A Microsphere-Based Vaccine Prevents and Reverses New-Onset Autoimmune Diabetes
| Autor: | Janet Knox, Jo Harnaha, Debra Lafreniere, Kenneth Hogeland, Karen Nylander, Brett E. Phillips, Massimo Trucco, Michael Gallo, Jennifer Machen, Nick Giannoukakis, Robert Lakomy, Alexis Styche, Kimberly A. Gillis, Larry Brown |
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| Rok vydání: | 2008 |
| Předmět: |
Blood Glucose
Adoptive cell transfer T-Lymphocytes Endocrinology Diabetes and Metabolism Spleen Lymphocyte Activation medicine.disease_cause Antibodies Article Autoimmunity Mice Immune system Antigen Mice Inbred NOD Internal Medicine Animals Insulin Medicine CD40 Antigens NOD mice CD40 biology business.industry FOXP3 Oligonucleotides Antisense Microspheres Mice Inbred C57BL Diabetes Mellitus Type 1 medicine.anatomical_structure Immunology B7-1 Antigen biology.protein Female B7-2 Antigen business |
| Zdroj: | Diabetes. 57:1544-1555 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db07-0507 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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