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-celldepleted 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 ϩ T-cells into NOD.SCID hosts. Most individuals affected by type 1 diabetes exhibit multiple features associated with impaired B-cell function, including autoantibodies against a variety of islet cell antigens (6,7). Data from different groups using NOD mice, the best animal model for the study of type 1 diabetes, have confirmed the importance of B-cells in the onset of diabetes (2-4,8,9). NOD mice that are deficient in B-cells have been shown to be protected from autoimmune diabetes (3,10,11) and are deficient in the development of a T-cell response to major autoantigens (such as 65-kDa glutamate decarboxylase) (3,10,11). In humans, the production of autoantibodies to islet antigens is well documented as an early indicator of disease onset (12). These observations render B-cell targeting a particularly attractive and novel strategy for the treatment of type 1 diabetes (13-15). Unfortunately, this strategy has not been fully described in naïve NOD mice. Only recently did a publication show the positive effects of an anti-CD20 -based B-cell-depleting strategy in transgenic NOD mice expressing the humanized CD20 receptor on B-cells (8). Interestingly, use of B-cell depletion as a therapy for human autoimmune disease (16 -20), including in patients with new-onset type 1 diabetes, is ongoing (21,22). CONCLUSIONS-TargetingWe made use of a newly developed reagent (anti-CD22 calicheamicin-conjugated monoclonal antibody [anti-CD22/cal mAb]) that efficiently depletes mature B-cells in mice (13) to establish a therapeutic approach for type 1 diabetes. Our main hypothesis was that depleting B-cells by targeting CD22 should prevent diabetes onset and restore normoglycemia in newly hyperglycemic NOD mice. Furthermore, we hypothesize that our approach will generate a pool of reemerging B-cells that may function to regulate the autoimmune response in vivo, establishing a state of long-term tolerance toward autoantigens. RESEA...

Innate pro–B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells

“…Surprisingly, follicular B cells, MZ B cells, and T2-MZP-Bs largely prevailed among the suppressive CpG-proB progeny in NOD recipients. Notably, tolerogenic properties of T2-MZP-Bs have been abundantly reported in several experimental models of autoimmune diseases (23,24,(54)(55)(56)(57).…”

TCR Bias of In Vivo Expanded T Cells in Pancreatic Islets and Spleen at the Onset in Human Type 1 Diabetes

“…B cells are good candidate APCs in this scenario. Several groups have reported their role in disease progression and B cell deletion protects NOD mice from diabetes (45,46). B cells are efficient presenters of peptides derived from the Ag recognized by the BCR, as proposed by GAD65 presentation in mouse and human T1D (47,48).…”

Antibody combination therapy targeting CD25, CD70 and CD8 reduces islet inflammation and improves glycaemia in diabetic mice

“…CD70 and CD25 are expressed on activated T and B cells, suggesting that these specific antibodies may target both cell populations. As recent data emphasize the importance of both B cells [25][26][27] and T cells [28] in autoimmune diabetes, this antibody combination may result in strong, synergistic effects on the key cells involved in disease pathology. There are other reagents with promising therapeutic potential, such as CD154-specific antibody and rapamycin, which could be used as single therapeutics or as part of a combination therapy [29,30].…”