Prevention of Type 1 Diabetes with Acetalated Dextran Microparticles Containing Rapamycin and Pancreatic Peptide P31

Type 1 diabetes (T1D) is a common autoimmune disease with no cure. T1D subjects are dependent on daily exogenous insulin administration, due to the loss of functional insulin‐producing β cells. Needed are immunotherapies that prevent and/or treat T1D. One approach of immunotherapy is to administer an autoantigen to selectively tolerize diabetogenic effector T cells without global immunosuppression. To date, however, strategies of antigen‐specific immunotherapy are largely ineffective in the clinic. Using an antigen‐specific approach, a biodegradable polymeric delivery vehicle, acetalated dextran microparticles (Ace‐DEX MPs), is applied and T1D development is prevented through coadministration of the immunosuppressant rapamycin and the diabetogenic peptide P31 (Rapa/P31/MPs), via alterations of both innate and adaptive immunity. Ex vivo, adoptively transferred CD4 + T cells exhibit reduced proliferation and an increased ratio of FoxP3 + to IFNγ + T cells. In vitro analysis indicates dendritic cells exhibit a less mature phenotype following coculture with Rapa/P31/MPs, which results in reduced CD4 + T cell proliferation and proinflammatory cytokine production (IFNγ and IL‐2), but promotes PD‐1 expression. Together these results demonstrate Ace‐DEX MP‐based antigen‐specific therapy effectively tolerizes diabetogenic CD4 + T cells to prevent T1D, thereby demonstrating one of the first successful attempts of T1D prevention using a single‐formulation particulate delivery platform.