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Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

Danijela Tatovic Orcid Logo, Ashish Marwaha, Peter Taylor, Stephanie J. Hanna Orcid Logo, Kym Carter Orcid Logo, Ivy Cheung, Steve Luzio Orcid Logo, Gareth Dunseath Orcid Logo, Hayley Hutchings Orcid Logo, Gail Holland Orcid Logo, Steve Hiles, Greg Fegan, Evangelia Williams, Jennie H. M. Yang Orcid Logo, Clara Domingo-Vila, Emily Pollock Orcid Logo, Muntaha Wadud, Kirsten Ward-Hartstonge, Susie Marques-Jones, Jane Bowen-Morris, Rachel Stenson, Megan K. Levings Orcid Logo, John W. Gregory, Timothy I. M. Tree, Colin Dayan, Evelien Gevers, Shankar Kanumakala, Sunil Nair, Chris Gardner, Michal Ajzensztejn, Christina Wei, Chris Mouditis, Fiona Campbell, James Greening, Emma Webb, Mimi Chen, Rakesh Amin, Billi White, Ambika Shetty, Chris Bidder, Nicholas Conway, Amalia Mayo, Eleni Christakou, Kamila Sychowska, Yasaman Shahrabi, Maximilian Robinson, Simi Ahmed, Jan Dutz, Laura Cook, (USTEKID Study Group)

Nature Medicine

Swansea University Authors: Kym Carter Orcid Logo, Ivy Cheung, Steve Luzio Orcid Logo, Gareth Dunseath Orcid Logo, Hayley Hutchings Orcid Logo, Gail Holland Orcid Logo, Steve Hiles, Greg Fegan

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DOI (Published version): 10.1038/s41591-024-03115-2

Abstract

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of...

