CD19⁺IgM⁺ Cells from NOD Mice Demonstrate Enhanced Therapeutic Efficacy in Type 1 Diabetes Mellitus

We describe a protective effect on autoimmune diabetes and a reduced destructive insulitis in NOD.scid recipients following splenocyte injections from diabetic NOD donors and sorted CD19⁺ cells compared to NOD.scid recipients receiving splenocytes alone. This protective effect was age-specific (only CD19⁺ cells from young NOD donors exerted this effect; p < 0.001). Furthermore, we found that CD19⁺IgM⁺ cells is the primary cell subpopulation of B cells that delayed adoptive transfer of diabetes mediated by diabetogenic T cells from NOD mice (p = 0.002). In fact, removal of IgM⁺ cells from the CD19⁺ pool did not result in diabetes protection. Blockade of IL-10 with neutralizing antibodies at the time of CD19⁺ cell co-transfers also abrogated the therapeutic effect, suggesting that IL-10 secretion was an important component of the protective effect. These results were strengthened by ex vivo incubation of CD19⁺ cells with IL-5, which resulted in enhanced IL-10 production and significantly delayed diabetes progression compared to controls (p = 0.0005). To the best of our knowledge, this is the first study demonstrating that CD19⁺IgM⁺ cells is the primary cell subpopulation of regulatory B cells delaying diabetes mediated by diabetogenic T cells from NOD mice. The potential to expand CD19⁺IgM⁺ cells, especially in response to increased stimulation using IL-5 or by pharmacologic agents, may be a new therapeutic option for type 1 diabetes.