Cyclophosphamide-Induced Diabetes in NOD/WEHI Mice: Evidence for Suppression in Spontaneous Autoimmune Diabetes Mellitus

Abstract

Nonobese diabetic (NOD) mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis) that may progress to overt diabetes. Virtually all NOD/WEHI mice develop insulitis, but very few progress to diabetes. However, cyclophosphamide (CY) can promote the onset of diabetes in NOD mice, including the NOD/WEHI strain. The means by which CY produces diabetes was investigated in NOD/WEHI mice, in which it was hypothesized that active suppression mechanisms prevented the progression from insulitis to diabetes. A study of the time course of insulitis in the islets after CY was given showed that insulitis was initially reduced but rapidly increased over 16 days, and T-lymphocytes were predominant in the lesion. This suggested a compression of the normal time course of the disease seen in NOD mice. CY did not produce diabetes in any of 11 non-NOD strains studied. Fetal isografts in NOD mice given CY several days before were subjected to lymphocytic infiltration and β-cell destruction. These findings suggested that CY was not directly (β-cell toxic and that altered β-cells were not essential for β-cell destruction. This was further demonstrated with subdiabetogenic doses of streptozocin, which significantly damaged β-cells but did not increase the severity of insulitis or induce diabetes as did CY. Most important, the transfer of mononuclear cells from nondiabetic NOD mice to mice given CY prevented diabetes, which indicated that the likely effect of CY was via immunomodulation, possibly by allowing poised effector cells to act on (β-cells. The NOD/WEHI mice appear to have suppressor mechanisms acting to halt the progression of the early insulitis lesion and so preventing diabetes occurring in most mice. We propose that CY removes these suppressors and thereby induces a rapid progression to diabetes by compressing the normal immune destruction process into a 2-wk period. This model affords the opportunity to study the process in ways not practicable in the usual time course of events.