Targeting B-cells Mitigates Autoimmune Diabetes in NOD Mice: What Is Plan B?

  1. Susan H. Smith and
  2. Thomas F. Tedder
  1. Department of Immunology, Duke University Medical Center, Durham, North Carolina.
  1. Corresponding author: Thomas F. Tedder, thomas.tedder{at}duke.edu.

In this issue of Diabetes, Grey and colleagues (1) demonstrate that therapeutic B-cell depletion delays diabetes onset and reduces diabetes incidence in NOD mice. B-cell depletion in pre-diabetic NOD mice was accomplished using an extended regime of recombinant B-cell maturation antigen (BCMA)-Fc chimerized protein that targets B-lymphocyte stimulator (BLyS)/B-cell–activating factor of the tumor necrosis factor family (BAFF)—a cytokine critical for maintenance of the peripheral B-cell pool. This follows recent studies demonstrating significant effects of B-cell depletion on diabetes onset and severity (25); however, no other studies have reported profound and complete protection from hyperglycemia as observed here. Following B-cell depletion therapy during 9–15 weeks of age, NOD mice remained diabetes free for ≥50 weeks of age, even after B-cell reconstitution. An increase in CD25+Foxp3+CD4+ regulatory T-cells (Tregs) following B-cell depletion may mediate prolonged tolerance given that the CD25 monoclonal antibody (mAb) treatment neutralized the long-term therapeutic benefits of B-cell depletion (Fig. 1). This mechanism may explain why B-cell–deficient NOD.μMT mice do not develop hyperglycemia given that autoimmune diabetes was also precipitated in these mice by Treg depletion.

FIG. 1.

Model for autoantigen presentation in B-cell–depleted NOD mice. Autoantigen presentation is normally balanced between B-cells and dendritic cells (DCs) in mice (16). A: NOD autoantigen presentation. However, B-cell cognate presentation of pancreatic autoantigens may dominate in NOD mice because B-cell selection (17) and innate cell APC function are impaired (18). As a …

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