Authors: Robin Assfalg, Jan Knoop, Kristi L. Hoffman, Markus Pfirrmann, Jose Maria Zapardiel-Gonzalo, Anna Hofelich, Anne Eugster, Marc Weigelt, Claudia Matzke, Julia Reinhardt, Yannick Fuchs, Melanie Bunk, Andreas Weiss, Markus Hippich, Kathrin Halfter, Stefanie M. Hauck, Jörg Hasford, Joseph F. Petrosino, Peter Achenbach, Ezio Bonifacio, Anette-Gabriele Ziegler
Published: 2021-01-30
DOI: 10.1007/s00125-020-05376-1
Source: Full article
AbstractAims/hypothesisOral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome.MethodsA phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptibleHLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory.ResultsRandomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by theINSgenotype Among children with the type 1 diabetes-susceptibleINSgenotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%;p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes.Conclusions/interpretationThe study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptibleINSgenotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells.Trial registrationClinicaltrials.gov NCT02547519FundingThe main funding source was the German Center for Diabetes Research (DZD e.V.)Graphical abstract