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Published in: Nature Medicine
ISSN: 1078-8956 1546-170X
Published: Springer Science and Business Media LLC 2024
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Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. 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The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. Additional funding for mechanistic laboratory tests has been provided by Breakthrough T1D (formerly JDRF (Juvenile Diabetes Research Foundation)) International awards (3-SRA-2018-629-S-B and 4-SRA-2020-882-S-B). The UK Type 1 Diabetes Consortium supported the USTEKID study via grants from Diabetes UK (19/0005951 and 15/0005232) and Breakthrough T1D (formerly JDRF) (3-SRA-2019-774-A-N). S.J.H. is funded by the Diabetes Research and Wellness Foundation Professor David Matthews Non-Clinical Research Fellowship. M.K.L. receives a salary award from the BC Children’s Hospital Research Institute and is a Canada Research Chair in Engineered Immune Tolerance. 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spelling v2 67256 2024-07-30 Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial 1b1870c5c1ec66eed0bf209e50a6ee25 0000-0003-0691-6282 Kym Carter Kym Carter true false a9142ffd398f89eff40ada503e315639 Ivy Cheung Ivy Cheung true false 01491e1cd582746a654fad9addf0de16 0000-0002-7206-6530 Steve Luzio Steve Luzio true false fccbba9edcaee08a839a3c5cff8cbe19 0000-0001-6022-862X Gareth Dunseath Gareth Dunseath true false bdf5d5f154d339dd92bb25884b7c3652 0000-0003-4155-1741 Hayley Hutchings Hayley Hutchings true false b9f3a8bf7478db012c8856b7bbbc7597 0000-0002-6924-2521 Gail Holland Gail Holland true false 5ecd70f8c0f27219f84a7f297d99b22b Steve Hiles Steve Hiles true false a9005418b89918776f3d8895ba42e850 Greg Fegan Greg Fegan true false 2024-07-30 MEDS Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380). Journal Article Nature Medicine 0 Springer Science and Business Media LLC 1078-8956 1546-170X 30 7 2024 2024-07-30 10.1038/s41591-024-03115-2 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This project (project reference 16/36/01) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, a partnership between the National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC). The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. Additional funding for mechanistic laboratory tests has been provided by Breakthrough T1D (formerly JDRF (Juvenile Diabetes Research Foundation)) International awards (3-SRA-2018-629-S-B and 4-SRA-2020-882-S-B). The UK Type 1 Diabetes Consortium supported the USTEKID study via grants from Diabetes UK (19/0005951 and 15/0005232) and Breakthrough T1D (formerly JDRF) (3-SRA-2019-774-A-N). S.J.H. is funded by the Diabetes Research and Wellness Foundation Professor David Matthews Non-Clinical Research Fellowship. M.K.L. receives a salary award from the BC Children’s Hospital Research Institute and is a Canada Research Chair in Engineered Immune Tolerance. K.W.H. received a fellowship from the Canadian Institutes for Health Research. 2024-08-05T17:05:12.3307276 2024-07-30T12:27:58.2751335 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Health Data Science Danijela Tatovic 0000-0002-3879-2686 1 Ashish Marwaha 2 Peter Taylor 3 Stephanie J. Hanna 0000-0002-0821-4498 4 Kym Carter 0000-0003-0691-6282 5 Ivy Cheung 6 Steve Luzio 0000-0002-7206-6530 7 Gareth Dunseath 0000-0001-6022-862X 8 Hayley Hutchings 0000-0003-4155-1741 9 Gail Holland 0000-0002-6924-2521 10 Steve Hiles 11 Greg Fegan 12 Evangelia Williams 13 Jennie H. M. Yang 0000-0001-6171-833x 14 Clara Domingo-Vila 15 Emily Pollock 0000-0002-7297-4205 16 Muntaha Wadud 17 Kirsten Ward-Hartstonge 18 Susie Marques-Jones 19 Jane Bowen-Morris 20 Rachel Stenson 21 Megan K. Levings 0000-0002-0305-5790 22 John W. Gregory 23 Timothy I. M. Tree 24 Colin Dayan 25 Evelien Gevers 26 Shankar Kanumakala 27 Sunil Nair 28 Chris Gardner 29 Michal Ajzensztejn 30 Christina Wei 31 Chris Mouditis 32 Fiona Campbell 33 James Greening 34 Emma Webb 35 Mimi Chen 36 Rakesh Amin 37 Billi White 38 Ambika Shetty 39 Chris Bidder 40 Nicholas Conway 41 Amalia Mayo 42 Eleni Christakou 43 Kamila Sychowska 44 Yasaman Shahrabi 45 Maximilian Robinson 46 Simi Ahmed 47 Jan Dutz 48 Laura Cook 49 (USTEKID Study Group) 50 67256__31011__0e889aa34a5243b5b979b2f9a8124b97.pdf Ustekid nature medicine.pdf 2024-07-30T12:47:13.0259847 Output 5080500 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
spellingShingle Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
Kym Carter
Ivy Cheung
Steve Luzio
Gareth Dunseath
Hayley Hutchings
Gail Holland
Steve Hiles
Greg Fegan
title_short Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
title_full Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
title_fullStr Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
title_full_unstemmed Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
title_sort Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
author_id_str_mv 1b1870c5c1ec66eed0bf209e50a6ee25
a9142ffd398f89eff40ada503e315639
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bdf5d5f154d339dd92bb25884b7c3652
b9f3a8bf7478db012c8856b7bbbc7597
5ecd70f8c0f27219f84a7f297d99b22b
a9005418b89918776f3d8895ba42e850
author_id_fullname_str_mv 1b1870c5c1ec66eed0bf209e50a6ee25_***_Kym Carter
a9142ffd398f89eff40ada503e315639_***_Ivy Cheung
01491e1cd582746a654fad9addf0de16_***_Steve Luzio
fccbba9edcaee08a839a3c5cff8cbe19_***_Gareth Dunseath
bdf5d5f154d339dd92bb25884b7c3652_***_Hayley Hutchings
b9f3a8bf7478db012c8856b7bbbc7597_***_Gail Holland
5ecd70f8c0f27219f84a7f297d99b22b_***_Steve Hiles
a9005418b89918776f3d8895ba42e850_***_Greg Fegan
author Kym Carter
Ivy Cheung
Steve Luzio
Gareth Dunseath
Hayley Hutchings
Gail Holland
Steve Hiles
Greg Fegan
author2 Danijela Tatovic
Ashish Marwaha
Peter Taylor
Stephanie J. Hanna
Kym Carter
Ivy Cheung
Steve Luzio
Gareth Dunseath
Hayley Hutchings
Gail Holland
Steve Hiles
Greg Fegan
Evangelia Williams
Jennie H. M. Yang
Clara Domingo-Vila
Emily Pollock
Muntaha Wadud
Kirsten Ward-Hartstonge
Susie Marques-Jones
Jane Bowen-Morris
Rachel Stenson
Megan K. Levings
John W. Gregory
Timothy I. M. Tree
Colin Dayan
Evelien Gevers
Shankar Kanumakala
Sunil Nair
Chris Gardner
Michal Ajzensztejn
Christina Wei
Chris Mouditis
Fiona Campbell
James Greening
Emma Webb
Mimi Chen
Rakesh Amin
Billi White
Ambika Shetty
Chris Bidder
Nicholas Conway
Amalia Mayo
Eleni Christakou
Kamila Sychowska
Yasaman Shahrabi
Maximilian Robinson
Simi Ahmed
Jan Dutz
Laura Cook
(USTEKID Study Group)
format Journal article
container_title Nature Medicine
container_volume 0
publishDate 2024
institution Swansea University
issn 1078-8956
1546-170X
doi_str_mv 10.1038/s41591-024-03115-2
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Health Data Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Health Data Science
document_store_str 1
active_str 0
description Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).
published_date 2024-07-30T17:05:11Z
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score 11.037581

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