Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.
Mohammad Alhadj AliYuk-Fun LiuSefina ArifDanijela TatovicHina ShariffVivienne B GibsonNorkhairin YusufRoman BaptistaMartin EichmannNedyalko PetrovSusanne HeckJennie Hsiu Mien YangTimothy I M TreeIrma Pujol-AutonellLorraine YeoLucas BaumardRachel StensonAlex HowellAlison ClarkZoe BoultJake PowrieLaura AdamsFlorence Susan WongStephen LuzioGareth DunseathKate GreenAlison O'KeefeGraham BaylyNatasha ThorogoodRobert AndrewsNicola LeechFrank JosephSunil NairSusan SealHoYee CheungCraig A BeamRobert HillsMark PeakmanColin M DayanPublished in: Science translational medicine (2018)
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.
Keyphrases
- type diabetes
- regulatory t cells
- newly diagnosed
- endothelial cells
- glycemic control
- cardiovascular disease
- end stage renal disease
- randomized controlled trial
- cell therapy
- dendritic cells
- stem cells
- chronic kidney disease
- poor prognosis
- ejection fraction
- immune response
- metabolic syndrome
- peritoneal dialysis
- skeletal muscle
- open label
- amino acid
- smoking cessation