Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes.
beta-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 beta-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 beta-cell recovery is possible. We studied changes in beta-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). beta-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 beta-cell mass. The pathogenic cells are responsible for increasing beta-cell replication because replication was reduced during diabetes remission induced by anti-CD3 mAb or Tregs. beta-Cell replication stimulated by the initial inflammatory infiltrate results in increased production of new beta-cells after immune therapy and increased beta-cell area, but the majority of this increased beta-cell area represents regranulated beta-cells rather than newly produced cells. We conclude that beta-cell replication is closely linked to the islet inflammatory process. A significant proportion of degranulated beta-cells remain, at the time of diagnosis of diabetes, that can recover after metabolic correction of hyperglycemia. Correction of the beta-cell loss in type 1 diabetes will, therefore, require strategies that target both the immunologic and cellular mechanisms that destroy and maintain beta-cell mass.
Sherry
Nicole A
NA
Section of Immunobiology, Yale University, 300 Cedar St., Room S155B, New Haven, CT 06520, USA.
Kushner
Jake A
JA
Glandt
Mariela
M
Kitamura
Tadahiro
T
Brillantes
Anne-Marie B
AM
Herold
Kevan C
KC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis; D015551:Autoimmunity; D017252:CD3 Complex / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D007167:Immunotherapy; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex