What is it about?

Type 1 diabetes (T1D) results from the reactivity of specific T cells against insulin-producing beta cell proteins (antigens), because these T cells had not been properly eliminated or tolerized. The goal of antigen-specific immunotherapy is to desensitize these specific T cells, and only those, in order to stop the destruction of beta cells while keeping a fully functional immune system (i.e., no global immunosuppression). T cell responses and antigens targeted vary from patient to patient, such that if given the same treatment, some will respond better than others. The goal of precision medicine is to develop approaches that desensitize disease-related T cells with relevant antigens. DNA vaccines are easier and cheaper to manufacture, and can be produced in different variants tailored for subgroups of T1D patients. The NOD mouse is a model that has been used extensively for preclinical studies, but is most representative of one subgroup of T1D patient. We designed and tested a DNA vaccine that is tailored for this mouse strain and demonstrate its efficacy at re-educating antigen-specific T cells and limiting the progression of the disease at different stages.

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Why is it important?

Treatment developed and optimized in NOD mice have not been successful in T1D patients because only a small proportion of these patients were responders. These responders had unique characteristics (HLA haplotype, autoantibodies) that point to major antigens targeted and the ability of the patients to be able to present fragments of these antigens to their T cells. There are also new and important neoantigens that play a role, and these can be conveniently produced by the patient's own cells from a DNA vaccine. The Endotope platform takes into account this information to produce a customized and more targeted vaccine.

Perspectives

The heterogeneity of the T1D patient population has been underestimated for a long time, and this likely applies to other autoimmune diseases as well. More customized vaccines will undoubtedly be more effective, yet more costly to produce. Thankfully, DNA and mRNA vaccines offer great versatility in manufacturing multiple variants of a vaccine, but further developments are required to improve delivery and persistence in vivo.

Remi Creusot
Columbia University

Read the Original

This page is a summary of: Preclinical evaluation of a precision medicine approach to DNA vaccination in type 1 diabetes, Proceedings of the National Academy of Sciences, April 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2110987119.
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