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A Microsphere-Based Vaccine Prevents and Reverses New-Onset Autoimmune Diabetes

¹ Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Epic Therapeutics, a wholly owned subsidiary of Baxter Healthcare Corporation, Norwood, Massachusetts
³ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Corresponding author: Nick Giannoukakis, PhD, Department of Pathology, University of Pittsburgh School of Medicine, Diabetes Institute, Rangos Research Center, 3460 Fifth Ave., Pittsburgh, PA 15213. E-mail: ngiann1{at}pitt.edu

Abbreviations: APC, allophycocyanin; AS-MSP, antisense microsphere; FACS, fluorescence-activated cell sorter; HPLC, high-performance liquid chromatography; IFN-, interferon-; IL, interleukin; PE, phycoerythrin; PEG, polyethylene glycol; PLGA, poly-(lactic-co-glycolic acid); PVP, polyvinyl pyrrolidone; SCR-MSP, scrambled control sequences microsphere; TNF-, tumor necrosis factor-; Treg cell, regulatory T-cell

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 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 to determine the prevalence of Foxp3⁺ putative regulatory T-cells (Treg 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 β-cell antigen or 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⁺ Treg cells and induced hyporesponsiveness to NOD-derived pancreatic β-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 after 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 that confers an immunoregulatory phenotype to endogenous dendritic cells.

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