American Diabetes Association
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Cell-surface ZnT8 antibody prevents and reverses autoimmune diabetes in mice

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posted on 2024-02-22, 22:11 authored by Devi Kasinathan, Zheng Guo, Dylan C. Sarver, G. William Wong, Shumei Yun, Aaron W. Michels, Liping Yu, Chandan Sona, Matthew N. Poy, Maria L. Golson, Dax Fu

Type 1 diabetes (T1D) is an autoimmune disease where pathogenic lymphocytes target autoantigens expressed in the pancreatic islets, leading to the destruction of insulin-producing β-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the β-cell surface. This unique molecular target offers the potential to shield β-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 can home in on the pancreatic islets and prevent autoantibodies from recognizing β-cells. This study demonstrates that mAb43 binds to exocytotic sites on the β-cell surface, masking the antigenic exposure of ZnT8 and insulin following glucose-stimulated insulin secretion. In vivo administration of mAb43 to nonobese diabetic (NOD) mice selectively increased the proportion of regulatory T-cells (Tregs) in the islet, resulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation and exhibited no adverse effects during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of β-cells suppresses the immunological cascade from B-cell antigen presentation to T-cell mediated β-cell destruction, providing a novel islet-targeted and antigen-specific immunotherapy to prevent and reverse clinical T1D.


This study was supported by the National Institutes of Health, R01DK125746 (D.F), P30DK116073 (L.Y), R01DK110183 (M.L.G.), R01 DK135688 (M.N.P) and RO1DK084171 (G.W.W). The authors thank Xiaoling Zhang from Ross Flow Cytometry Core, Johns Hopkins University School of Medicine for her assistance in flow cytometry data acquisition and analysis. The Aurora-4L spectral flow cytometer is funded through a National Institutes of Health Grant S10OD026859. The Zeiss confocal microscope was funded through a National Institutes of Health shared instrumentation Grant S10OD016374. Human pancreatic islets (RRID: SAMN34130383) were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) (RRID:SCR _014387) at City of Hope, NIH Grant # U24DK098085.