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CD19+IgM+ cells demonstrate enhanced therapeutic efficacy in type 1 diabetes mellitus
Andrew D. Vonberg, … , Steven K. Lundy, Massimo Pietropaolo
Andrew D. Vonberg, … , Steven K. Lundy, Massimo Pietropaolo
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e99860. https://doi.org/10.1172/jci.insight.99860.
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Research Article Immunology

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

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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 1

Adoptive transfer of diabetes is significantly delayed in the presence of purified CD19+ cell cotransfers.

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Adoptive transfer of diabetes is significantly delayed in the presence o...
(A) Survival plots for comparison between female NOD.scid mice (n = 44) receiving splenocytes taken from a diabetic NOD female donor (n = 22, dashed line), or the same splenocytes plus bead-purified CD19+ cells from 6-week-old prediabetic NOD female mice (n = 22, solid line). Results analyzed using the Mantel-Cox Log Rank test for survivability (****P < 0.0001). (B) Representative staining of reconstitution after adoptive transfer with CD3 and CD19 markers on splenocytes from NOD.scid transfer recipients. Cells initially gated on CD3+CD19– to illustrate differences in CD4 and CD8 specific T cell populations. (C) Flow analysis of traditional regulatory B cell markers using 6-week-old female NOD, C57BL/6, and Balb/c mice. Splenocytes were gated on CD19+IgM+ cells and then stained for CD5 and CD1d. (D) Intracellular T cell levels after 6 hours of stimulation with PMA and Ionomycin. Splenocytes from NOD.scid recipients following adoptive transfers were analyzed for resulting T cells by gating on CD3+CD4+ and then intracellularly gating on IFN-γ and IL-17A.

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