| Autor: |
Joseph F. Petrosino, Jan Knoop, Robin Assfalg, Ezio Bonifacio, Andreas Weiss, Peter Achenbach, Kristi L. Hoffman, Melanie Bunk, Anne Eugster, Jörg Hasford, Markus Pfirrmann, Anette-Gabriele Ziegler, Yannick F. Fuchs, Jose Zapardiel-Gonzalo, Anna Hofelich, Julia Reinhardt, Marc Weigelt, Claudia Matzke, Markus Hippich, Stefanie M. Hauck, Kathrin Halfter |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
BackgroundOral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes with insulin autoimmunity often appearing in the first years of life. 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 actions on immunity and the gut microbiome.MethodsA phase I/II randomized controlled trial was performed in 44 islet autoantibody-negative children aged 6 months to 2 years with genetic risk for type 1 diabetes. Children were randomized 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months. Primary outcome was safety and immune efficacy pre-specified as hypoglycemia and induction of antibody or T cell responses to insulin, respectively.ResultsOral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in both children who received insulin (55%) and placebo (67%), and were modified by theINSULINgene. Among children with type 1 diabetes-susceptibleINSULINgenotype, antibody responses to insulin were more frequent in insulin-treated (cumulative response, 75.8%) as compared to placebo-treated children (18.2%;P=0.0085), and T cell responses to insulin were modified by treatment-independent inflammatory episodes. Changes in the microbiome were related toINSULINgenotype.ConclusionThe study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe and engaged the adaptive immune system in anINSULINgenotype-dependent manner, and linked inflammatory episodes to the activation of insulin-responsive T cells.Trial registrationClinicaltrials.govNCT02547519FundingGerman Center for Diabetes Research (DZD e.V.), Juvenile Diabetes Research Foundation (JDRF, grant 1-SRA-2018-546-S-B), Federal Ministry of Education and Research (BMBF, grant FKZ01KX1818). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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