Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice.
ABSTRACT In the NOD mouse, an autoimmune process beginning by 5 weeks of age with lymphocyte infiltration and destruction of insulin-secreting beta cells leads to overt diabetes which begins to appear by 11 weeks of age. Although there is a high incidence of insulitis by 10 weeks of age (greater than 80%) in both males and females, by 30 weeks of age diabetic symptoms have occurred in 53-80% of females and in 12-40% of males. Intraperitoneal injection of a high dose (200 mg/kg) of cyclophosphamide (CY) consistently induces the onset of diabetes in male and female NOD mice at an age when spontaneous diabetes rarely occurs. Spleen T cells from CY-induced diabetic mice are capable of transferring the disease into irradiated nondiabetic syngeneic recipients. This indicates that the diabetogenic effect of CY is not mediated by direct toxicity on pancreatic beta cells but is mediated by abrogation of a suppressor mechanism which may prevent activation of T cells responsible for the development of diabetes in the NOD mouse. Additionally, CY is only effective in NOD mice and not in F1 hybrids between NOD and other strains of mice. Thus, the potential beta cell aggressor mechanism is not present in these hybrids as it is in homozygous mice, which indicates that it is not under the control of dominant genes.
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ABSTRACT: Infection of DBA 2 male mice with the M variant of encephalomyocarditis virus resulted in a diabetes-like syndrome. Histologic examination of the pancreas revealed damage to the beta cells with little involvement of the acinar cells. The severity of the hyperglycemia correlated closely with the degree of beta cell damage. By immunofluorescence, viral antigens could be detected in the beta cells during the first 10 days of the infection. In contrast to the response found in male DBA 2 mice, infection of DBA 2 female mice and male mice of several other strains resulted in little if any elevation of blood glucose concentration. Histologic examination of the pancreas of these animals revealed only minimal damage to the beta cells. It is concluded that differences in the severity of the hyperglycemia between DBA 2 males and females and among the different strains of male mice tested are directly related to the degree of beta cell damage produced by the viral infection.American Journal Of Pathology 05/1974; 75(1):91-102. · 4.52 Impact Factor
- American Journal Of Pathology 04/1975; 78(3):537-40. · 4.52 Impact Factor
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ABSTRACT: Encephalomyocarditis virus (EMC) induces diabetes in certain inbred strains of mice by infecting and destroying pancreatic beta cells, the severity of the diabetes depending on the number of beta cells destroyed. In strains of mice resistant to EMC-induced diabetes, insufficient beta cells are damaged to alter glucose homeostasis. However, diabetes can be produced in many species by streptozotocin, a highly specific beta-cell toxin. Here, we used concentrations of streptozotocin that did not produce diabetes, but reduced the beta-cell reserve. When strains of mice normally resistant to EMC-induced diabetes were first treated with sub-diabetogenic doses of streptozotocin, then infected with EMC virus, diabetes developed. Furthermore, when mice were infected with viruses such as Coxsackie B3 and B5, which ordinarily produce little if any beta-cell damage, diabetes developed if the mice were first treated with sub-diabetogenic doses of streptozotocin. These findings suggest that diabetes may result from cumulative beta-cell damage induced by sequential environmental insults.Nature 12/1980; 288(5789):383-5. · 38.60 Impact Factor