{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:04:59Z","timestamp":1790687099715,"version":"4.1.0"},"reference-count":32,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T00:00:00Z","timestamp":1582502400000},"content-version":"unspecified","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005632","name":"Narodowe Centrum Bada\u0144 i Rozwoju","doi-asserted-by":"publisher","award":["LIDER\/160\/L-6\/14\/NCBR\/2015"],"award-info":[{"award-number":["LIDER\/160\/L-6\/14\/NCBR\/2015"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005632","name":"Narodowe Centrum Bada\u0144 i Rozwoju","doi-asserted-by":"publisher","award":["STRATEGMED1\/233368\/1\/NCBR\/2014"],"award-info":[{"award-number":["STRATEGMED1\/233368\/1\/NCBR\/2014"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open Diab Res Care"],"accepted":{"date-parts":[[2020,1,20]]},"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Here we looked for possible mechanisms regulating the progression of type 1 diabetes mellitus (T1DM). In this disease, autoaggressive T cells (T conventional cells, Tconvs) not properly controlled by T regulatory cells (Tregs) destroy pancreatic islets.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Research design and methods<\/jats:title>\n                  <jats:p>We compared the T-cell compartment of patients with newly diagnosed T1DM (NDT1DM) with long-duration T1DM (LDT1DM) ones. The third group consisted of patients with LDT1DM treated previously with polyclonal Tregs (LDT1DM with Tregs). We have also looked if the differences might be dependent on the antigen specificity of Tregs expanded for clinical use and autologous sentinel Tconvs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Patients with LDT1DM were characterized by T-cell immunosenescence-like changes and expansion of similar v\u03b2\/T-cell receptor (TCR) clones in Tconvs and Tregs. The treatment with Tregs was associated with some inhibition of these effects. Patients with LDT1DM possessed an increased percentage of various proinsulin-specific T cells but not GAD65-specific ones. The percentages of all antigen-specific subsets were higher in the expansion cultures than in the peripheral blood. The proliferation was more intense in proinsulin-specific Tconvs than in specific Tregs but the levels of some proinsulin-specific Tregs were exceptionally high at baseline and remained higher in the expanded clinical product than the levels of respective Tconvs in sentinel cultures.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>T1DM is associated with immunosenescence-like changes and reduced diversity of T-cell clones. Preferential expansion of the same TCR families in both Tconvs and Tregs suggests a common trigger\/autoantigen responsible. Interestingly, the therapy with polyclonal Tregs was associated with some inhibition of these effects. Proinsulin-specific Tregs appeared to be dominant in the immune responses in patients with T1DM and probably associated with better control over respective autoimmune Tconvs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>EudraCT 2014-004319-35.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjdrc-2019-000873","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T05:45:13Z","timestamp":1582609513000},"page":"e000873","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Proinsulin-specific T regulatory cells may control immune responses in type 1 diabetes: implications for adoptive therapy"],"prefix":"10.1136","volume":"8","author":[{"given":"Mateusz","family":"Gliwi\u0144ski","sequence":"first","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Iwaszkiewicz-Grze\u015b","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wo\u0142oszyn-Durkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pediatric Diabetology and Endocrinology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Tarnowska","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"\u017bali\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Pediatric Diabetology and Endocrinology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matylda","family":"Hennig","sequence":"additional","affiliation":[{"name":"Department of Pediatric Diabetology and Endocrinology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Zieli\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dukat-Mazurek","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Zielkowska-D\u0119bska","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Zieli\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ja\u017awi\u0144ska-Cury\u0142\u0142o","sequence":"additional","affiliation":[{"name":"Regional Center of Blood Donation and