CD19+IgM+ cells demonstrate enhanced therapeutic efficacy in type 1 diabetes mellitus
Andrew D. Vonberg, Maria Acevedo-Calado, Aaron R. Cox, Susan L. Pietropaolo, Roberto Gianani, Steven K. Lundy, Massimo Pietropaolo
Andrew D. Vonberg, Maria Acevedo-Calado, Aaron R. Cox, Susan L. Pietropaolo, Roberto Gianani, Steven K. Lundy, Massimo Pietropaolo
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Research Article Immunology

CD19+IgM+ cells demonstrate enhanced therapeutic efficacy in type 1 diabetes mellitus

Abstract

We describe a protective effect on autoimmune diabetes and reduced destructive insulitis in NOD.scid recipients following splenocyte injections from diabetic NOD donors and sorted CD19+ cells compared with 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). We found that the CD19+IgM+ cell is the primary subpopulation of B cells that delayed transfer of diabetes mediated by diabetogenic T cells from NOD mice (P = 0.002). Removal of IgM+ cells from the CD19+ pool did not result in protection. Notably, protection conferred by CD19+IgM+ cotransfers were not dependent on the presence of Tregs, as their depletion did not affect their ability to delay onset of diabetes. Blockade of IL-10 with neutralizing antibodies at the time of CD19+ cell cotransfers also abrogated the therapeutic effect, suggesting that IL-10 secretion was an important component of protection. These results were strengthened by ex vivo incubation of CD19+ cells with IL-5, resulting in enhanced proliferation and IL-10 production and equivalently delayed diabetes progression (P = 0.0005). The potential to expand CD19+IgM+ cells, especially in response to IL-5 stimulation or by pharmacologic agents, may be a new therapeutic option for type 1 diabetes.

Authors

Andrew D. Vonberg, Maria Acevedo-Calado, Aaron R. Cox, Susan L. Pietropaolo, Roberto Gianani, Steven K. Lundy, Massimo Pietropaolo

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Figure 3

CD19+ cells cotransferred from 6-week-old NOD donors into NOD.scid recipients leads to decreased islet infiltration.

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CD19+ cells cotransferred from 6-week-old NOD donors into NOD.scid recip...
Representative islets for each group after staining with H&E. Images captured at 40× magnification. (A) Untreated 10-week-old NOD.scid female. (B) Diabetic NOD.scid recipient receiving only splenocytes from a diabetic NOD female donor. (C) Diabetic NOD.scid recipient receiving cotransfers of diabetic splenocytes and CD19+ cells purified from a 6-week-old prediabetic NOD female. (D) Diabetic NOD.scid recipient receiving cotransferred diabetic splenocytes and CD19+ cells from a NOD female mouse older than 15 weeks of age. (E) Insulitis scoring results from pancreatic sections stained with H&E of NOD.scid recipients that received either diabetic splenocytes (n = 9 mice), splenocytes cotransferred with bead-purified CD19+ cells from 6-week-old NOD donors (n = 9 mice), or splenocytes cotransferred with CD19+ cells purified from >15-week-old NOD female donors (n = 8 mice). Islets were individually scored on a 1–4 scale of increasing insulitis severity, and the percentage of each score as a part of the whole was graphically represented. Islets scoring a 1 resulted in P = 0.0051, and islets scoring a 4 resulted in P < 0.0001 when compared using 2 × 2 contingency tables and a χ2 analysis. Serum was collected from NOD.scid recipients receiving either splenocytes from a diabetic NOD donor, diabetic splenocytes and CD19+ cells from 6-week-old NOD donors, or splenocytes from a diabetic NOD donor with CD19+ cells from >15-week-old NOD donors. The presence of (F) IL-1β, (G) TNF-α, (H) IFN-γ, (I) IL-17 was measured by ELISAs across the multiple treatment groups (**P = 0.02).