Immune and Metabolic Effects of Antigen-Specific Immunotherapy Using Multiple β-Cell Peptides in Type 1 Diabetes
figureposted on 2022-01-24, 23:54 authored by Yuk-Fun Liu, Jake Powrie, Sefina Arif, Jennie H.M. Yang, Evangelia Williams, Leena Khatri, Mamta Joshi, Loic Lhuillier, Nikolaos Fountoulakis, Emma Smith, Craig Beam, Anna Lorenc, Mark Peakman, Timothy Tree
Type 1 diabetes is characterized by a loss of tolerance to pancreatic β-cell autoantigens and defects in T regulatory cell (Treg) function. In preclinical models, immunotherapy with MHC-selective, autoantigenic peptides restores immune tolerance, prevents diabetes and shows greater potency when multiple peptides are used. To translate this strategy into the clinical setting we administered a mixture of 6 HLA-DRB1*0401 -selective, β-cell peptides intradermally to patients with recent-onset type 1 diabetes possessing this genotype in a randomized placebo-controlled study at monthly doses of 10, 100 and 500µg for 24 weeks. Stimulated C-peptide (measuring insulin functional reserve) had declined in all placebo subjects at 24 weeks, but was maintained at ≥100% baseline levels in half of the treated group. Treatment was accompanied by significant changes in islet specific immune responses and a dose-dependent increase in Treg expression of the canonical transcription factor FoxP3 and changes in Treg gene expression. In this first-in-human study, multiple-peptide immunotherapy shows promise as a strategy to correct immune regulatory defects fundamental to the pathobiology of autoimmune diabetes.