ORCID Profile
0000-0002-0764-7267
Current Organisations
Novoviah Pharmaceuticals Pty Ltd
,
Mackay Hospital and Health Service
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Publisher: International Union of Crystallography (IUCr)
Date: 21-11-2007
Publisher: BMJ
Date: 09-2005
Publisher: Wiley
Date: 02-1990
DOI: 10.1111/J.1440-1746.1990.TB01766.X
Abstract: Bacterial chemotactic peptides (F-met-oligopeptides) are secreted by several species of commensal enteric bacteria and can be assayed by bioassay techniques in human colonic luminal fluid. We have previously demonstrated intestinal absorption and enterohepatic circulation of radiolabelled F-met peptides introduced into rat colon, and an eightfold increase in absorption and biliary excretion in rats with experimental colitis. This paper describes the application of a radio-immunoassay to measurements of formyl oligopeptides in human faecal dialysates, colonic and systemic venous blood and bile. All s les were fractionated by reverse-phase high performance liquid chromatography (HPLC) prior to assay. Immunoreactivity was found in faecal dialysates (5-700 nmol/L F-met-leu-phe equivalents) and bile s les (3-150 nmol/L) from normal subjects. After HPLC fractionation, up to five distinct peaks of immunoreactivity were identified. One of these co-chromatographed with authentic F-met-leu-phe the others probably represented either closely related peptides or peptides of different chain lengths originating from the same F-met-leu-phe precursor protein. Colonic venous blood from two patients with ulcerative colitis contained immunoreactive peptide (10-30 nmol/L) and substantial immunoreactivity was found in ileostomy fluid and bile from two patients with primary sclerosing cholangitis. These results suggest the presence of an enterohepatic circulation of bacterial F-met oligopeptides in man and provide a basis for studies of the role of such pro-inflammatory peptides in patients with inflammatory bowel disease and associated hepatobiliary disorders.
Publisher: BMJ
Date: 02-1988
DOI: 10.1136/ADC.63.2.204
Abstract: An 11 year old girl who was being treated for enuresis with imipramine developed acrocyanosis of the hands and feet. All biochemical and haematological investigations gave normal results. When imipramine was stopped the girl recovered within three days.
Publisher: Oxford University Press (OUP)
Date: 06-2005
DOI: 10.1093/BIOINFORMATICS/BTI1013
Abstract: T-cell response to peptides bound on MHC Class I or Class II molecules is essential for immune recognition of pathogens. T-cells are activated by specific peptide epitopes that are determined within the antigen processing pathways and presented on the surface of other cells bound to MHC molecules. To determine which part of allergenic or pathogenic proteins can stimulate T-cells is important for the treatment of diseases. We sought to take advantage of the falling cost of synthetic, screening grade peptides, and devise a comprehensive, non-hypothesis-driven screen for T-cell epitopes. We were interested in the study of celiac disease (CD) and used the ELISPOT technique to perform a large number of T-cell assays. We therefore needed to compensate for the lack of statistical data analysis methods for ELISPOT assays. We describe a method to comprehensively screen for T-cell epitopes within a family or a group of proteins. We have implemented an algorithm to generate a set of unique short peptide sequences that incorporate all possible epitopes within a group of proteins. T-cell assays were performed in 96-well plates using the ELISPOT assay to screen for responses in CD patients against any epitopes in glutens. We describe a statistical model to fit the data and an Expectation Maximization algorithm to estimate the parameters of interest and analyze the resulting data. Implementations of our algorithms in R or Perl are available at bioinf.wehi.edu.au/folders/immunol.
Publisher: S. Karger AG
Date: 1990
DOI: 10.1159/000171257
Publisher: Springer Science and Business Media LLC
Date: 02-1992
DOI: 10.1007/BF01308179
Publisher: Wiley
Date: 10-2019
DOI: 10.1111/APT.15494
Publisher: Springer Science and Business Media LLC
Date: 23-12-2020
DOI: 10.1038/S41594-019-0353-4
Abstract: The human leukocyte antigen (HLA) locus is strongly associated with T cell-mediated autoimmune disorders. HLA-DQ2.5-mediated celiac disease (CeD) is triggered by the ingestion of gluten, although the relative roles of genetic and environmental risk factors in CeD is unclear. Here we identify microbially derived mimics of gliadin epitopes and a parental bacterial protein that is naturally processed by antigen-presenting cells and activated gliadin reactive HLA-DQ2.5-restricted T cells derived from CeD patients. Crystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry underpins cross-reactivity toward the gliadin epitopes. Accordingly, gliadin reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby suggesting microbial exposure as a potential environmental factor in CeD.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2012
Publisher: AMPCo
Date: 10-1998
DOI: 10.5694/J.1326-5377.1982.TB132470.X
Abstract: IBD results from the interaction of genetic and environmental factors (e.g., smoking). Clinical suspicion is the key to diagnosis, which then rests on colonoscopy, histopathological examination of multiple biopsy specimens, small bowel barium radiology and faecal examination. The primary goal of treatment is remission--histological in ulcerative colitis and symptomatic in Crohn's disease. Treating active disease and maintaining remission require different approaches. For active disease, short term corticosteroids are the mainstay of treatment, while immunosuppressive drugs are important in chronically active disease. For maintenance, mesalazine-delivering drugs and immunosuppressive agents are efficacious in both ulcerative colitis and Crohn's disease patients with Crohn's disease should not smoke.
