Targeting CD22 reprograms B-cells and reverses autoimmune diabetes.

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.

• Authors: Paolo Fiorina, Andrea Vergani, Shirine Dada, Mollie Jurewicz, Masie Wong, Kenneth Law, Erxi Wu, Ze Tian, Reza Abdi, Indira Guleria, Scott Rodig, Kyri Dunussi-Joannopoulos, Jeffrey Bluestone, Mohamed H Sayegh
• Journal: Diabetes (Diabetes) Vol. 57 Issue 11 Pg. 3013-24 (Nov 2008) ISSN: 1939-327X [Electronic] United States
• PMID: 18689692 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• CD4 Antigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2 Receptor alpha Subunit
• Sialic Acid Binding Ig-like Lectin 2

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• B-Lymphocytes (cytology, immunology)
• CD4 Antigens (immunology)
• Diabetes Mellitus, Type 1 (drug therapy, immunology)
• Forkhead Transcription Factors (immunology)
• Interleukin-2 Receptor alpha Subunit (immunology)
• Lymph Nodes (drug effects, immunology)
• Mice
• Mice, Inbred NOD
• Pancreas (drug effects, immunology)
• Prediabetic State (immunology)
• Sialic Acid Binding Ig-like Lectin 2 (immunology)