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Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["2018PG-T1D053"],"award-info":[{"award-number":["2018PG-T1D053"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007028","name":"Leona M. and Harry B. Helmsley Charitable Trust","doi-asserted-by":"publisher","award":["G-2108-04793"],"award-info":[{"award-number":["G-2108-04793"]}],"id":[{"id":"10.13039\/100007028","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017804","name":"City of Hope","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017804","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Aims\/hypothesis<\/jats:title>\n            <jats:p>Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, <jats:italic>n<\/jats:italic>=41) or with only insulin-deficient islets (T1D-IDI, <jats:italic>n<\/jats:italic>=42); donors without diabetes who are AAb-negative (ND, <jats:italic>n<\/jats:italic>=83); and rare donors without diabetes expressing a single AAb (AAb<jats:sup>+<\/jats:sup>, <jats:italic>n<\/jats:italic>=22) or multiple AAbs (AAb<jats:sup>++<\/jats:sup>, <jats:italic>n<\/jats:italic>=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (<jats:italic>p<\/jats:italic>&lt;0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb<jats:sup>+<\/jats:sup> 24.6%; AAb<jats:sup>++<\/jats:sup> 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1\/HLA class I [HLA-I], <jats:italic>p<\/jats:italic>&lt;0.0001; VP1\/enterovirus-specific RT-PCR (EV-PCR), <jats:italic>p<\/jats:italic>=0.076; EV-PCR\/HLA-I, <jats:italic>p<\/jats:italic>=0.016; proteomics\/HLA-I, <jats:italic>p<\/jats:italic>&lt;0.0001; VP1\/proteomics, <jats:italic>p<\/jats:italic>=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (<jats:italic>p<\/jats:italic>&lt;0.001), 26.7% of AAb<jats:sup>+<\/jats:sup> (<jats:italic>p<\/jats:italic>=0.006), 28.6% of AAb<jats:sup>++<\/jats:sup> (<jats:italic>p<\/jats:italic>=0.023) and 0% of T1D-IDI (<jats:italic>p<\/jats:italic>&lt;0.001) donors.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb<jats:sup>++<\/jats:sup> donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or indirectly, even after diagnosis. The relatively small number of infected cells and the low amount of viral RNA support the existence of non-acute, low level, possibly persistent enterovirus infections in the pancreas.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06401-x","type":"journal-article","created":{"date-parts":[[2025,3,16]],"date-time":"2025-03-16T23:01:44Z","timestamp":1742166104000},"page":"1226-1241","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1160-6062","authenticated-orcid":false,"given":"Sarah 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The authors are grateful to JDRF Program Officers who envisioned the formation of and provided programmatic guidance to the nPOD-Virus Group (R. Insel, J. Greenstein, T. Staeva, M. Nierras, J. Dunne). The authors thank all the members of the nPOD-Virus group. A list is included as electronic supplementary material (ESM).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Data generated and analysed during this study are available through the corresponding author upon request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This research was performed with the support of the Network for Pancreatic Organ donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project supported by grants from JDRF\/The Leona M. & Harry B. Helmsley Charitable Trust (3-SRA-2023-1417-S-B) and the Helmsley Charitable Trust (2018PG-T1D053, G-2108-04793). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official view of nPOD. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at . The nPOD-Virus Group was supported by Breakthrough T1D (formerly JDRF) grants (3-SRA-25-2012-516 and 3-SRA-2017-492-A-N awarded to AP). This work was supported by a Breakthrough T1D Career Development Award (5-CDA-2014-221-A-N) to SJR, an MRC Project Grant MR\/P010695\/1 awarded to SJR and NGM, and a Steve Morgan Foundation Grand Challenge Senior Research Fellowship awarded to SJR (22\/0006504). The studies from the University of Exeter were supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Part of the studies were supported by the European Union program Frame Programme 7 (Persistent Virus Infection in Diabetes Network [PEVNET], contract no. 261441). JSK is also supported by a grant from the NIDDK-sponsored Human Islet Research Network (HIRN, RRID:SCR_014393; ; UC24 DK104162). KM was supported by a German Research Foundation grant (DFG).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"HH is a board member and stock owner of Vactech Oy, a Finnish biotech company that has contributed to the development of a CVB vaccine. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"SJR, TRC, JEL, JSK, REL, JON, JLN, IK, MAA, MvH, NGM, HH and AP made substantial contributions to the conception and design of the work. Assays were performed by SJR, TRC, JEL, JON, SM, KM, JFP and REL and interpretation of the individual specific assay experiments was performed by SJR, TRC, JEL, JON, REL, KM, MAM, VP, JFP, NGM, HH and AP. Formal combined analysis and interpretations were completed by SJR, TRC, JEL, JSK, JON, REL, HH and AP. MAM helped in sample selection, coordination, and procurement for proteomics assays, as well as editing of the manuscript. SJR, TRC, JEL, JSK and AP wrote the first draft of the manuscript. All authors reviewed critically the manuscript for important intellectual content and edited the manuscript. All authors have read and approved the final version of the manuscript. SJR, TRC, JL, JSK and AP are the guarantors of this work and, as such, have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}