Predisposing effect of anti-Beta cell autoimmune process in NOD mice on the induction of diabetes by environmental insults

Abstract

In NOD mice, 50-70% of females and 10-20% of males develop diabetes, although almost all the animals show insulitis. To see if environmental insults could induce diabetes in subjects with pre-clinical anti-Beta cell autoimmunity, non-diabetic NOD mice were selected and injected with a sub-diabetogenic dose of streptozotocin at 6 or 20 weeks of age. The streptozotocin failed to induce diabetes in 16 male and 16 female NOD mice within 4 weeks when they were injected at the age of 6 weeks. In contrast, 6 of 16 male and 10 of 16 female NOD mice developed diabetes within 4 weeks when they were injected at the age of 20 weeks. In untreated age-matched control NOD mice, none of the male and only 2 of 16 female mice became diabetic during the same 4 week period. On histotogic examination, the degree of insulitis in streptozotocin-treated NOD mice (at the age of 24 weeks) was not significantly dif-ferent from that of untreated control NOD mice. However, the streptozotocin-treated animals showed significantly lower pancreatic insulin content than the control mice. These results show that an anti-Beta cell autoimmune process in NOD mice has a predisposing effect on the induction of diabetes by a sub-diabetogenic dose of streptozotocin, and suggest that the precipitation of clinical diabetes by some environmental insults in subjects with pre-existing pre-clinical autoimmune Beta-cell destruction may be one mechanism of disease presentation in human Type 1 (insulin-dependent) diabetes.

Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes

“…Treatment with a single subdiabetogenic dose of STZ damages β cells directly with only minimal immune cell involvement (14)(15)(16)(17). While a multiple high-or low-dose regime of STZ leaves the mouse without functional β cells and induces autoimmune diabetes, a single lowdose treatment causes significantly less damage and does not induce clinical disease (14,15,17). During coxsackievirus infection of most mouse strains, limited damage to the β cells is observed.…”

“…Treatment with poly I:C effectively induces type 1 cytokine activation similar to that observed following viral infection (13). Alternatively, administration of a single subdiabetogenic dose of streptozotocin (STZ) directly damages β cells in the pancreatic islets of Langerhans with only minimal immune cell involvement (14)(15)(16)(17). If coxsackievirus induces IDDM through damage to β cells, antigen release, and activation of self-reactive T cells, then treatment of BDC2.5 Tg mice with STZ and not poly I:C should activate the resting anti-islet memory T cells,…”

The Countervailing Actions of Myeloid and Plasmacytoid Dendritic Cells Control Autoimmune Diabetes in the Nonobese Diabetic Mouse

“…11). Islet Ag-loaded macrophages can transfer diabetes, whereas silica-mediated inhibition of macrophages reduces diabetes onset (12)(13)(14)(15). Moreover, macrophages are among the first cell populations to infiltrate the islets and, when fully activated, can mediate cell cytotoxicity against ␤ cells via the production of IFN-␥, TNF-␣, and reactive oxygen intermediates such as NO (16 -18).…”

IDDM in Rats Induced by Thymectomy and Irradiation

“…Diabetes has been induced experimentally in animals with various chemical agents or hormones (5), and chemical agents have been used to enhance or inhibit diabetes expression in spontaneous models (6)(7)(8)(9). In addition, viral agents have been shown to induce diabetes in animals not predisposed to disease inducement (10) and to modify disease expression in NOD mice (11,12) and BB rats (13).…”