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Journal articleCondamine T, Dominguez GA, Youn JI, et al., 2016,
Lectin-type oxidized LDL receptor 1 defines a population of polymorphonuclear myeloid-derived suppressor cells in cancer patients
, Science Immunology, Vol: 1, ISSN: 2470-9468Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are important regulators of immune responses in cancer and have been directly implicated in the promotion of tumor progression. However, the heterogeneity of these cells and the lack of distinct markers hamper the progress in understanding the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation, we determined that low-density PMN-MDSC and high-density neutrophils from the same cancer patients had a distinct gene profile. The most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Unexpectedly, low-density lipoprotein (LDL) was one of the most increased regulators, and its receptor oxidized LDL receptor 1 (OLR1) was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor-1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5 to 15% of total neutrophils in cancer patients and 15 to 50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immunosuppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSCs. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSCs. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insights into the biology and potential therapeutic targeting of these cells.
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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 articleKnight SC, 2016,
Dendritic cell-T cell circuitry in health and changes in inflammatory bowel disease and its treatment
, Digestive Diseases, Vol: 34, Pages: 51-57, ISSN: 1421-9875Abstract Background:Dendritic, antigen-presenting cells (DCs) determine not only whether lymphocytes produce different types of immune response but also tissue-homing profiles of lymphocytes they stimulate. For example, in health, mucosal DC stimulate T cells focused to home to the mucosa; DC/T-cell circuitry thus targets immune responses to specific tissue locations. Therapies being introduced for inflammatory bowel disease (IBD) include antibodies to gut-homing molecules such as α4β7 (Vedolizumab) used ostensibly to block gut-homing lymphocytes. However, such lymphocytes are dependent on the tissue specificity of DC that stimulated them. Key Messages:In health, blood DCs have the potential to home to multiple tissues including gut (α4β7+) and skin (CLA+). DCs have become gut-specific within the intestinal microenvironment stimulated partially by local retinoid to express α4β7 (mucosal homing marker) and/or CCR9 (ileal homing marker) in the absence of skin-specific indicators. They spread veiled extensions, sample their environment, acquire/process antigens, produce cytokines and initiate innate immunity. Myeloid DC also traffic to draining lymph nodes where compartmentalization of adaptive immune responses is determined by DCs from the site of antigen expo-sure which dictate the homing profiles of lymphocytes they stimulate. In IBD, changes in homing/activation of gut DCs stimulate T-cells, and also, greater gut specificity and activation of blood DC reflect site and activity of disease. Homing potential of DC can be modulated toward mucosa or skin by vitamins A and D, respectively. Infliximab or interleukin-6 can divert homing profiles toward skin, perhaps predisposing to skin involvement in IBD. Probiotic bacteria or their products can also change homing profiles of gut DC toward skin homing and away from gut. Conclusions:In conclusion, development of gut focused inflammation and its treatment relies on changes in DC tissue spec
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Journal articleHendy P, Reddi D, Bernardo D, et al., 2016,
Anti-TNF-alpha therapy normalises aberrant cytokine production and homing profile of circulating dendritic cells in Crohn's disease
, JOURNAL OF CROHNS & COLITIS, Vol: 10, Pages: S105-S105, ISSN: 1873-9946 -
Journal articleComino I, Bernardo D, Bancel E, et al., 2016,
Identification and molecular characterization of oat peptides implicated on coeliac immune response
, Food & Nutrition Research, Vol: 60, ISSN: 1654-6628Background: Oats provide important nutritional and pharmacological properties,although their safety in coeliac patients remains controversial. Previous studies haveconfirmed that the reactivity of the anti-33-mer monoclonal antibody with different oatvarieties is proportional to the immune responses in terms of T-cell proliferation.Although the impact of these varieties on the adaptive response has been studied, therole of the dendritic cells is still poorly understood. The aim of this study is tocharacterize different oat fractions and to study their effect on dendritic cells fromcoeliac patients.Methods and results: Protein fractions were isolated from oat grains and analysed bySDS-PAGE. Several proteins were characterized in the prolamin fraction usingimmunological and proteomic tools, and by Nano-LC-MS/MS. These proteins,analogous to α- and γ-gliadin-like, showed reactive sequences to anti-33-mer antibodysuggesting their immunogenic potential. That was further confirmed as some of thenewly identified oat peptides had a differential stimulatory capacity on circulatingdendritic cells from coeliac patients compared with healthy controls.Conclusions : This is the first time, to our knowledge, where newly identified oatpeptides have been shown to elicit a differential stimulatory capacity on circulatingdendritic cells obtained from coeliac patients, potential identifying immunogenicproperties of these oat peptides.
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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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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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Conference paperMalietzis G, Lee GH, Knight SC, et al., 2015,
The Prognostic Significance of CCR7-Positive Cells and Relationship with Body Composition in Colorectal Cancer
, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland, Publisher: WILEY-BLACKWELL, Pages: 60-60, ISSN: 0007-1323
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