Publisher: Springer Science and Business Media LLC
Date: 03-2000
DOI: 10.1038/73200
Abstract: Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200-1:300) that is induced by dietary exposure to wheat gliadins (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (alpha1*0501, beta1*0201), which is present in over 90% of CD patients. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge, it has been unclear whether a 'dominant' T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from in idual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57-73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 26-11-2020
DOI: 10.1186/S12916-020-01828-Y
Abstract: Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and erse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production. A total of 295 adults treated for CD were observed for 6 h after an unmasked food challenge consisting of 10 g vital wheat gluten (low in FODMAPs) in 100 ml water. Assessments included patient-reported outcomes, serum IL-2 and adverse events. Responses were analysed according to patient characteristics, HLA-DQ genotype, duodenal histology and response to a second gluten challenge. Peak symptom severity was at 3 h (median severity 5/10). Peak IL-2 was at 4 h (median 4 pg/ml, range undetectable to 1028 pg/ml). Older age, older age at diagnosis, HLA-DQ2.5 positivity and homozygosity for HLA-DQB1*02 were each significantly associated with IL-2 elevations after gluten. Patients positive for HLA-DQ2.5, DQ8, DQ2.2 or DQ7 showed elevated IL-2 after gluten. Patient factors were not significantly associated with severity of digestive symptoms, but symptoms were correlated to one another and serum IL-2. Gluten challenge after 5 months caused more vomiting and higher IL-2 levels, but responses correlated with the first. Gluten-induced symptoms and cytokine release is common in adults with treated CD. Age, genetics and previous response to gluten predict these acute reactions to gluten challenge. Structured symptom assessment and serum IL-2 after standardised gluten challenge may inform on patient diagnosis, the role of gluten in symptomatology and the need for adjunctive treatment. ClinicalTrials.gov , NCT03644069 Registered 21 May 2018.
Publisher: Oxford University Press (OUP)
Date: 28-02-2021
DOI: 10.1111/CEI.13578
Abstract: Whole blood cytokine release assays (CRA) assessing cellular immunity to gluten could simplify the diagnosis and monitoring of coeliac disease (CD). We aimed to determine the effectiveness of electrochemiluminescence CRA to detect responses to immunodominant gliadin peptides. HLA-DQ2·5+ CD adults (cohort 1, n = 6 cohort 2, n = 12) and unaffected controls (cohort 3, n = 9) were enrolled. Cohort 1 had 3-day gluten challenge (GC). Blood was collected at baseline, and for cohort 1 also at 3 h, 6 h and 6 days after commencing 3-day GC. Gliadin peptide-stimulated proliferation, interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and 14- and 3-plex electrochemiluminescence CRA were performed. Poisson distribution analysis was used to estimate responding cell frequencies. In cohort 1, interleukin (IL)-2 dominated the gliadin peptide-stimulated cytokine release profile in whole blood. GC caused systemic IL-2 release acutely and increased gliadin peptide-stimulated IFN-γ ELISPOT and whole blood CRA responses. Whole blood CRA after GC was dominated by IL-2, but also included IFN-γ, C-X-C motif chemokine ligand 10/IFN-γ-induced protein 10 (CXCL10/IP-10), CXCL9/monokine induced by IFN-γ (MIG), IL-10, chemokine (C-C motif) ligand 3/macrophage inflammatory protein 1-alpha (CCL3/MIP-1α), TNF-α and IL-8/CXCL8. In cohorts 2 and 3, gliadin peptide-stimulated whole blood IL-2 release was 100% specific and 92% sensitive for CD patients on a gluten-free diet the estimated frequency of cells in CD blood secreting IL-2 to α-gliadin peptide was 0·5 to 11 per ml. Whole blood IL-2 release successfully mapped human leucocyte antigen (HLA)-DQ2·5-restricted epitopes in an α-gliadin peptide library using CD blood before and after GC. Whole blood IL-2 release assay using electrochemiluminescence is a sensitive test for rare gliadin-specific T cells in CD, and could aid in monitoring and diagnosis. Larger studies and validation with tetramer-based assays are warranted.
Publisher: Frontiers Media SA
Date: 11-12-2020
DOI: 10.3389/FIMMU.2020.594243
Abstract: The pathological mechanisms that lead to the onset and reactivation of celiac disease (CD) remain largely unknown. While gluten free diet (GFD) improves the intestinal damage and associated clinical symptoms in majority of cases, it falls short of providing full recovery. Additionally, late or misdiagnosis is also common as CD presents with a wide range of symptoms. Clear understanding of CD pathogenesis is thus critical to address both diagnostic and treatment concerns. We aimed to study the molecular impact of short gluten exposure in GFD treated CD patients, as well as identify biological pathways that remain altered constitutively in CD regardless of treatment. Using RNAseq profiling of PBMC s les collected from treated CD patients and gluten challenged patient and healthy controls, we explored the peripheral transcriptome in CD patients following a short gluten exposure. Short gluten exposure of just three days was enough to alter the genome-wide PBMC transcriptome of patients. Pathway analysis revealed gluten-induced upregulation of mainly immune response related pathways, both innate and adaptive, in CD patients. We evaluated the perturbation of biological pathways in s le-specific manner. Compared to gluten exposed healthy controls, pathways related to tight junction, olfactory transduction, metabolism of unsaturated fatty acids (such as arachidonic acid), metabolism of amino acids (such as cysteine and glutamate), and microbial infection were constitutively altered in CD patients regardless of treatment, while GFD treatment appears to mostly normalize immune response pathways to “healthy” state. Upstream regulator prediction analysis using differentially expressed genes identified constitutively activated regulators relatively proximal to previously reported CD associated loci, particularly SMARCA4 on 19p13.2 and CSF2 on 5q31. We also found constitutively upregulated genes in CD that are in CD associated genetic loci such as MEF2BNB-MEF2B (BORCS8-MEF2B) on 19p13.11 and CSTB on 21q22.3. RNAseq revealed strong effects of short oral gluten challenge on whole PBMC fraction and constitutively altered pathways in CD PBMC suggesting important factors other than gluten in CD pathogenesis.
Publisher: Wiley
Date: 03-2010
Publisher: BMJ
Date: 09-2004
Publisher: The American Association of Immunologists
Date: 04-2009
Abstract: The identification of gluten peptides eliciting intestinal T cell responses is crucial for the design of a peptide-based immunotherapy in celiac disease (CD). To date, several gluten peptides have been identified to be active in CD. In the present study, we investigated the recognition profile of gluten immunogenic peptides in adult HLA-DQ2+ celiac patients. Polyclonal, gliadin-reactive T cell lines were generated from jejunal mucosa and assayed for both proliferation and IFN-γ production in response to 21 peptides from wheat glutenins and α-, γ-, and ω-gliadins. A magnitude analysis of the IFN-γ responses was performed to assess the hierarchy of peptide potency. Remarkably, 12 of the 14 patients recognized a different array of peptides. All α-gliadin stimulatory peptides mapped the 57–89 N-terminal region, thus confirming the relevance of the known polyepitope 33-mer, although it was recognized by only 50% of the patients. By contrast, γ-gliadin peptides were collectively recognized by the great majority (11 of 14, 78%) of CD volunteers. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, containing only one copy of DQ2-α-I and DQ2-α-II epitopes, was as potent as 33-mer in stimulating intestinal T cell responses. A peptide from ω-gliadin, QPQQPFPQPQQPFPWQP, although structurally related to the α-gliadin 17-mer, is a distinct epitope and was active in 5 out of 14 patients. In conclusion, these results showed that there is a substantial heterogeneity in intestinal T cell responses to gluten and highlighted the relevance of γ- and ω-gliadin peptides for CD pathogenesis. Our findings indicated that α-gliadin (57–73), γ-gliadin (139–153), and ω-gliadin (102–118) are the most active gluten peptides in DQ2+ celiac patients.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1096
Publisher: Elsevier BV
Date: 10-2012
Publisher: Wiley
Date: 24-04-2023
DOI: 10.1111/APT.17425
Abstract: This article is linked to Sonnenberg and Genta's papers. To view these articles, visit 0.1111/apt.17408 and 0.1111/apt.17436
Publisher: Springer Science and Business Media LLC
Date: 21-12-2017
DOI: 10.1038/S41598-017-18137-9
Abstract: Celiac disease (CD) patients mount an abnormal immune response to gluten. T-cell receptor (TCR) repertoires directed to some immunodominant gluten peptides have previously been described, but the global immune response to in vivo gluten exposure in CD has not been systematically investigated yet. Here, we characterized signatures associated with gluten directed immune activity and identified gluten-induced T-cell clonotypes from total blood and gut TCR repertoires in an unbiased manner using immunosequencing. CD patient total TCR repertoires showed increased overlap and substantially altered TRBV-gene usage in both blood and gut s les, and increased ersity in the gut during gluten exposure. Using differential abundance analysis, we identified gluten-induced clonotypes in each patient that were composed of a large private and an important public component. Hierarchical clustering of public clonotypes associated with dietary gluten exposure identified subsets of highly similar clonotypes, the most proliferative of which showing significant enrichment for the motif ASS[LF]R[SW][TD][DT][TE][QA][YF] in PBMC repertoires. These results show that CD-associated clonotypes can be identified and that common gluten associated immune response features can be characterized in vivo from total repertoires, with potential use in disease stratification and monitoring.
Publisher: Wiley
Date: 15-09-2010
DOI: 10.1111/J.1365-2036.2010.04452.X
Abstract: Wheat, rye and barley prolamins are toxic to patients with coeliac disease. Barley is diploid with pure inbred cultivars available, and is attractive for genetic approaches to detoxification. To identify barley hordein fractions which activated the interferon-γ (IFN-γ) secreting peripheral blood T-cells from coeliac volunteers, and compare immunotoxicity of hordeins from experimental barley lines. To reactivate a T-cell response to hordein, volunteers underwent a 3-day oral barley challenge. Peripheral blood mononuclear cells (PBMC) were isolated from twenty-one HLA DQ2(+) patients with confirmed coeliac disease. IFN-γ ELISpot assays enumerated T-cells activated by purified prolamins and positive controls. Hordein-specific T-cells were induced by oral barley challenge. All prolamin fractions were immunotoxic, but D- and C-hordeins were most active. Barley lines lacking B- and C-hordeins had a 5-fold reduced hordein-content, and immunotoxicity of hordein extracts were reduced 20-fold compared with wild-type barley. In vivo oral barley challenge offers a convenient and rapid approach to test the immunotoxicity of small amounts of purified hordeins using fresh T-cells from patients in high throughput overnight assays. Barley lines that did not accumulate B- and C-hordeins were viable, yet had substantially reduced immunotoxicity. Creation of hordein-free barley may therefore be possible.
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.IMMUNI.2007.05.015
Abstract: The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the in idual.
Publisher: American College of Physicians
Date: 08-1997
DOI: 10.7326/0003-4819-127-3-199708010-00026
Abstract: After traumatic brain injury (TBI), peripheral monocytes infiltrate into the central nervous system due to disruption of the blood-brain barrier, and play an important role in neuroinflammation. However, the mechanisms regulating the movement and function of peripheral monocytes after TBI have not been fully investigated. TBI patients who underwent surgery at our hospital were recruited. CXCR2 expression in CD14 Transient CXCR2 upregulation in monocytes from the peripheral blood and CSF of TBI patients was detected soon after surgery and was associated with unfavorable outcomes. TBI serum and CSF promoted CXCR2 expression in monocytes, and dexamethasone reversed this effect. Peripheral monocytes from TBI patients showed enhanced chemotaxis toward the CSF and increased inflammatory cytokine secretion. The CXCR2 antagonist SB225002 decreased monocyte chemotaxis toward TBI CSF, and lowered pro-inflammatory cytokine secretion in monocytes treated with TBI serum. SB225002 also relieved ICD in nerve cells co-cultured with TBI serum-treated monocytes. CXCR2 is transiently overexpressed in the peripheral monocytes of TBI patients post-surgery, and drives peripheral monocyte chemotaxis toward CSF and monocyte-mediated ICD of nerve cells. Therefore, CXCR2 may be a target for monocyte-based therapies for TBI.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1053/J.GASTRO.2015.07.013
Abstract: Developing antigen-specific approaches for diagnosis and treatment of celiac disease requires a detailed understanding of the specificity of T cells for gluten. The existing paradigm is that T-cell lines and clones from children differ from those of adults in the hierarchy and ersity of peptide recognition. We aimed to characterize the T-cell response to gluten in children vs adults with celiac disease. Forty-one children with biopsy-proven celiac disease (median age, 9 years old 17 male), who had been on strict gluten-free diets for at least 3 months, were given a 3-day challenge with wheat blood s les were collected and gluten-specific T cells were measured. We analyzed responses of T cells from these children and from 4 adults with celiac disease to a peptide library and measured T-cell receptor bias. We isolated T-cell clones that recognized dominant peptides and assessed whether gluten peptide recognition was similar between T-cell clones from children and adults. We detected gluten-specific responses by T cells from 30 of the children with celiac disease (73%). T cells from the children recognized the same peptides that were immunogenic to adults with celiac disease deamidation of peptides increased these responses. Age and time since diagnosis did not affect the magnitude of T-cell responses to dominant peptides. T-cell clones specific for dominant α- or ω-gliadin peptides from children with celiac disease had comparable levels of reactivity to wheat, rye, and barley peptides as T-cell clones from adults with celiac disease. The α-gliadin-specific T cells from children had biases in T-cell receptor usage similar to those in adults. T cells from children with celiac disease recognize similar gluten peptides as T cells from adults with celiac disease. The findings indicate that peptide-based diagnostics and therapeutics for adults may also be used for children.
Publisher: Springer Science and Business Media LLC
Date: 20-10-2013
Publisher: AMPCo
Date: 06-1996
DOI: 10.5694/J.1326-5377.1996.TB122235.X
Abstract: To determine the incidence of hospital admissions for adverse events related to drug therapy, and to assess whether these drug-related admissions (DRAs) could have been reasonably prevented. A tertiary teaching hospital. Prospective assessment of all admissions through the emergency department and resulting in a stay of more than 24 hours during 30 consecutive days in November and December 1994 to determine if the admission was related to drug therapy. Cases of intentional overdose were excluded. The number, type, causality and avoidability of drug-related admissions. Of 965 admissions, 55 (5.7%) were assessed as being drug-related. Drug-related admissions (DRAs) were designated possibly (38%), probably (46%) or definitely (16%) drug-related caused by prescribing factors (26%), patient noncompliance (27%) and adverse drug reactions (47%) and classified as definitely (5.5%), possibly (60.0%) and not (34.5%) avoidable. The estimated annual cost to the hospital for all DRAs was $3,496,956 and for unavoidable DRAs was $1,629,494. The DRA rate we found lies around the middle of the range of other published rates. Few DRAs were judged definitely avoidable and over one-third were unavoidable. Nevertheless, the largest proportion were judged possibly avoidable. As the drugs identified in this study are clearly needed in the community, efforts to reduce DRAs must concentrate on education, counselling and monitoring of drug therapy.
Publisher: Informa UK Limited
Date: 02-01-2021
Publisher: Elsevier BV
Date: 12-2017
Publisher: Wiley
Date: 02-2020
Publisher: Wiley
Date: 10-2008
DOI: 10.1111/J.1445-5994.2008.01741.X
Abstract: Public anxiety over gluten has fuelled widespread demand for gluten-free food, yet coeliac disease remains significantly underdiagnosed and some confusion remains regarding optimal diagnostic practices. Small bowel histology is the gold standard for diagnosis. High-quality commercial enzyme-linked immunosorbent assays for transglutaminase immunoglobulin A and deamidated gliadin immunoglobulin A and G are sensitive tools for screening, but almost 10% of coeliac disease is seronegative and serological testing is unreliable in the very young, in people already following a gluten-reduced diet, and those using immunosuppressive medications. HLA DQA and DQB genotyping to show that alleles encoding HLA DQ2 and DQ8 are absent virtually excludes coeliac disease. Confirming histological remission reduces the risks of later complications, such as osteoporosis and cancer. Monitoring remission by serology is unreliable. Because gluten is an exogenous antigen and the small intestine is readily accessible, the immunopathogenesis of coeliac disease is better understood than other strongly major histocompatibility complex class II-associated diseases, such as type 1 diabetes mellitus. Therapeutic targets have been identified and drugs are under development to supplement or even replace gluten-free diet. With greater awareness and non-dietary therapeutics, diagnosis and treatment of coeliac disease will be increasingly prominent in medical practice.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.JAUT.2014.10.003
Abstract: Celiac disease (CD) is a common CD4(+) T cell mediated enteropathy driven by gluten in wheat, rye, and barley. Whilst clinical feeding studies generally support the safety of oats ingestion in CD, the avenin protein from oats can stimulate intestinal gluten-reactive T cells isolated from some CD patients in vitro. Our objective was to establish whether ingestion of oats or other grains toxic in CD stimulate an avenin-specific T cell response in vivo. We fed participants a meal of oats (100 g/day over 3 days) to measure the in vivo polyclonal avenin-specific T cell responses to peptides contained within comprehensive avenin peptide libraries in 73 HLA-DQ2.5(+) CD patients. Grain cross-reactivity was investigated using oral challenge with wheat, barley, and rye. Avenin-specific responses were observed in 6/73 HLA-DQ2.5(+) CD patients (8%), against four closely related peptides. Oral barley challenge efficiently induced cross-reactive avenin/hordein-specific T cells in most CD patients, whereas wheat or rye challenge did not. In vitro, immunogenic avenin peptides were susceptible to digestive endopeptidases and showed weak HLA-DQ2.5 binding stability. Our findings indicate that CD patients possess T cells capable of responding to immuno-dominant hordein epitopes and homologous avenin peptides ex vivo, but the frequency and consistency of these T cells in blood is substantially higher after oral challenge with barley compared to oats. The low rates of T cell activation after a substantial oats challenge (100 g/d) suggests that doses of oats commonly consumed are insufficient to cause clinical relapse, and supports the safety of oats demonstrated in long-term feeding studies.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2021
Publisher: Hindawi Limited
Date: 2020
DOI: 10.1002/YGH2.380
Publisher: The American Association of Immunologists
Date: 15-06-2009
Abstract: Celiac disease is a chronic inflammatory enteropathy caused by cellular immunity to dietary gluten. More than 90% of patients carry HLA-DQ2 encoded by HLA-DQA1*05 and DQB1*02, and gluten-specific CD4+ T cells from intestinal biopsies of these patients are HLA-DQ2-restricted, produce Th1 cytokines and preferentially recognize gluten peptides deamidated by tissue transglutaminase. We generated mice lacking murine MHC class II genes that are transgenic for human CD4 and the autoimmunity and celiac disease-associated HLA-DR3-DQ2 haplotype. Immunization with the α-gliadin 17-mer that incorporates the overlapping DQ2-α-I and DQ2-α-II epitopes immunodominant in human celiac disease generates peptide-specific HLA-DQ2-restricted CD4+ T cells. When exposed to dietary gluten, naive or gliadin-primed mice do not develop pathology. Coincident introduction of dietary gluten and intestinal inflammation resulted in low-penetrance enteropathy and tissue transglutaminase-specific IgA. Two further strains of transgenic mice expressing HLA-DR3-DQ2 and human CD4, one with a NOD background and another TCR transgenic having over 90% of CD4+ T cells specific for the DQ2-α-II epitope with a Th1 phenotype, were also healthy when consuming gluten. These humanized mouse models indicate that gluten ingestion can be tolerated without intestinal pathology even when HLA-DQ2-restricted CD4+ T cell immunity to gluten is established, thereby implicating additional factors in controlling the penetrance of celiac disease.
Publisher: Wiley
Date: 07-10-2008
DOI: 10.1111/J.1365-2036.2008.03820.X
Abstract: While gluten-free diet is an effective treatment for coeliac disease, the need for and goals of long-term management of patients are poorly defined. To review systematically the complications and associations of coeliac disease, to identify potential risk factors, to define ways of assessing risk factors and to provide a strategy for management. Review of medical literature from 1975. There is an increasing list of potential complications and/or conditions associated with coeliac disease, in particular, autoimmune disease, malignancy and bone disease. Risk factors that may predict or influence long-term outcomes include genetic susceptibility, environmental factors predominantly gluten ingestion, persistent small intestinal inflammation/injury and nutritional deficiencies. Genotyping of patients is yet to have an established clinical role in long-term management. Assessment of adherence to the gluten-free diet largely relies upon skilled dietary history, but the ultimate test is duodenal histopathology, which is the only currently established means of assessing healing. Symptoms, serology or other non-invasive means are poor predictors of healing and the likelihood of complications. Evidence (albeit limited) that adherence to a gluten-free diet and mucosal healing prevent and/or ameliorate complications indicates that a planned long-term strategy for follow-up is essential.
