Pancreatic beta-cell destruction in non-obese diabetic mice.

We determined the natural history of the widespread pancreatic islet β-cell destruction that precedes the onset of spontaneous putative autoimmune diabetes mellitus in NOD mice. For this purpose, we performed both histological and immunocytochemical examinations of pancreata retrieved from mice at 2 through 30 weeks of age. An overexpression of la antigens was identified on islet β cells at 4 weeks of age, without evidence of mononuclear cell infiltration. The abnormal expression of la antigens was age-related and was associated with hyperexpression of class I antigens and progressive islet cell histologic damage after 17 weeks of age. Immunocytochemical examination of islet cell infiltrate showed that the number of macrophages did not increase during the early phase of islet cell damage in these mice. The L3T4 Lyt-2 ratio increased after 7 weeks of age, but was 1:1 in the late stage of insulitis. These findings suggest that widespread islet β-cell destruction is a process that begins primarily with derangements of the pancreatic β-cell immune pattern, which may trigger a mononuclear cell reaction.