Abstract

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.