Publisher: Wiley
Date: 13-08-2019
DOI: 10.1111/APT.15435
Abstract: Nexvax2 contains three gluten-derived peptides, intended to tolerize coeliac disease patients to gluten. Sequences cover six epitopes that trigger immune activation in human leucocyte antigen-DQ2.5-positive patients, most notably after an initial dose. Patients experience gastrointestinal symptoms with increases in serum interleukin-2. Consistent with Nexvax2's induction of non-responsiveness, reactivity disappears after repeated doses, or is avoided with gradual dose escalation. Early clinical trials used intradermal dosing, but pharmacokinetics and rapid onset of effect suggest that subcutaneous delivery may also be effective. To document the relative bioavailability of Nevax2 peptides after subcutaneous and intradermal dosing, and the tolerability and ability of subcutaneous dosing to induce non-responsiveness to Nexvax2 peptides. A randomised, double-blind, placebo-controlled study was conducted to assess plasma pharmacokinetics after subcutaneous and intradermal Nexvax2 dosing in HLA DQ2.5-positive patients, who had symptoms after an oral gluten challenge. Randomisation was to semi-weekly Nexvax2 (n = 12) or placebo (n = 2) injections, over a 5-week subcutaneous dose escalation and 2-week maintenance period, the latter with four doses of 900 µg, two subcutaneous and two intradermal. Post-dose circulating peptide and interleukin-2 levels were assessed. Investigators recorded adverse events experienced by patients. Subcutaneous dosing resulted in slightly greater exposure. Interleukin-2 responses were seen with the gluten challenge but not after subcutaneous or intradermal dosing of 900 µg. Adverse events were generally mild and self-limited. Subcutaneous and intradermal dosing of Nexvax2 yield similar bioavailability of constituent peptides subcutaneous dose escalation avoids an immune response to dominant gluten epitopes.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 02-08-2019
Abstract: Acute gastrointestinal symptoms induced by gluten, within 4 hours, are mediated by reactivation of antigen-specific memory T cells.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2019
DOI: 10.1007/S00251-019-01141-W
Abstract: Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4
Publisher: Frontiers Media SA
Date: 19-05-2021
DOI: 10.3389/FIMMU.2021.661622
Abstract: Improved blood tests assessing the functional status of rare gluten-specific CD4+ T cells are needed to effectively monitor experimental therapies for coeliac disease (CD). Our aim was to develop a simple, but highly sensitive cytokine release assay (CRA) for gluten-specific CD4+ T cells that did not require patients to undergo a prior gluten challenge, and would be practical in large, multi-centre clinical trials. We developed an enhanced CRA and used it in a phase 2 clinical trial (“RESET CeD”) of Nexvax2, a peptide-based immunotherapy for CD. Two participants with treated CD were assessed in a pilot study prior to and six days after a 3-day gluten challenge. Dye-dilution proliferation in peripheral blood mononuclear cells (PBMC) was assessed, and IL-2, IFN-γ and IL-10 were measured by multiplex electrochemiluminescence immunoassay (ECL) after 24-hour gluten-peptide stimulation of whole blood or matched PBMC. Subsequently, gluten-specific CD4+ T cells in blood were assessed in a subgroup of the RESET CeD Study participants who received Nexvax2 (maintenance dose 900 μg, n = 12) or placebo (n = 9). The pilot study showed that gluten peptides induced IL-2, IFN-γ and IL-10 release from PBMCs attributable to CD4+ T cells, but the PBMC CRA was substantially less sensitive than whole blood CRA. Only modest gluten peptide-stimulated IL-2 release could be detected without prior gluten challenge using PBMC. In contrast, whole blood CRA enabled detection of IL-2 and IFN-γ before and after gluten challenge. IL-2 and IFN-γ release in whole blood required more than 6 hours incubation. Delay in whole blood incubation of more than three hours from collection substantially reduced antigen-stimulated IL-2 and IFN-γ secretion. Nexvax2, but not placebo treatment in the RESET CeD Study was associated with significant reductions in gluten peptide-stimulated whole blood IL-2 and IFN-γ release, and CD4+ T cell proliferation. We conclude that using fresh whole blood instead of PBMC substantially enhances cytokine secretion stimulated by gluten peptides, and enables assessment of rare gluten-specific CD4+ T cells without requiring CD patients to undertake a gluten challenge. Whole blood assessment coupled with ultra-sensitive cytokine detection shows promise in the monitoring of rare antigen-specific T cells in clinical studies.
Publisher: Wiley
Date: 26-11-2020
DOI: 10.1111/APT.15551
Abstract: In patients with coeliac disease, FODMAPs in gluten-containing foods, and participant anticipation of a harmful ('nocebo') effect, may contribute to acute symptoms after gluten challenge. To establish acute gluten-specific symptoms linked to immune activation in coeliac disease METHODS: We included 36 coeliac disease patients on a gluten-free diet receiving placebo in the RESET CeD trial. Double-blind, bolus vital wheat gluten (~6-g gluten protein) and sham challenges low in FODMAPs were consumed 2 weeks apart. Assessments included daily Coeliac Disease Patient Reported Outcome (CeD PRO) symptom scores (0-10), adverse events and serum interleukin-2 (baseline and 4 hours). Median CeD PRO score for nausea increased most (sham: 0 vs gluten: 5.5 P < .001). Apart from tiredness (1 vs 4, P = .005) and headache (0 vs 2, P = .002), changes in other symptoms were small or absent. Only nausea increased significantly in occurrence with gluten (11% vs 69%, P < .001). Without nausea, only tiredness and flatulence were common after gluten. Nausea (6% vs 61%, P < .001 median onset: 1:34 hours) and vomiting (0% vs 44%, P < .001 1:51 hours) were the only adverse events more common with gluten than sham. Interleukin-2 was always below the level of quantitation (0.5 pg/mL) at baseline, and after sham. Interleukin-2 was elevated after gluten in 97% of patients (median fold-change: 20), and correlated with severity of nausea (r Nausea and vomiting are relatively specific indicators of acute gluten ingestion, and correlate with immune activation. IBS-like symptoms without nausea are unlikely to indicate recent gluten exposure.
