Characterization of the dynamic immunophenotype during type 1 diabetes progression to identify predictive biomarkers of anti-CD3 mono- and combination therapy in disease prevention and reversal in mice

Type 1 diabetes (T1D) is a T cell-mediated disease resulting in the destruction of the insulin- producing pancreatic β-cells. Immunotherapies like teplizumab (a humanized anti-CD3 antibody) are put forward as promising strategies to delay, even prevent, and reverse disease onset. However, the clinical outcome of anti-CD3 therapy, especially in newly diagnosed T1D individuals, is variable for reasons yet unknown. We propose that the success of anti-CD3 therapy in T1D intervention may be disease stage- and/or age-dependent . To test this hypothesis, we will perform an in-depth analysis of the T cell compartment in the non-obese diabetic (NOD) mouse model during T1D development. Subsequently, we will investigate by multi-parameter flow cytometry and cytokine profiling the effects of anti-CD3 therapy on the T cell compartment of NOD mice when administered at various disease stages/ages. Access to human blood samples from newly diagnosed T1D patients enrolled in INNODIA HARVEST studies will allow verification of the mouse findings. To enhance efficacy of the anti-CD3 therapy and induce antigen-specific tolerance, we will add native or deamidated GAD65 peptides, delivered by genetically modified Lactococcus lactis. Combining immunotherapies with autoantigens, either as full proteins or peptide epitopes, delivered via a tolerogenic route, hold the promise of greater disease specificity, of lower toxicity, and of a longer-term solution for preventing and even reversing autoimmune T1D.