Journal
DIABETES
Volume 57, Issue 11, Pages 3013-3024Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db08-0420
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Funding
- American Society of Transplantation (AST)
- Juvenile Diabetes Research Foundation (JDRF) [4-2007-1065]
- National Institutes of Health (NIH) [PO1-AI-41521, P50-NS-40828, P30-HD-18655]
- Scott and Heidi Schuster Foundation
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OBJECTIVES-To investigate a B-cell-depleting strategy to reverse diabetes in naive NOD mice. RESEARCH DESIGN AND METHODS-We targeted the CD22 receptor on B-cells of naive NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune diabetes. RESULTS-Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-cell-depleted mice became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells failed to present autoantigen and prevented diabetes when cotransferred with autoreactive CD4(+) T-cells into NOD.SCID hosts. CONCLUSIONS-Targeting CD22 depletes and reprograms B-cells and reverses autoimmune diabetes, thereby providing a blueprint for development of novel therapies to cure autoimmune diabetes. Diabetes 57:3013-3024, 2008
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