Context: Immunotherapy trials to prevent type 1 diabetes have been unsuccessful for >15 years. Understanding pitfalls and knowledge gaps in the immunology of type 1 diabetes should lead us in new directions that will yield better trial outcomes. A proposal is made for precision medicine trial design in future type 1 diabetes studies.
Evidence acquisition: High-quality peer-reviewed basic science and clinical research trials for type 1 diabetes were used in this Perspective article. Type 1 diabetes publications were reviewed from 2000 to 2018 by using Google Scholar and PubMed reference databases.
Evidence synthesis: Personalized medicine for type 1 diabetes should recognize that each individual has phenotypic and genotypic quirks that distinguish them from other study participants. A uniform protocol for antigen-specific immunotherapy has consistently failed to prevent disease. An alternative approach using molecular tools to personalize the preventive treatment strategy might be a road forward for type 1 diabetes research. Assumptions or lack of knowledge about disease stratification (not all type 1 diabetes is the same disease), individualized antigen-specific T cells, regulatory T-cell populations, and T-cell receptor rearrangement are just a few aspects of immunology that require integration with clinical trial design.
Conclusions: The type 1 diabetes research community continues to bring forward novel immunotherapy trials to prevent disease, but this approach is unlikely to succeed until several fundamental aspects of clinical immunology are recognized and addressed. Here, we identify several knowledge gaps that could rectify type 1 diabetes trial design and lead to future success.