Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice.

Autor:	Kasinathan D; Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD., Guo Z; Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD., Sarver DC; Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD., Wong GW; Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD., Yun S; Office of Graduate Medical Education, University of Maryland Medical System, Largo, MD., Michels AW; Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO., Yu L; Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO., Sona C; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and Institute for Fundamental Biomedical Research, Johns Hopkins School of Medicine, St. Petersburg, FL., Poy MN; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine and Institute for Fundamental Biomedical Research, Johns Hopkins School of Medicine, St. Petersburg, FL., Golson ML; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD., Fu D; Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2024 May 01; Vol. 73 (5), pp. 806-818.
DOI:	10.2337/db23-0568
Abstrakt:	Type 1 diabetes (T1D) is an autoimmune disease in which pathogenic lymphocytes target autoantigens expressed in 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 could home in on 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 after glucose-stimulated insulin secretion. In vivo administration of mAb43 to NOD mice selectively increased the proportion of regulatory T cells 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 no adverse effects were exhibited 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. (© 2024 by the American Diabetes Association.)
Databáze:	MEDLINE
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