{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:08:52Z","timestamp":1791828532536,"version":"4.3.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"ImmusanT, Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,13]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:p>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\u00b75+ 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\u00a0h, 6\u00a0h and 6\u00a0days after commencing 3-day GC. Gliadin peptide-stimulated proliferation, interferon (IFN)-\u03b3 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-\u03b3 ELISPOT and whole blood CRA responses. Whole blood CRA after GC was dominated by IL-2, but also included IFN-\u03b3, C-X-C motif chemokine ligand 10\/IFN-\u03b3-induced protein 10 (CXCL10\/IP-10), CXCL9\/monokine induced by IFN-\u03b3 (MIG), IL-10, chemokine (C-C motif) ligand 3\/macrophage inflammatory protein 1-alpha (CCL3\/MIP-1\u03b1), TNF-\u03b1 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 \u03b1-gliadin peptide was 0\u00b75 to 11\u00a0per ml. Whole blood IL-2 release successfully mapped human leucocyte antigen (HLA)-DQ2\u00b75-restricted epitopes in an \u03b1-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.<\/jats:p>","DOI":"10.1111\/cei.13578","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T05:34:51Z","timestamp":1611120891000},"page":"321-334","source":"Crossref","is-referenced-by-count":48,"title":["Whole blood interleukin-2 release test to detect and characterize rare circulating gluten-specific T cell responses in coeliac disease"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0764-7267","authenticated-orcid":false,"given":"R P","family":"Anderson","sequence":"first","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Goel","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Y","family":"Hardy","sequence":"additional","affiliation":[{"name":"Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, Parkville, VIC, Australia"},{"name":"University of Melbourne, Parkville, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A K","family":"Russell","sequence":"additional","affiliation":[{"name":"Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, Parkville, VIC, Australia"},{"name":"University of Melbourne, Parkville, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Wang","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Szymczak","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Zhang","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K E","family":"Goldstein","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Neff","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K E","family":"Truitt","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L J","family":"Williams","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J L","family":"Dzuris","sequence":"additional","affiliation":[{"name":"ImmusanT, Inc., Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7687-9654","authenticated-orcid":false,"given":"J A","family":"Tye-Din","sequence":"additional","affiliation":[{"name":"Immunology Division, Department of Medical Biology, The Walter and Eliza Hall Institute, Parkville, VIC, Australia"},{"name":"University of Melbourne, Parkville, VIC, Australia"},{"name":"Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"2021121023261734000_cei13578-bib-0001","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.4049\/jimmunol.1601693","article-title":"T cells in celiac disease","volume":"198","author":"Jabri","year":"2017","journal-title":"J Immunol"},{"key":"2021121023261734000_cei13578-bib-0002","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1053\/j.gastro.2017.11.006","article-title":"HLA-DQ-Gluten tetramer blood test accurately identifies patients with and without celiac disease in absence of gluten consumption","volume":"154","author":"Sarna","year":"2018","journal-title":"Gastroenterology"},{"key":"2021121023261734000_cei13578-bib-0003","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1177\/2050640619874183","article-title":"CD38 expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac disease","volume":"7","author":"Zuhlke","year":"2019","journal-title":"United Euro Gastroenterol J"},{"key":"2021121023261734000_cei13578-bib-0004","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41575-018-0043-4","article-title":"T cells in coeliac disease: a rational target for diagnosis and therapy","volume":"15","author":"Hardy","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2021121023261734000_cei13578-bib-0005","doi-asserted-by":"crossref","first-page":"177","DOI":"10.7326\/0003-4819-149-3-200808050-00241","article-title":"Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update","volume":"149","author":"Pai","year":"2008","journal-title":"Ann Intern Med"},{"key":"2021121023261734000_cei13578-bib-0006","doi-asserted-by":"crossref","first-page":"5217","DOI":"10.4049\/jimmunol.167.9.5217","article-title":"Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment","volume":"167","author":"Pathan","year":"2001","journal-title":"J Immunol"},{"key":"2021121023261734000_cei13578-bib-0007","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1136\/gut.2004.059998","article-title":"T cells in peripheral blood after gluten challenge in coeliac disease","volume":"54","author":"Anderson","year":"2005","journal-title":"Gut"},{"key":"2021121023261734000_cei13578-bib-0008","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/73200","article-title":"In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope","volume":"6","author":"Anderson","year":"2000","journal-title":"Nat Med"},{"key":"2021121023261734000_cei13578-bib-0009","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/cei.12232","article-title":"Ex-vivo whole blood secretion of interferon (IFN)-gamma and IFN-gamma-inducible protein-10 measured by enzyme-linked immunosorbent assay are as sensitive as IFN-gamma enzyme-linked immunospot for the detection of gluten-reactive T cells in human leucocyte antigen (HLA)-DQ2.5(+) -associated coeliac disease","volume":"175","author":"Ontiveros","year":"2014","journal-title":"Clin Exp Immunol"},{"key":"2021121023261734000_cei13578-bib-0010","doi-asserted-by":"crossref","first-page":"eaaw7756","DOI":"10.1126\/sciadv.aaw7756","article-title":"Cytokine release and gastrointestinal symptoms after gluten challenge in celiac disease","volume":"5","author":"Goel","year":"2019","journal-title":"Sci Adv"},{"key":"2021121023261734000_cei13578-bib-0011","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/apt.15551","article-title":"Masked bolus gluten challenge low in FODMAPs implicates nausea and vomiting as key symptoms associated with immune activation in treated