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A MICROSPHERE-BASED VACCINE PREVENTS AND REVERSES NEW-ONSET AUTOIMMUNE DIABETES

¹Diabetes Institute, Division of Immunogenetics, Dept. Of Pediatrics, University of Pittsburgh School of Medicine, PA USA 15213
²Epic Therapeutics, a wholly-owned subsidiary of Baxter Healthcare Corporation, 220 Norwood Park South, Norwood, MA USA 02062
³Dept. of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA USA, 15213

Objective: This study was aimed at ascertaining the efficacy of antisense oligonucleotide-formulated microspheres to prevent type 1 diabetes and to reverse new-onset disease.

Research Design And Methods: Microspheres carrying antisense oligonucleotides to CD40, CD80 and CD86 were delivered into non-obese diabetic (NOD) mice. Glycemia was monitored to determine disease prevention and reversal. In recipients that remained and/or became diabetes-free, spleen and lymph node T-cells were enriched in order to determine the prevalence of Foxp3+ putative T regulatory cells. Splenocytes from diabetes-free microsphere-treated recipients were adoptively cotransferred with splenocytes from diabetic NOD mice into NOD-scid recipients. Live animal in vivo imaging measured the microsphere accumulation pattern. To rule out nonspecific systemic immunosuppression, splenocytes from successfully-treated recipients were pulsed with beta cell antigen, ovalbumin or cocultured with allogeneic splenocytes.

Results: The microspheres prevented type 1 diabetes and, most importantly, exhibited a capacity to reverse clinical hyperglycemia, suggesting reversal of new onset disease. The microspheres augmented Foxp3⁺ T regulatory cells, induced hyporesponsiveness to NOD-derived pancreatic beta cell antigen, without compromising global immune responses to alloantigens and nominal antigens. T-cells from successfully-treated mice suppressed adoptive transfer of disease by diabetogenic splenocytes into secondary immunodeficient recipients. Finally, microspheres accumulated within the pancreas and the spleen following either intraperitoneal or subcutaneous injection. Dendritic cells from spleen of the microsphere-treated mice exhibit decreased cell surface CD40, CD80 and CD86.

Conclusions: This novel microsphere formulation represents the first diabetes-suppressive and reversing nucleic acid vaccine which confers an immunoregulatory phenotype to endogenous dendritic cells.

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