Treatment, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rados\u0142aw","family":"Owczuk","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Critical Care, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemys\u0142awa","family":"Jarosz-Chobot","sequence":"additional","affiliation":[{"name":"Department of Children\u2019s Diabetology, Medical University of Silesia, Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Bossowski","sequence":"additional","affiliation":[{"name":"Department of Peadiatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Bia\u0142ystok, Bia\u0142ystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Szadkowska","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Diabetology, Endocrinology and Nephrology, Medical University of \u0141\u00f3d\u017a, \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"M\u0142ynarski","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Oncology, and Haematology, Medical University of \u0141\u00f3d\u017a, \u0141\u00f3d\u017a, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Marek-Trzonkowska","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Laboratory of Immunoregulation and Cellular Therapies, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"},{"name":"International Centre for Cancer Vaccine Science, University of Gda\u0144sk, Gda\u0144sk, Poland"},{"name":"Poltreg S.A, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gra\u017cyna","family":"Moszkowska","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janusz","family":"Siebert","sequence":"additional","affiliation":[{"name":"Department of Family Medicine, Laboratory of Immunoregulation and Cellular Therapies, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"My\u015bliwiec","sequence":"additional","affiliation":[{"name":"Department of Pediatric Diabetology and Endocrinology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"},{"name":"Poltreg S.A, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5287-5210","authenticated-orcid":false,"given":"Piotr","family":"Trzonkowski","sequence":"additional","affiliation":[{"name":"Department of Medical Immunology, Medical University of Gda\u0144sk, Gda\u0144sk, Poland"},{"name":"Poltreg S.A, Gda\u0144sk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2020,2,24]]},"reference":[{"key":"2025073113121410000_8.1.e000873.1","doi-asserted-by":"crossref","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2025073113121410000_8.1.e000873.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30507-4"},{"key":"2025073113121410000_8.1.e000873.3","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0119"},{"key":"2025073113121410000_8.1.e000873.4","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/MED.0000000000000323","article-title":"Narrowing in on the anti-\u03b2 cell-specific T cells: looking 'where the action is'","volume":"24","author":"Kent","year":"2017","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"2025073113121410000_8.1.e000873.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198605223142106"},{"key":"2025073113121410000_8.1.e000873.6","doi-asserted-by":"crossref","DOI":"10.1007\/s11892-017-0932-x","article-title":"Emerging concepts on disease-modifying therapies in type 1 diabetes","volume":"17","author":"Greenbaum","year":"2017","journal-title":"Curr Diab Rep"},{"key":"2025073113121410000_8.1.e000873.7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/imm.12454","article-title":"Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance?","volume":"145","author":"Maddux","year":"2015","journal-title":"Immunology"},{"key":"2025073113121410000_8.1.e000873.8","first-page":"3011","article-title":"The Presence and Preferential Activation of Regulatory T-cells Diminish Adoptive Transfer of Autoimmune Diabetes by Polyclonal Nonobese Diabetic (NOD) T-cell Effectors into NSG versus NOD- scid Mice","volume":"195","author":"Presa","year":"2015","journal-title":"J.i."},{"key":"2025073113121410000_8.1.e000873.9","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aad4134","article-title":"Type 1 diabetes immunotherapy using polyclonal regulatory T cells","volume":"7","author":"Bluestone","year":"2015","journal-title":"Sci Transl Med"},{"key":"2025073113121410000_8.1.e000873.10","doi-asserted-by":"publisher","DOI":"10.2337\/dc12-0038"},{"key":"2025073113121410000_8.1.e000873.11","doi-asserted-by":"crossref","DOI":"10.1186\/s12967-016-1090-7","article-title":"Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes","volume":"14","author":"Marek-Trzonkowska","year":"2016","journal-title":"J Transl Med"},{"key":"2025073113121410000_8.1.e000873.