Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial.
Nat Med
; 30(9): 2657-2666, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-39079992
ABSTRACT
Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of ß-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, ß-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 ß-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).
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus, Type 1
/
Ustekinumab
Limits:
Adolescent
/
Child
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Female
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Humans
/
Male
Language:
En
Journal:
Nat Med
Journal subject:
BIOLOGIA MOLECULAR
/
MEDICINA
Year:
2024
Document type:
Article
Country of publication:
United States