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Effects of Autoimmunity and Immune Therapy on ß-Cell Turnover in Type 1 Diabetes

¹ Department of Pediatrics, Division of Pediatric Endocrinology, the Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, New York
² Children’s Hospital of Philadelphia, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
³ Department of Medicine, Division of Endocrinology, Naomi Berrie Diabetes Center, College of Physicians and Surgeons, Columbia University, New York, New York

Address correspondence and reprint requests to Kevan C. Herold, MD, Section of Immunobiology, Yale University, 300 Cedar St., Room S155B, New Haven, CT 06520. E-mail: kevan.herold{at}yale.edu

Abbreviations: BrdU, 5-bromo-2-deoxyuridine; DAPI, 4',6-diamidine-2-phenylindole dihydrochloride; mAb, monoclonal antibody; Treg, regulatory T-cells

ß-Cell mass can expand in response to demand: during pregnancy, in the setting of insulin resistance, or after pancreatectomy. It is not known whether similar ß-cell hyperplasia occurs following immune therapy of autoimmune diabetes, but the clinical remission soon after diagnosis and the results of recent immune therapy studies suggest that ß-cell recovery is possible. We studied changes in ß-cell replication, mass, and apoptosis in NOD mice during progression to overt diabetes and following immune therapy with anti-CD3 monoclonal antibodies (mAbs) or immune regulatory T-cells (Tregs). ß-Cell replication increases in pre-diabetic mice, after adoptive transfer of diabetes with increasing islet inflammation but before an increase in blood glucose concentration or a significant decrease in ß-cell mass. The pathogenic cells are responsible for increasing ß-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. ß-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new ß-cells after immune therapy and increased ß-cell area, but the majority of this increased ß-cell area represents regranulated ß-cells rather than newly produced cells. We conclude that ß-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated ß-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the ß-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain ß-cell mass.

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