Prevention of type I diabetes in nonobese diabetic mice by virus infection

Abstract

The nonobese diabetic (NOD) mouse is an animal model of type I diabetes and develops a characteristic autoimmune lesion in the islets of Langerhans with lymphocytic infiltration and destruction of pancreatic beta cells. The result is hypoinsulinemia, hyperglycemia, ketoacidosis, and death. Diabetes usually begins by the sixth month of age but can occur earlier when young NOD mice are infused with lymphocytes from older NOD donors. When newborn or adult NOD mice were infected with a lymphotropic virus they did not become diabetic. The interaction between viruses and lymphocytes is pivotal in aborting diabetes, as established by experiments in which lymphocytes from virus-infected donors failed to transfer diabetes. In contrast, lymphocytes from age- and sex-matched uninfected donors caused disease. Therefore, viruses and, presumably, their products can be developed to be beneficial and may have potential as a component for treatment of human diseases. Further, these results point to the utility of viruses as probes for dissecting the pathogenesis of a nonviral disease.

Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease

“…1988;Coleman et al, 1990) and exposure to pathogens (Oldstone, 1988;Leiter, 1990), Here we show that it is possible to induce diabetes in relatively resistant animals at a rate indistinguishable from fully predisposed individuals. These experiments throw little light on the mechanism of resistance to diabetes in the NOD/Wehi mice.…”

“…STZ is a broad spectrum antibiotic with diabetogenic properties mediated by direct (i cell cytotoxicity (Rakieten, Rakieten & Nadkarni, 1963). Five daily i.p.…”

“…Since their description in 1980, many colonies have been established throughout the world, and maintained in separate breeding programmes. In addition to this potential genetic heterogeneity, NOD mice are profoundly affected by environmental variables such as diet (Elliott, et al, 1988;Scott, Daneman & Martin, 1988;Coleman, Kuzava & Leiter 1990) and exposure to pathogens (Oldstone, 1988;Leiter, 1990). As a result, the incidence of diabetes in different lines varies greatly (Colony Information Sheets, 1989).…”

Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference?

“…61 LCMV is a natural occurring rodent virus that interestingly has been demonstrated to block the development of T1D in the NOD mouse. 62 Similarly, secondary infection of RIP-LCMV-NP mice at a time when the autoimmune destruction of the b-cells was already ongoing (i.e., 4 weeks post-LCMV infection) with a LCMV strain that predominantly replicates outside of the pancreas abrogated the destructive process. 5 It was found that the increased inflammation at the auxiliary site attracts aggressive CD8 T cells along a CXCL10 gradient and causes activationinduced cell death.…”

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

“…Additionally, various pathogens can protect NOD mice from disease, including viruses such as Coxsackie B and lymphocytic choriomeningitis virus [93,101], and parasites such as Schistosoma mansoni or only the eggs [102], and Trichinella spiralis or Heligmosomoides polygyrus [103]. Finally, bacteria in the gut play an important role in the development of diabetes.…”