coeliac disease","volume":"51","author":"Daveson","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"2021121023261734000_cei13578-bib-0012","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/cei.13369","article-title":"Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease","volume":"199","author":"Goel","year":"2020","journal-title":"Clin Exp Immunol"},{"key":"2021121023261734000_cei13578-bib-0013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scitranslmed.3001012","article-title":"Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease","volume":"2","author":"Tye-Din","year":"2010","journal-title":"Sci Transl Med"},{"key":"2021121023261734000_cei13578-bib-0014","doi-asserted-by":"crossref","first-page":"i29","DOI":"10.1093\/bioinformatics\/bti1013","article-title":"A systematic approach for comprehensive T-cell epitope discovery using peptide libraries","volume":"21","author":"Beissbarth","year":"2005","journal-title":"Bioinformatics"},{"key":"2021121023261734000_cei13578-bib-0015","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jaut.2014.10.003","article-title":"Ingestion of oats and barley in patients with celiac disease mobilizes cross-reactive T cells activated by avenin peptides and immuno-dominant hordein peptides","volume":"56","author":"Hardy","year":"2015","journal-title":"J Autoimmun"},{"key":"2021121023261734000_cei13578-bib-0016","doi-asserted-by":"crossref","first-page":"e42340","DOI":"10.1371\/journal.pone.0042340","article-title":"Estimating point and interval frequency of antigen-specific CD4+ T cells based on short in vitro expansion and improved poisson distribution analysis","volume":"7","author":"Di Lullo","year":"2012","journal-title":"PLOS ONE"},{"key":"2021121023261734000_cei13578-bib-0017","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ymeth.2005.11.006","article-title":"Measurement of cytokine release at the single cell level using the ELISPOT assay","volume":"38","author":"Cox","year":"2006","journal-title":"Methods"},{"key":"2021121023261734000_cei13578-bib-0018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jim.2012.02.012","article-title":"New and improved methods for measuring lymphocyte proliferation in vitro and in vivo using CFSE-like fluorescent dyes","volume":"379","author":"Quah","year":"2012","journal-title":"J Immunol Methods"},{"key":"2021121023261734000_cei13578-bib-0019","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1177\/2050640614540154","article-title":"Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge","volume":"2","author":"Christophersen","year":"2014","journal-title":"United Euro Gastroenterol J"},{"key":"2021121023261734000_cei13578-bib-0020","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1177\/2050640619874173","article-title":"Cytokine release after gluten ingestion differentiates coeliac disease from self-reported gluten sensitivity","volume":"8","author":"Tye-Din","year":"2020","journal-title":"United Euro Gastroenterol J"},{"key":"2021121023261734000_cei13578-bib-0021","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1084\/jem.20012028","article-title":"Specificity of tissue transglutaminase explains cereal toxicity in celiac disease","volume":"195","author":"Vader","year":"2002","journal-title":"J Exp Med"},{"key":"2021121023261734000_cei13578-bib-0022","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00251-019-01141-w","article-title":"Update 2020: nomenclature and listing of celiac disease-relevant gluten epitopes recognized by CD4(+) T cells","volume":"72","author":"Sollid","year":"2020","journal-title":"Immunogenetics"},{"key":"2021121023261734000_cei13578-bib-0023","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1111\/j.1365-3083.1994.tb03414.x","article-title":"T cells from the peripheral blood of coeliac disease patients recognize gluten antigens when presented by HLA-DR, -DQ, or -DP molecules","volume":"39","author":"Gjertsen","year":"1994","journal-title":"Scand J Immunol"},{"key":"2021121023261734000_cei13578-bib-0024","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1399-0039.1998.tb03066.x","article-title":"HLA restriction patterns of gliadin- and astrovirus-specific CD4+ T cells isolated in parallel from the small intestine of celiac disease patients","volume":"52","author":"Molberg","year":"1998","journal-title":"Tissue Antigens"},{"key":"2021121023261734000_cei13578-bib-0025","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1073\/pnas.0608610104","article-title":"Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients","volume":"104","author":"Raki","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021121023261734000_cei13578-bib-0026","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/s41591-019-0403-9","article-title":"Distinct phenotype of CD4(+) T cells driving celiac disease identified in multiple autoimmune conditions","volume":"25","author":"Christophersen","year":"2019","journal-title":"Nat Med"},{"key":"2021121023261734000_cei13578-bib-0027","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.molmed.2019.05.009","article-title":"Therapeutic and diagnostic implications of t cell scarring in celiac disease and beyond","volume":"25","author":"Christophersen","year":"2019","journal-title":"Trends Mol Med"},{"key":"2021121023261734000_cei13578-bib-0028","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.tube.2018.08.011","article-title":"Cytokine biomarkers for the diagnosis of tuberculosis infection and disease in adults in a low prevalence setting","volume":"114","author":"Clifford","year":"2019","journal-title":"Tuberculosis"},{"key":"2021121023261734000_cei13578-bib-0029","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1186\/s12916-020-01828-y","article-title":"Patient factors influencing acute gluten reactions and cytokine release in treated coeliac disease","volume":"18","author":"Tye-Din","year":"2020","journal-title":"BMC Med"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cei.13578","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cei.13578","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/204\/3\/321\/41634714\/cei13578.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/204\/3\/321\/41634714\/cei13578.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T11:25:21Z","timestamp":1641036321000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/204\/3\/321\/6407870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,28]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2,28]]},"published-print":{"date-parts":[[2021,5,13]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13578","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,6]]},"published":{"date-parts":[[2021,2,28]]}}}