Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes
- Paolo Fiorina12,
- Andrea Vergani12,
- Shirine Dada1,
- Mollie Jurewicz1,
- Masie Wong1,
- Kenneth Law3,
- Erxi Wu4,
- Ze Tian4,
- Reza Abdi1,
- Indira Guleria1,
- Scott Rodig3,
- Kyri Dunussi-Joannopoulos5,
- Jeffrey Bluestone6 and
- Mohamed H. Sayegh1
- 1Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- 2Department of Medicine, San Raffaele Scientific Institute, Milan, Italy
- 3Department of Pathology, Division of Hematopathology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts
- 4Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts
- 5Inflammation, Wyeth Research, Cambridge, Massachusetts
- 6University of California San Francisco Diabetes Center, San Francisco, California
- Corresponding author: Mohamed H. Sayegh, msayegh{at}rics.bwh.harvard.edu
Abstract
OBJECTIVES—To investigate a B-cell–depleting strategy to reverse diabetes in naïve NOD mice.
RESEARCH DESIGN AND METHODS—We targeted the CD22 receptor on B-cells of naïve 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.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 8 August 2008.
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- Accepted July 29, 2008.
- Received March 27, 2008.
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