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

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)722-732
Number of pages11
JournalDiabetes
Volume71
Issue number4
DOIs
Published1 Apr 2022

Bibliographical note

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.

King's Authors

Abstract

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.

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