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

TY - JOUR

T1 - Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes

AU - Ali, Mohammad Alhadj

AU - Liu, Yuk-Fun

AU - Arif, Sefina

AU - Tatovic, Danijela

AU - Shariff, Hina

AU - Gibson, Vivienne B.

AU - Yusuf, Norkhairin

AU - Baptista, Roman

AU - Eichmann, Martin

AU - Petrov, Nedyalko

AU - Heck, Susanne

AU - Yang, Jennie H.M.

AU - Tree, Timothy I.M.

AU - Pujol-Autonell, Irma

AU - Yeo, Lorraine

AU - Baumard, Lucas R.

AU - Stenson, Rachel

AU - Howell, Alex

AU - Clark, Alison

AU - Boult, Zoe

AU - Powrie, Jake

AU - Adams, Laura

AU - Wong, Florence S.

AU - Luzio, Stephen

AU - Dunseath, Gareth

AU - Green, Kate

AU - O'Keefe, Alison

AU - Bayly, Graham

AU - Thorogood, Natasha

AU - Andrews, Robert

AU - Leech, Nicola

AU - Joseph, Frank

AU - Nair, Sunil

AU - Seal, Susan

AU - Cheung, HoYee

AU - Beam, Craig

AU - Hills, Robert

AU - Peakman, Mark

AU - Dayan, Colin M.

N1 - Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2017/8/9

Y1 - 2017/8/9

N2 - 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.

AB - 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.

KW - Journal Article

UR - http://www.scopus.com/inward/record.url?scp=85027408203&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aaf7779

DO - 10.1126/scitranslmed.aaf7779

M3 - Article

C2 - 28794283

SN - 1946-6234

VL - 9

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 402

M1 - eaaf7779

ER -