Jason A. Tye-Din
Walter and Eliza Hall Institute of Medical Research
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Featured researches published by Jason A. Tye-Din.
Gut | 2005
Robert P. Anderson; D A van Heel; Jason A. Tye-Din; Martin Barnardo; Mariolina Salio; Derek P. Jewell; Adrian V. S. Hill
Background: Current understanding of T cell epitopes in coeliac disease (CD) largely derives from intestinal T cell clones in vitro. T cell clones allow identification of gluten peptides that stimulate T cells but do not quantify their contribution to the overall gluten specific T cell response in individuals with CD when exposed to gluten in vivo. Aims: To determine the contribution of a putative dominant T cell epitope to the overall gliadin T cell response in HLA-DQ2 CD in vivo. Patients: HLA-DQ2+ individuals with CD and healthy controls. Methods: Subjects consumed 20 g of gluten daily for three days. Interferon γ (IFN-γ) ELISPOT was performed using peripheral blood mononuclear cells (PBMC) to enumerate and characterise peptide and gliadin specific T cells before and after gluten challenge. Results: In 50/59 CD subjects, irrespective of homo- or heterozygosity for HLA-DQ2, IFN-γ ELISPOT responses for an optimal concentration of A-gliadin 57–73 Q-E65 were between 10 and 1500 per million PBMC, equivalent to a median 51% of the response for a “near optimal” concentration of deamidated gliadin. Whole deamidated gliadin and gliadin epitope specific T cells induced in peripheral blood expressed an intestinal homing integrin (α4β7) and were HLA-DQ2 restricted. Peripheral blood T cells specific for A-gliadin 57–73 Q-E65 are rare in untreated CD but can be predictably induced two weeks after gluten exclusion. Conclusion: In vivo gluten challenge is a simple safe method that allows relevant T cells to be analysed and quantified in peripheral blood by ELISPOT, and should permit comprehensive high throughput mapping of gluten T cell epitopes in large numbers of individuals with CD.
Immunity | 2012
Sophie E. Broughton; Jan Petersen; Alex Theodossis; Stephen W. Scally; Khai Lee Loh; Allan Thompson; Jeroen van Bergen; Yvonne Kooy-Winkelaar; Kate Henderson; Travis Beddoe; Jason A. Tye-Din; Stuart I. Mannering; Anthony W. Purcell; James McCluskey; Robert P. Anderson; Frits Koning; Hugh H. Reid; Jamie Rossjohn
Celiac disease is a human leukocyte antigen (HLA)-DQ2- and/or DQ8-associated T cell-mediated disorder that is induced by dietary gluten. Although it is established how gluten peptides bind HLA-DQ8 and HLA-DQ2, it is unclear how such peptide-HLA complexes are engaged by the T cell receptor (TCR), a recognition event that triggers disease pathology. We show that biased TCR usage (TRBV9(∗)01) underpins the recognition of HLA-DQ8-α-I-gliadin. The structure of a prototypical TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-α-I-gliadin, in which all complementarity-determining region-β (CDRβ) loops interact with the gliadin peptide. Mutagenesis at the TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin interface provides an energetic basis for the Vβ bias. Moreover, CDR3 diversity accounts for TRBV9(∗)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.
