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Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

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Mohammad Alhadj Ali, Yuk-Fun Liu, Sefina Arif, Danijela Tatovic, Hina Shariff, Vivienne B. Gibson, Norkhairin Yusuf, Roman Baptista, Martin Eichmann, Nedyalko Petrov, Susanne Heck, Jennie H.M. Yang, Timothy I.M. Tree, Irma Pujol-Autonell, Lorraine Yeo, Lucas R. Baumard, Rachel Stenson, Alex Howell, Alison Clark, Zoe Boult & 19 more Jake Powrie, Laura Adams, Florence S. Wong, Stephen Luzio, Gareth Dunseath, Kate Green, Alison O'Keefe, Graham Bayly, Natasha Thorogood, Robert Andrews, Nicola Leech, Frank Joseph, Sunil Nair, Susan Seal, HoYee Cheung, Craig Beam, Robert Hills, Mark Peakman, Colin M. Dayan

Original languageEnglish
Article numberaaf7779
Pages (from-to)1-9
JournalScience Translational Medicine
Volume9
Issue number402
DOIs
Publication statusPublished - 9 Aug 2017

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Abstract

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.

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