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2014.03.016"},{"key":"2025073113121410000_8.1.e000873.13","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.88242","article-title":"Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes","volume":"1","author":"Seay","year":"2016","journal-title":"JCI Insight"},{"key":"2025073113121410000_8.1.e000873.14","first-page":"A45","article-title":"The 2017 guidelines on the management of diabetic patients","volume":"6","author":"Poland","year":"2017","journal-title":"Diabetologia Kliniczna"},{"key":"2025073113121410000_8.1.e000873.15","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.bbmt.2016.01.014","article-title":"Thymic activity and T cell repertoire recovery after autologous hematopoietic stem cell transplantation preceded by myeloablative radiotherapy or chemotherapy","volume":"22","author":"G\u0142owala-Kosi\u0144ska","year":"2016","journal-title":"Biol Blood Marrow Transplant"},{"key":"2025073113121410000_8.1.e000873.16","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.01844","article-title":"Minimum information about T regulatory cells: a step toward reproducibility and standardization","volume":"8","author":"Fuchs","year":"2018","journal-title":"Front Immunol"},{"key":"2025073113121410000_8.1.e000873.17","doi-asserted-by":"crossref","DOI":"10.3390\/ijms18081742","article-title":"Markers of T cell senescence in humans","volume":"18","author":"Xu","year":"2017","journal-title":"Int J Mol Sci"},{"key":"2025073113121410000_8.1.e000873.18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.clim.2010.07.007","article-title":"Increased spontaneous production of VEGF by CD4+ T cells in type 1 diabetes","volume":"137","author":"Marek","year":"2010","journal-title":"Clin Immunol"},{"key":"2025073113121410000_8.1.e000873.19","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-0867"},{"key":"2025073113121410000_8.1.e000873.20","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3031"},{"key":"2025073113121410000_8.1.e000873.21","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2005.00759.x"},{"key":"2025073113121410000_8.1.e000873.22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2012.04008.x"},{"key":"2025073113121410000_8.1.e000873.23","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1002\/eji.201445101","article-title":"With a little help from my old T cell: memory follicular T helper cells driving autoimmunity?","volume":"44","author":"Winkler","year":"2014","journal-title":"Eur J Immunol"},{"key":"2025073113121410000_8.1.e000873.24","doi-asserted-by":"crossref","DOI":"10.1007\/s11892-017-0889-9","article-title":"Memory T cells in type 1 diabetes: the devil is in the detail","volume":"17","author":"Narsale","year":"2017","journal-title":"Curr Diab Rep"},{"key":"2025073113121410000_8.1.e000873.25","doi-asserted-by":"publisher","DOI":"10.2337\/db16-1025"},{"key":"2025073113121410000_8.1.e000873.26","doi-asserted-by":"publisher","DOI":"10.3727\/096368911X566217"},{"key":"2025073113121410000_8.1.e000873.27","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-011-9573-z"},{"key":"2025073113121410000_8.1.e000873.28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jneuroim.2017.06.001","article-title":"Characterization of na\u00efve, memory and effector T cells in progressive multiple sclerosis","volume":"310","author":"Nielsen","year":"2017","journal-title":"J Neuroimmunol"},{"key":"2025073113121410000_8.1.e000873.29","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.cell.2016.09.050","article-title":"Regulatory T cell specificity directs tolerance versus allergy against Aeroantigens in humans","volume":"167","author":"Bacher","year":"2016","journal-title":"Cell"},{"key":"2025073113121410000_8.1.e000873.30","doi-asserted-by":"publisher","DOI":"10.1038\/nature03625"},{"key":"2025073113121410000_8.1.e000873.31","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0666"},{"key":"2025073113121410000_8.1.e000873.32","doi-asserted-by":"crossref","DOI":"10.1007\/s11892-018-1066-5","article-title":"Immune mechanisms and pathways targeted in type 1 diabetes","volume":"18","author":"Jacobsen","year":"2018","journal-title":"Curr Diab Rep"}],"container-title":["BMJ Open Diabetes Research &amp; Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjdrc-2019-000873","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T20:12:28Z","timestamp":1753992748000},"score":1,"resource":{"primary":{"URL":"https:\/\/drc.bmj.com\/lookup\/doi\/10.1136\/bmjdrc-2019-000873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,2,24]]},"published-print":{"date-parts":[[2020,2]]}},"alternative-id":["10.1136\/bmjdrc-2019-000873"],"URL":"https:\/\/doi.org\/10.1136\/bmjdrc-2019-000873","relation":{},"ISSN":["2052-4897"],"issn-type":[{"value":"2052-4897","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2]]}}}