Immune and Metabolic Effects of Antigen-Specific Immunotherapy Using Multiple β-Cell Peptides in Type 1 Diabetes

TY - JOUR

T1 - Immune and Metabolic Effects of Antigen-Specific Immunotherapy Using Multiple β-Cell Peptides in Type 1 Diabetes

AU - Liu, Yuk Fun

AU - Powrie, Jake

AU - Arif, Sefina

AU - Yang, Jennie H.M.

AU - Williams, Evangelia

AU - Khatri, Leena

AU - Joshi, Mamta

AU - Lhuillier, Loic

AU - Fountoulakis, Nikolaos

AU - Smith, Emma

AU - Beam, Craig

AU - Lorenc, Anna

AU - Peakman, Mark

AU - Tree, Timothy

N1 - Funding Information: This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy?s and St. Thomas? NHS Foundation Trust and King?s College London and/or the NIHR Clinical Research Facility. Flow cytometry studies were supported by the T1DUK Immunotherapy Consortium funded by Diabetes UK (grants 15/ 0005232 and 15/0005233). The study was cosponsored by King?s College London and Guy?s and St. Thomas? NHS Foundation Trust. UCB Pharma provided grant funding and input into the study design, outcome analysis, and data interpretation. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care. Funding Information: Funding. This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility. Flow cytometry studies were supported by the T1DUK Immunotherapy Consortium funded by Diabetes UK (grants 15/ 0005232 and 15/0005233). The study was cosponsored by King’s College London and Guy’s and St. Thomas’ NHS Foundation Trust. UCB Pharma Publisher Copyright: © 2022 by the American Diabetes Association.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Type 1 diabetes is characterized by a loss of tolerance to pancreatic β-cell autoantigens and defects in regulatory T-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 six 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 500 μg 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 one-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.

AB - Type 1 diabetes is characterized by a loss of tolerance to pancreatic β-cell autoantigens and defects in regulatory T-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 six 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 500 μg 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 one-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.

UR - http://www.scopus.com/inward/record.url?scp=85126345849&partnerID=8YFLogxK

U2 - 10.2337/db21-0728

DO - 10.2337/db21-0728

M3 - Article

C2 - 35073398

AN - SCOPUS:85126345849

SN - 1939-327X

VL - 71

SP - 722

EP - 732

JO - Diabetes

JF - Diabetes

IS - 4

ER -