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Randomized Controlled Trial
. 2017 Aug 9;9(402):eaaf7779.
doi: 10.1126/scitranslmed.aaf7779.

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

Mohammad Alhadj Ali  1 , Yuk-Fun Liu  2   3 , Sefina Arif  2 , Danijela Tatovic  1 , Hina Shariff  2 , Vivienne B Gibson  2 , Norkhairin Yusuf  2 , Roman Baptista  2   4 , Martin Eichmann  2 , Nedyalko Petrov  4 , Susanne Heck  4 , Jennie H M Yang  2 , Timothy I M Tree  2 , Irma Pujol-Autonell  2 , Lorraine Yeo  2 , Lucas Baumard  2 , Rachel Stenson  1 , Alex Howell  1 , Alison Clark  1 , Zoe Boult  5 , Jake Powrie  3 , Laura Adams  3 , Florence S Wong  1 , Stephen Luzio  6 , Gareth Dunseath  6 , Kate Green  7 , Alison O'Keefe  7 , Graham Bayly  7 , Natasha Thorogood  7 , Robert Andrews  7 , Nicola Leech  8 , Frank Joseph  9 , Sunil Nair  9 , Susan Seal  9 , HoYee Cheung  9 , Craig Beam  10 , Robert Hills  11 , Mark Peakman  12   4   13 , Colin M Dayan  1
Affiliations
Randomized Controlled Trial

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

Mohammad Alhadj Ali et al. Sci Transl Med. .

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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Comment in

  • Therapy: Immunotherapy advance for T1DM.
    Greenhill C. Greenhill C. Nat Rev Endocrinol. 2017 Oct;13(10):564. doi: 10.1038/nrendo.2017.113. Epub 2017 Aug 29. Nat Rev Endocrinol. 2017. PMID: 28849787 No abstract available.

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