RT Journal Article
SR Electronic
T1 Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaaf7779
DO 10.1126/scitranslmed.aaf7779
VO 9
IS 402
A1 Alhadj Ali, Mohammad
A1 Liu, Yuk-Fun
A1 Arif, Sefina
A1 Tatovic, Danijela
A1 Shariff, Hina
A1 Gibson, Vivienne B.
A1 Yusuf, Norkhairin
A1 Baptista, Roman
A1 Eichmann, Martin
A1 Petrov, Nedyalko
A1 Heck, Susanne
A1 Yang, Jennie H. M.
A1 Tree, Timothy I. M.
A1 Pujol-Autonell, Irma
A1 Yeo, Lorraine
A1 Baumard, Lucas R.
A1 Stenson, Rachel
A1 Howell, Alex
A1 Clark, Alison
A1 Boult, Zoe
A1 Powrie, Jake
A1 Adams, Laura
A1 Wong, Florence S.
A1 Luzio, Stephen
A1 Dunseath, Gareth
A1 Green, Kate
A1 O’Keefe, Alison
A1 Bayly, Graham
A1 Thorogood, Natasha
A1 Andrews, Robert
A1 Leech, Nicola
A1 Joseph, Frank
A1 Nair, Sunil
A1 Seal, Susan
A1 Cheung, HoYee
A1 Beam, Craig
A1 Hills, Robert
A1 Peakman, Mark
A1 Dayan, Colin M.
YR 2017
UL http://stm.sciencemag.org/content/9/402/eaaf7779.abstract
AB Immunotherapy using peptides has been successful for some patients with allergies, but has not yet been deployed in autoimmune diseases, which may involve greater safety risks. Alhadj Ali et al. designed a placebo-controlled trial to determine whether a proinsulin peptide could safely elicit immune and metabolic responses in people recently diagnosed with type 1 diabetes without accelerating disease. This small trial showed that treatment seemed to modify T cell responses and did not interfere with residual β cell function. In contrast to subjects in the placebo arm, treated subjects did not need to increase their insulin use. These encouraging results support a larger trial to investigate efficacy of the peptide therapy for treating disease.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.