Publisher: Elsevier BV
Date: 06-2012
Publisher: Wiley
Date: 07-2022
DOI: 10.1111/APT.16840
Abstract: Diagnostics will play a central role in addressing the ongoing dramatic rise in global prevalence of coeliac disease, and in deploying new non‐dietary therapeutics. Clearer understanding of the immunopathogenesis of coeliac disease and the utility of serology has led to partial acceptance of non‐biopsy diagnosis in selected cases. Non‐biopsy diagnosis may expand further because research methods for measuring gluten‐specific CD4+ T cells and the acute recall response to gluten ingestion in patients is now relatively straightforward. This perspective on diagnosis in the context of the immunopathogenesis of coeliac disease sets out to highlight current consensus, limitations of current practices, gluten food challenge for diagnosis and the potential for diagnostics that measure the underlying cause for coeliac disease, gluten‐specific immunity.
Publisher: Wiley
Date: 04-09-2019
DOI: 10.1111/APT.15477
Abstract: Coeliac disease patients on a gluten-free diet experience reactions to gluten, but these are not well characterised or understood. Systemic cytokine release was recently linked to reactivation of gluten immunity in coeliac disease. To define the nature and time-course of symptoms and interleukin-2 changes specific for coeliac disease patients. 25 coeliac disease patients on a gluten-free diet and 25 healthy volunteers consumed a standardised 6 gram gluten challenge. Coeliac Disease Patient-Reported Outcome survey and global digestive symptom assessment were completed hourly up to 6 hours after gluten. Adverse events over 48 hours were recorded. Serum interleukin-2 was measured at baseline, and 2, 4 and 6 hours. Serum interleukin-2 was always undetectable in healthy controls, whereas it was undetectable at baseline and elevated >0.5 pg/ml at 4 hours in 92% of coeliac disease patients. All patient-reported outcome severity scores increased significantly after gluten in coeliac disease patients (P < .001 Wilcoxon signed rank test), but not in controls. Symptoms began after 1 hour, and peaked in the third. Nausea and vomiting characterised severe reactions, but mild reactions were limited to headache and tiredness. Peak interleukin-2 correlated with symptom severity, particularly for nausea and vomiting. Serum interleukin-2 elevations correlate with timing and severity of symptoms after gluten in coeliac disease. Standardised bolus gluten food challenge and interleukin-2 assessment could provide a valuable clinical test to monitor and diagnose coeliac disease in patients established on a gluten-free diet.
Publisher: Elsevier BV
Date: 07-2017
Publisher: Public Library of Science (PLoS)
Date: 08-03-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-09-2020
Publisher: Public Library of Science (PLoS)
Date: 16-09-2011
Publisher: Oxford University Press (OUP)
Date: 1996
Publisher: Informa UK Limited
Date: 02-2021
DOI: 10.2147/TACG.S276596
Publisher: AMPCo
Date: 03-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2012
Publisher: Oxford University Press (OUP)
Date: 10-2019
DOI: 10.1111/CEI.13369
Abstract: Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early elevations in serum interleukin (IL)-2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten-mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free-diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour 187 cytokines were assessed. Confirmatory analyses were performed by high-sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL-2, chemokine (C-C motif) ligand 20 (CCL20), IL-6, chemokine (C-X-C motif) ligand (CXCL)9, CXCL8, interferon (IFN)-γ, IL-10, IL-22, IL-17A, tumour necrosis factor (TNF)-α, CCL2 and hiregulin. IL-2 and IL-17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL-2 increased most (median 57-fold), then CCL20 (median 10-fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL-2, IL-17A, IL-22 and IFN-γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-07-2010
DOI: 10.1126/SCITRANSLMED.3001012
Abstract: Three highly immunogenic peptides from gluten are primarily responsible for celiac disease, suggesting a rational immunotherapeutic approach that could replace the need for strict, lifelong dietary gluten avoidance.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2014
DOI: 10.1038/NSMB.2817
Abstract: Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of in iduals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-α1a and DQ2.5-glia-α2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-α2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3β loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-α1a and DQ2.5-glia-α2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
Publisher: Oxford University Press (OUP)
Date: 03-01-2014
DOI: 10.1111/CEI.12232
Abstract: T cell cytokine release assays are used to diagnose infectious diseases, but not autoimmune or allergic disease. Coeliac disease (CD) is a common T cell-mediated disease diagnosed by the presence of gluten-dependent intestinal inflammation and serology. Many patients cannot be diagnosed with CD because they reduce dietary gluten before medical workup. Oral gluten challenge in CD patients treated with gluten-free diet (GFD) mobilizes gluten-reactive T cells measurable by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) or major histocompatibility complex (MHC) class II tetramers. Immunodominant peptides are quite consistent in the 90% of patients who possess HLA-DQ2·5. We aimed to develop whole blood assays to detect gluten-specific T cells. Blood was collected before and after gluten challenge from GFD donors confirmed to have CD (n = 27, all HLA-DQ2·5+), GFD donors confirmed not to have CD (n = 6 HLA-DQ2·5+, 11 HLA-DQ2·5−) and donors with CD not following GFD (n = 4, all HLA-DQ2·5+). Plasma IFN-γ and IFN-γ inducible protein-10 (IP-10) were measured by enzyme-linked immunosorbent assay (ELISA) after whole blood incubation with peptides or gliadin, and correlated with IFN-γ ELISPOT. No T cell assay could distinguish between CD patients and controls prior to gluten challenge, but after gluten challenge the whole blood IFN-γ ELISA and the ELISPOT were both 85% sensitive and 100% specific for HLA-DQ2·5+ CD patients the whole blood IP-10 ELISA was 94% sensitive and 100% specific. We conclude that whole blood cytokine release assays are sensitive and specific for detection of gluten-reactive T cells in CD further clinical studies addressing the utility of these tests in patients with an uncertain diagnosis of CD is warranted.
