus between 2005 and 2011, were identified. The median duration of tacrolimus treatment was 9 months (IQR 3.7–18.2 months). The median duration of follow-up was 27 months (range 3–66 months). At six months thirteen (52%) patients had achieved and maintained clinical response and eleven (44%) were in clinical remission. The mean mTW score decreased from 10 +/− 0.5 before therapy, to 5.8 +/− 0.8 (p ≤ 0.001 95% CI 2.7–5.8) at cessation of treatment or last follow-up. Mayo endoscopy subscore decreased from 2.6 +/− 0.1 to 1.2 +/− 0.2 (p ≤ 0.001 mean reduction 1.4, 95% CI 0.8–1.9). Eight patients (32%) subsequently underwent a colectomy within a mean time of 17 months (range 2–45 months).
Conclusion: Tacrolimus is effective for the maintenance of refractory UC and can deliver sustained improvement in mucosal inflammation.
Journal of Crohn s and Colitis 04/2013; 7(11). DOI:10.1016/j.crohns.2013.03.008 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: : Crohn's disease (CD) is characterized by inflammation that can affect any part of the gastrointestinal tract. It is a chronic destructive condition that follows a relapsing-remitting course and can lead to disability and a poor quality of life. Lifelong pharmacotherapy with systemic immunomodulator therapies remains the cornerstone of CD management. Advances in understanding of the immunopathogenic mechanisms underlying chronic gut inflammation in CD have led to the development of effective biological therapies for patients with CD. Tumor necrosis factor α (TNF-α) is a potent proinflammatory cytokine that plays a pivotal role in the development of Crohn's inflammation. Therapies designed to target this cytokine have revolutionized treatment of CD since their introduction in the late 1990s, thanks to their ability to induce and maintain remission, heal mucosa, reduce hospital admissions and surgical procedures, and restore quality of life. Despite widespread use of these therapies in CD, their precise mechanism of action remains unclear, although several different mechanisms have been proposed. This review summarizes the biology of the TNF-α cytokine and the development of biological therapies targeting TNF-α, and updates our current understanding of mechanisms of action of the commercially available anti-TNF-α therapies used in the treatment of CD.