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Diabetes Publish Ahead of Print published online ahead of print August 8, 2008
DOI: 10.2337/db08-0420
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Original Research

Targeting CD22 reprograms B cells and reverses autoimmune diabetes

Paolo Fiorina, MD, PhD1,2, Andrea Vergani, MD1,2, Shirine Dada, MD1, Mollie Jurewicz, BA1, Masie Wong, BS1, Kenneth Law, BS3, Erxi Wu, PhD4, Ze Tian, PhD4, Reza Abdi, MD1, Indira Guleria, PhD1, Scott Rodig, MD, PhD3, Kyri Dunussi-Joannopoulos, MD, PhD5, Jeffrey Bluestone, PhD6, and Mohamed H. Sayegh, MD1

1Transplantation Research Center (TRC), Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, USA
2Medicine, San Raffaele Scientific Institute, Milan, Italy
3Department of Pathology, Division of Hematopathology, Brigham & Women's Hospital
4Children's Hospital Informatics Program at the Harvard–MIT Division of Health Sciences and Technology, Boston, USA
5Inflammation, Wyeth Research, Cambridge, MA 02140
6University of California San Francisco (UCSF) Diabetes Center, San Francisco, CA

Rationale: A B cell-depleting strategy to reverse diabetes has not been fully investigated in naïve NOD mice.

Objectives: We targeted the CD22 receptor on B cells of naïve NOD mice to deplete and reprogram B cells to effectively reverse autoimmune diabetes.

Findings: Anti-CD22/cal mAb therapy resulted in early and prolonged B cell depletion and delayed disease in prediabetic 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, as well as a diminished immune response to islet peptides in vitro. Trascriptome analysis of re-emerging B cells showed significant changes of a set of pro-inflammatory genes. Functionally, re-emerging B cells failed to present autoantigen and prevented diabetes when co-transferred 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.

Correspondence: msayegh{at}rics.bwh.harvard.edu


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