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Journal articleLandy J, Ronde E, English N, et al., 2016,
Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer
, World Journal of Gastroenterology, Vol: 22, Pages: 3117-3126, ISSN: 1007-9327 -
Journal articleMalietzis G, Lee GH, Al-Hassi HO, et al., 2016,
Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer
, Tumor Biology, Vol: 37, Pages: 11359-11364, ISSN: 1423-0380Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = −0.46, p = 0.03.) and with CD83 [all DCs (r = −0.63; p = 0.01) and myeloid DCs (r = −0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC.
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Journal articleVora R, Bernardo D, Durant L, et al., 2016,
Age-related alterations in blood and colonic dendritic cell properties
, Oncotarget, Vol: 7, Pages: 11913-11922, ISSN: 1949-2553Background Dendritic cells (DC) determine initiation, type and location of immuneresponses and, in adults, show decreased Toll-like receptors and some increasedcytokine levels on ageing. Few studies in children have characterised DC orexplored DC-related mechanisms producing age-related immune changes.Methods Blood and colonic DC phenotypes were determined in healthy adults andchildren by flow cytometry and correlated with aging. Blood DC were divided intoplasmacytoid (pDC) and myeloid (mDC) while only mDC were identified in colon.Serum cytokine levels were determined by multiplex cytokine assays and correlatedwith DC properties.Results The pDC marker BDCA2 (but not CD123) was absent in pre-pubertalchildren and numbers of pDC decreased with age. Blood and colonic DC were moremature and activated in adults. Decrease in pDC numbers correlated with reducedGM-CSF levels with aging, but increasing IL-4 and IL-8 levels correlated with a moreactivated DC profile in blood. CXCL16 levels decreased with age.Conclusions In children, lack of BDCA2, a receptor mediating antigen capture andinhibiting interferon induction, may be immunologically beneficial during immunedevelopment. Conversely, reduced pDC numbers, probably secondary todecreasing GM-CSF and increasing cytokine-induced maturation of DC are likely todetermine deteriorating immunity with ageing.
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Journal articleMalietzis G, Johns N, Al-Hassi HO, et al., 2016,
Low Muscularity and Myosteatosis Is Related to the Host Systemic Inflammatory Response in Patients Undergoing Surgery for Colorectal Cancer
, ANNALS OF SURGERY, Vol: 263, Pages: 320-325, ISSN: 0003-4932- Author Web Link
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- Citations: 138
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Journal articleBernardo D, Mann ER, Montalvillo E, et al., 2015,
CCR2 mediates dendritic cell recruitment to the human colon but is not responsible for differences observed in dendritic cell subsets, phenotype and function between the proximal and distal colon
, Cellular and Molecular Gastroenterology and Hepatology, Vol: 2, Pages: 22-39.e5, ISSN: 2352-345XBackground & aimsMost 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.MethodsPaired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing.ResultsColonic DC identified were myeloid (mDC, CD11c+CD123-) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3-CCR2-. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments.ConclusionsProximal colonic DC subsets differ from those in distal colon being more mature. Targeted immunotherapy using DC in T-cell mediated GI-tract inflammation may therefore need to reflect this immune compartmentalization.
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Journal articleLandy J, Walker AW, Li JV, et al., 2015,
Variable alterations of the microbiota, without metabolic or immunological change, following faecal microbiota transplantation in patients with chronic pouchitis
, Scientific Reports, Vol: 5, ISSN: 2045-2322Faecal microbiota transplantation (FMT) is effective in the treatment of Clostridium difficile infection, where efficacy correlates with changes in microbiota diversity and composition. The effects of FMT on recipient microbiota in inflammatory bowel diseases (IBD) remain unclear. We assessed the effects of FMT on microbiota composition and function, mucosal immune response, and clinical outcome in patients with chronic pouchitis. Eight patients with chronic pouchitis (current PDAI ≥7) were treated with FMT via nasogastric administration. Clinical activity was assessed before and four weeks following FMT. Faecal coliform antibiotic sensitivities were analysed, and changes in pouch faecal and mucosal microbiota assessed by 16S rRNA gene pyrosequencing and 1H NMR spectroscopy. Lamina propria dendritic cell phenotype and cytokine profiles were assessed by flow cytometric analysis and multiplex assay. Following FMT, there were variable shifts in faecal and mucosal microbiota composition and, in some patients, changes in proportional abundance of species suggestive of a “healthier” pouch microbiota. However, there were no significant FMT-induced metabolic or immunological changes, or beneficial clinical response. Given the lack of clinical response following FMT via a single nasogastric administration our results suggest that FMT/bacteriotherapy for pouchitis patients requires further optimisation.
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Journal articleMalietzis G, Lee GH, Bernardo D, et al., 2015,
The prognostic significance and relationship with body composition of CCR7-positive cells in colorectal cancer
, Journal of Surgical Oncology, Vol: 112, Pages: 86-92, ISSN: 1096-9098Background and ObjectivesThe host local immune response (LIR) to cancer is a determinant of cancer outcome. Regulation of this local response is largely achieved through chemokine synthesis from the tumor microenvironment such as C-Chemokine-Receptor-7 (CCR7). We examined the LIR measured as CCR7 expression, in colorectal cancers (CRC) and explored relationships with body composition (BC) and survival.MethodsA study of paraffin-embedded tissue specimens was carried out in 116 patients with non-metastatic CRC. CCR7 expression was determined by immunohistochemistry. Analysis of computer tomography scans was used to calculate BC parameters. Survival analyses and multivariate regression models were used.ResultsHigh CCR7+ cell density within the tumor stroma and at the margin was significantly associated with increased age, the presence of lymphovascular invasion, higher tumor stage, lymph node metastasis, high Klintrup-Makinen immune score, and myosteatosis. High CCR7+ cell density in the tumor margin was significantly associated with shorter disease-free (DFS) and overall survival (OS) (P < 0.001). This was also significantly associated with shorter survival in multivariate analysis (HR = 8.87; 95%CI [2.51–31.3]; P < 0.01 for OS and HR = 4.72; 95%CI (1.24–12.9); P = 0.02 for DFS).ConclusionsOur results suggest that a specific immune microenvironment may be associated with altered host's BC and tumor behavior, and that CCR7 may serve as a novel prognostic biomarker.
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Conference paperDaulatzai N, Hart AL, Phillips RKS, et al., 2015,
The Role of Dendritic and T-Cell Function and Migration in the Development of Cutaneous Wound Failure in Crohn's Disease
, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY-BLACKWELL, Pages: 166-166, ISSN: 0007-1323 -
Conference paperHendy PA, Bernardo D, Al-Hassi HO, et al., 2015,
PTH-057 Dendritic cell phenotype in crohn’s disease may correlate with disease severity and explain the high prevalence of cutaneous manifestations
, Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology, Pages: A430-A431 -
Journal articleLandy J, Al-Hassi HO, Ronde E, et al., 2014,
Innate Immune Factors in the Development and Maintenance of Pouchitis
, INFLAMMATORY BOWEL DISEASES, Vol: 20, Pages: 1942-1949, ISSN: 1078-0998- Author Web Link
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- Citations: 10
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