Effects of streptozotocin on autoimmune diabetes in NOD mice

Abstract

SUMMARYNon-obese diabetic (NOD) mice develop autoimmunity that destroys their native beta cells causing diabetes. Their autoimmunity will also destroy syngeneic transplanted islets and transfer both autoimmunity and diabetes via spleen cells to non-diabetic mice. In this report, we studied the effects of streptozotocin (STZ) on the autoimmune diabetes in NOD mice. We transplanted NOD.SCID islets into three groups of NOD mice: (1) spontaneously diabetic NOD mice (NOD-sp.); (2) prediabetic NOD mice made diabetic by streptozotocin (NOD-stz); and (3) diabetic NOD mice also treated with streptozotocin (NOD-sp./stz). In the first group, the transplants were rejected within 3 weeks. In the second and third groups, the transplants survived indefinitely. Alloxan, a drug similar to streptozotocin, did not have the same effect as streptozotocin. The ability of streptozotocin to prevent diabetes in young NOD mice was reversed by anti-CD8 antibody treatment but not by anti-CD4 treatment. Streptozotocin also made spleen cells from diabetic NOD mice less effective transferring diabetes. These results indicate that streptozotocin treatment both prevents and reverses the islet destructive autoimmunity in NOD mice. We postulate that the effects of streptozotocin treatment may be mediated in part by regulatory T cells.

Streptozotocin-associated lymphopenia in cynomolgus monkeys

“…22 STZ is a cytotoxic glucose analog that exerts its effects via interaction of its glucose moiety with the GLUT-2 glucose transport protein on pancreatic b-cells. 23 In experimental animals such as mice, highdose STZ (150-200 mg/ kg body weight) causes cellular DNA damage by alkylation or fragmentation of DNA or by generation of nitric oxide, 15 resulting in b-cell death. STZ also targets mitochondrial DNA and impairs mitochondrial function, resulting in inhibition of insulin secretion in response to glucose stimulation.…”

“…11,12 In rodents, STZ has been reported to affect the immune system, being associated with bone marrow suppression, derangements in leukocyte count (leukopenia), and lymphocyte depletion in the blood and spleen, the mechanisms of which are not completely understood. [13][14][15][16] Direct and irreversible damage to the bone marrow and the early precursors of T cells is seen in STZ-treated mice. 17 Levine et al studied the toxicological effects of STZ in mice and in large animals (dogs and rhesus monkeys), and reported necrosis of lymphoid organs, and bone marrow hypoplasia.…”

IDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes

“…Nonetheless, alternative microbial signals, apparently not engaging TLR3, can exert protective effects. Paradoxically, STZ treatment both prevents and reverts islet destructive autoimmunity in NOD mice (59). Considering that TLR9 can be activated also by host unmethylated CpG-containing DNA and non-CpG DNA (46) and that STZ can induce multiple DNA modifications, it might be speculated that the STZ treatment is capable of generating endogenous, regulatory TLR9 ligands.…”

Development of Either Split Tolerance or Robust Tolerance along with Humoral Tolerance to Donor and Third-Party Alloantigens in Nonmyeloablative Mixed Chimeras

“…Nevertheless, the general rate of diabetes was significantly reduced in chimeras, reducing the likelihood that any islet rejection we might observe would be due to autoimmunity. Furthermore, we gave high-dose streptozotocin to induce diabetes in those mixed chimeras that remained nondiabetic before islet transplantation, a treatment that is known to prevent islet autoimmunity in NOD mice (30). Despite the presence of mixed chimerism, NOD chimeras rejected donor islets as rapidly as control nonchimeric NOD mice (Fig.…”