Gut | 2006
Robert P. Anderson; D A van Heel; Jason A. Tye-Din; Derek P. Jewell; Adrian V. S. Hill
Background: Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon γ (IFN-γ) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an α/β-gliadin peptide (p57–73 QE65; QLQPFPQPELPYPQPQS) that includes two overlapping T cell epitopes (PFPQPELPY and PQPELPYPQ). Aim: To define minimally substituted variants of p57–73 QE65 universally devoid of IFN-γ stimulatory capacity but capable of antagonising IFN-γ secretion from polyclonal T cells specific for p57–73 QE65. Methods: Peripheral blood mononuclear cells collected from 75 HLA-DQ2+ CD patients after in vivo gluten challenge were used in overnight ELISPOT assays to screen 218 single or double substituted variants of p57–73 QE65 for cytokine stimulatory and antagonist activity. Results: The region p60–71 (PFPQPELPYPQP) and especially p64–67 (PELP) was sensitive to substitution. Twelve substitutions in p64–67 stimulated no IFN-γ ELISPOT response. Among 131 partial agonists identified, 45 produced statistically significant inhibition of IFN-γ ELISPOT responses when cocultured in fivefold excess with p57–73 QE65 (nu200a=u200a10). Four substituted variants of p57–73 QE65 were inactive by IFN-γ ELISPOT but consistently antagonised IFN-γ ELISPOT responses to p57–73 QE65, and also retained interleukin 10 stimulatory capacity similar to p57–73 QE65. Conclusions: Altered peptide ligands of p57–73 QE65, identified using polyclonal T cells from multiple HLA-DQ2+ CD donors, have properties in vitro that suggest that a single substitution to certain α/β-gliadins could abolish their capacity to stimulate IFN-γ from CD4 T cells and also have anti-inflammatory or protective effects in HLA-DQ2+ CD.
intelligent systems in molecular biology | 2005
Tim Beißbarth; Jason A. Tye-Din; Gordon K. Smyth; Terence P. Speed; Robert P. Anderson
MOTIVATIONnT-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.nnnRESULTSnWe 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.nnnAVAILABILITYnImplementations of our algorithms in R or Perl are available at http://bioinf.wehi.edu.au/folders/immunol.
Psychology Health & Medicine | 2017
Simon R. Knowles; David W. Austin; Suresh Sivanesan; Jason A. Tye-Din; Chris Wai Tung Leung; Jarrad Wilson; David Castle; Michael A. Kamm; Finlay Macrae; Geoff Hebbard
Abstract Irritable Bowel Syndrome (IBS) is a common condition affecting around 10–20% of the population and associated with poorer psychological well-being and quality of life. The aim of the current study was to explore the efficacy of the Common Sense Model (CSM) using Structural Equation Modelling (SEM) in an IBS cohort. One hundred and thirty-one IBS patients (29 males, 102 females, mean age 38 years) participating in the IBSclinic.org.au pre-intervention assessment were included. Measures included IBS severity (Irritable Bowel Syndrome Severity Scoring System), coping patterns (Carver Brief COPE), visceral sensitivity (Visceral Sensitivity Index), illness perceptions (Brief Illness Perceptions Questionnaire), psychological distress (Depression, Anxiety and Stress Scale), and quality of life (IBS Quality of Life scale; IBS-QoL). Using SEM, a final model with an excellent fit was identified (χ2 (8) = 11.91, p = .16, χ2/N = 1.49, CFI > .98, TLI > .96, SRMR < .05). Consistent with the CSM, Illness perceptions were significantly and directly influenced by IBS severity (β = .90, p < .001). Illness perceptions in turn directly influenced maladaptive coping (β = .40, p < .001) and visceral sensitivity (β = .70, p < .001). Maladaptive coping and visceral sensitivity were significantly associated with psychological distress (β = .55, p < .001; β = .22, p < .01) and IBS-QoL (β = –.28, p < .001; β = –.62, p < .001). Based on these findings, we argue that to augment the adverse impact of IBS severity on IBS-QoL and psychological distress, psychological interventions will be best to target the mediating psychological processes including illness beliefs, visceral sensitivity and maladaptive coping.
Archive | 2009
Robert P. Anderson; Jessica A. Stewart; James A. Dromey; Jason A. Tye-Din
Archive | 2005
Robert P. Anderson; Tim Beissbath; Jason A. Tye-Din
Archive | 2009
Robert P. Anderson; Jessica A. Stewart; James A. Dromey; Jason A. Tye-Din
Archive | 2015
Robert P. Anderson; Jason A. Tye-Din
Archive | 2015
Robert P. Anderson; Jason A. Tye-Din