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

Alhadj Ali, Mohammad, Liu, Yuk-Fun, Arif, Sefina, Tatovic, Danijela, Shariff, Hina, Gibson, Vivienne B., Yusuf, Norkhairin, Baptista, Roman, Eichmann, Martin, Petrov, Nedyalko, Heck, Susanne, Yang, Jennie H. M., Tree, Timothy I. M., Pujol-Autonell, Irma, Yeo, Lorraine, Baumard, Lucas R., Stenson, Rachel, Howell, Alex, Clark, Alison, Boult, Zoe, Powrie, Jake, Adams, Laura, Wong, Florence Susan, Luzio, Stephen, Dunseath, Gareth, Green, Kate, O'Keefe, Alison, Bayly, Graham, Thorogood, Natasha, Andrews, Robert, Leech, Nicola, Joseph, Frank, Nair, Sunil, Seal, Susan, Cheung, HoYee, Beam, Craig, Hills, Robert, Peakman, Mark and Dayan, Colin M. 2017. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Science Translational Medicine 9 (402) , eaaf7779. 10.1126/scitranslmed.aaf7779

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for the Advancement of Science
ISSN: 1946-6234
Date of First Compliant Deposit: 12 September 2017
Date of Acceptance: 11 July 2017
Last Modified: 28 Jun 2019 13:24
URI: http://orca.cf.ac.uk/id/eprint/104556

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