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Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
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)
,
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)
Nature Medicine
Swansea University Authors:
Kym Carter , Ivy Cheung, Steve Luzio , Gareth Dunseath , Hayley Hutchings , Gail Holland , 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...
| Published in: | Nature Medicine |
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| ISSN: | 1078-8956 1546-170X |
| Published: |
Springer Science and Business Media LLC
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa67256 |
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| 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 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). |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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. |