Effects of streptozotocin on autoimmune diabetes in NOD mice

Abstract

Non-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.

Fig. 1

The effect of islet transplantation, streptozotocin and alloxan treatment on the development of autoimmunity in NOD mice. Young NOD mice (6–8 weeks) were divided into four groups to study the effect of islet transplantation on the development of diabetes under various conditions. Group 1 NOD mice did not receive islet transplantation (control group) (n = 10) (□); Group 2 animals received islets without any other treatment (n = 10) (⋄); Group 3 NOD mice were treated with STZ and given NOD.SCID islets (n = 22) (○) and Group 4 mice were treated with alloxan and then given NOD.SCID islets (n = 8) (▵). The individual mice in Group 3 are shown in Table 2. Some mice in this group were removed for further experimental manipulation and others were sacrificed at various times for histology.

Fig. 2

(a) Destruction of islet isografts in NOD mice. Light micrograph of NOD.SCID islets transplanted into an NOD-sp. mouse. The specimen was obtained at the time of recurrent diabetes. The graft site shows destructive lymphocytic infiltration of the islet graft (insulin negative; glucagon positive, 200×). (b) Prevention of islet isograft destruction. Light micrograph of NOD.SCID islets transplanted into an NOD-sp./stz mouse. Graft site showing well-preserved intact islets with minimal peri-islet inflammation (insulin-positive cells, 200×). (c) Host pancreas of a diabetic NOD-sp./stz mouse. Light micrograph of streptozotocin-treated pancreas, showing atrophic islets negative for insulin but positive for glucagon. Composite of three representative islets (400×).