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

Alhadj Ali, Mohammad ORCID: https://orcid.org/0000-0002-9780-6443, 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 S. ORCID: https://orcid.org/0000-0002-2812-8845, 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. ORCID: https://orcid.org/0000-0002-6557-3462 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:	09 Nov 2024 09:00
URI:	https://orca.cardiff.ac.uk/id/eprint/104556

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