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

Tatovic, Danijela ORCID: https://orcid.org/0000-0002-3879-2686, Marwaha, Ashish, Taylor, Peter ORCID: https://orcid.org/0000-0002-3436-422X, Hanna, Stephanie J., Carter, Kym, Cheung, W. Y., Luzio, Steve, Dunseath, Gareth, Hutchings, Hayley A., Holland, Gail, Hiles, Steve, Fegan, Greg, Williams, Evangelia, Yang, Jennie H. M., Domingo-Vila, Clara, Pollock, Emily, Wadud, Muntaha, Ward-Hartstonge, Kirsten, Marques-Jones, Susie, Bowen-Morris, Jane, Stenson, Rachel, Levings, Megan K., Gregory, John W. ORCID: https://orcid.org/0000-0001-5189-3812, Tree, Timothy I. M., Dayan, Colin ORCID: https://orcid.org/0000-0002-6557-3462, Gevers, Evelien, Kanumakala, Shankar, Nair, Sunil, Gardner, Chris, Ajzensztejn, Michal, Wei, Christina, Mouditis, Chris, Campbell, Fiona, Greening, James, Webb, Emma, Chen, Mimi, Amin, Rakesh, White, Billi, Shetty, Ambika, Bidder, Chris, Conway, Nicholas, Mayo, Amalia, Christakou, Eleni, Sychowska, Kamila, Shahrabi, Yasaman, Robinson, Maximilian, Ahmed, Simi, Dutz, Jan and Cook, Laura 2024. Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial. Nature Medicine 30 , pp. 2657-2666. 10.1038/s41591-024-03115-2

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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).

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Research
ISSN:	1078-8956
Date of First Compliant Deposit:	15 August 2024
Date of Acceptance:	5 June 2024
Last Modified:	19 Sep 2024 13:13
URI:	https://orca.cardiff.ac.uk/id/eprint/171423

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