Publisher: Wiley
Date: 14-01-2020
DOI: 10.1111/APT.15629
Publisher: Springer Science and Business Media LLC
Date: 10-2008
DOI: 10.1007/S11894-008-0085-9
Abstract: Celiac disease is a chronic inflammatory disease caused by dietary gluten that affects 1% of Europeans and North Americans. Gluten is unusual because it is consumed in relatively large amounts, is partially resistant to luminal digestion in the human small intestine, and when absorbed, is susceptible to post-translational modification (deamidation) by mucosal transglutaminase. Deamidation of certain gluten peptides enhances their binding to HLA-DQ2 or HLA-DQ8 and creates neodeterminants capable of stimulating CD4+ T cells. Only 5% of in iduals with HLA-DQ2 and 0.5% of those with HLA-DQ8 have celiac disease, so immuno-logic tolerance to gluten is the norm. The critical steps in the immunopathogenesis of celiac disease are broadly understood, but little is known regarding mechanisms of tolerance to gluten. The effectiveness of therapies being developed for celiac disease will test the accuracy of our current understanding of disease pathogenesis.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.CLIM.2009.11.001
Abstract: Effective treatment of celiac disease is an unmet medical need. A glutenase that destroys immunogenic gluten peptides may be clinically valuable. Twenty patients with celiac disease were randomly assigned to ingest a large gluten meal (16 g daily for 3 days) pre-treated with ALV003, a mixture of highly specific glutenases (n=10), or pre-treated with placebo (n=10). Peripheral blood T-cell IFN-gamma ELISpot responses to gliadin and an immunogenic 33mer and symptoms were assessed. While baseline IFN-gamma ELISpot responses to gliadin and the 33mer were negative in all patients, a significant ELISpot response to gliadin or the 33mer was observed in 6 of 10 patients consuming placebo-treated gluten and 0 of 10 consuming ALV003 pre-treated gluten (p=0.011). Symptoms typically associated with gluten ingestion occurred in both groups and were not significantly reduced by ALV003 pre-treatment. ALV003 pre-treatment can abolish immune responses induced by gluten in patients with celiac disease.
Publisher: BMJ
Date: 04-2006
Publisher: Oxford University Press (OUP)
Date: 03-12-2010
Abstract: Coeliac disease (CD) remains under diagnosed with only 10–20% of patients identified. Genes encoding HLA DQ2 or DQ8 are found in the vast majority of those with CD and testing for their presence can be useful to rule out the possibility CD. CD is more common in certain ethnic groups including those of North Indian origin. The classical presentation tends to occur in younger children, while atypical presentations occur at an older age. The number of children being diagnosed with CD is increasing this may be due to greater recognition of the more atypical presentations, improved serologic tests, and the screening of asymptomatic groups at increased risk, but may also be due to an overall increased prevalence. Although serologic testing has become more reliable, there still remain significant problems around testing, particularly in those & months of age. All children should undergo a duodenal biopsy on a gluten containing diet in order to diagnose CD before recommending a gluten-free diet (GFD). A GFD should be offered to all children diagnosed with CD even when perceived as asymptomatic, as there is significant morbidity associated with CD later in life.
Publisher: Elsevier BV
Date: 03-1996
DOI: 10.1016/S0140-6736(96)91240-4
Abstract: Bisacodyl is a member of the diphenylmethane family and is considered to be a stimulant laxative. It has a dual prokinetic and secretory action and needs to be converted into the active metabolite bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) in the gut to achieve the desired laxative effect. Bisacodyl acts locally in the large bowel by directly enhancing the motility, reducing transit time, and increasing the water content of the stool. A recent network meta-analysis concluded that bisacodyl showed similar efficacy to prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, and sodium picosulfate for the primary endpoint of ≥3 complete spontaneous bowel movements (CSBM)/week and an increase of ≥1 CSBM/week over baseline. The meta-analysis also found that bisacodyl may be superior to the other laxatives for the secondary endpoint of change from baseline in the number of spontaneous bowel movements per week in patients with chronic constipation. This observation stimulated the authors to review the available literature on bisacodyl, which has been available on the market since the 1950 s. The aim of the current review was to provide an overview of the historic background, structure, function, and mechanism of action of bisacodyl. Additionally, we discuss the important features and studies for bisacodyl to understand its peculiar characteristics and guide its use in clinical practice, but also stimulate research on open questions.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.JACI.2017.02.015
Abstract: Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 This study provides the first estimation of FOXP3
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
No related grants have been discovered for Robert Anderson.