Preclinical evaluation of a precision medicine approach to DNA vaccination in type 1 diabetes

Abstract

Significance Antigen-specific immunotherapy may be improved by focusing on epitopes that are disease-relevant and known to be presented on an individual’s human leukocyte antigen (HLA) haplotype, while targeting T cells across multiple antigens and including specific neoepitopes that are not present in protein antigens and/or not produced beyond inflamed sites. Here, we provide proof of principle that such a strategy applied to tolerogenic DNA vaccination is effective in a preclinical model of autoimmune diabetes, paving the way for precision medicine using endogenously encoded epitopes. It takes a minimum number of regular treatments to achieve a level of tolerance and regulation that is needed to limit insulitis and provide sustained protection before treatment may be discontinued or reduced in frequency.

Toward a precision medicine approach for autoimmunity

“…These two attributes of immune tolerance, the absence of a response and its active suppression by a regulatory population, are the foundations for the precision medicine strategy pursued by Postigo-Fernandez et al. ( 1 ) to halt autoimmune diabetes.…”

“…These are features highlighted in the work by Postigo-Fernandez et al. ( 1 ), who developed an “endotope” platform to deliver multiple epitopes either as cleaved intracellular epitopes or as a secreted polypeptide from a single plasmid. This contrasts to earlier work by others who employed a mixture of plasmids to target multiple disease-relevant epitopes ( 15 ).…”

“…In the hope of optimizing the approach, Postigo-Fernandez et al. ( 1 ) proceeded to systematically test how the route of administration, frequency of dosing, and treatment duration would affect the outcome of a tolerizing DNA vaccine in a model for type 1 diabetes. In their work reported in PNAS, the group show that antigen produced from a single vaccination was still detectable up to 14 d later.…”

“…Overall, the study by Postigo-Fernandez et al. ( 1 ) is a rigorous demonstration that DNA vaccination can be effective but that it has to be fine-tuned. Significantly, the data suggest that the effective time window for a preventive vaccination in type 1 diabetes could be close to diagnosis because a treatment of short duration proved effective at this stage but not when administered to a larger group of mice long before disease onset, when a longer treatment duration was required to achieve some efficacy.…”

“…In PNAS, Postigo-Fernandez et al. ( 1 ) describe their systematic approach to testing this strategy in a mouse model for autoimmune (type 1) diabetes with a DNA vaccination platform they recently developed.…”