eNews April 01, 2015

Using NOD/LtJ males in diabetes research

The NOD mouse is the most genetically defined system for studying insulin-dependent diabetes mellitus (IDDM), type 1diabetes. Increases in funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Foundation have definitively increased the demand for NOD/LtJ mice (Stock No. 001976) and related strains (e.g. NON/LtJ, NOR/LtJ, and NOD/LtSz-Prkdcscid/J, and NOD mice congenic for IDDM-resistant MHC haplotypes).

• NOD/LtJ females are more widely used than males because the onset of IDDM symptoms occurs earlier and with a higher incidence (90-100% by 30 weeks of age). However, NOD/LtJ males can be particularly useful for certain applications described in this article.

• NOD/LtJ males develop IDDM at a frequency of between 40-60% by 30-40 weeks of age. The fact that diabetes progression is more protracted in NOD males makes them very useful to assess the presence of diabetogenic catalysts in the microbial or dietary environment that can precipitate IDDM.

 •NOD/LtJ males are also useful in pharmaceutical studies. Because of the more protracted rate of diabetogenesis in NOD males, a longer window of time is available for testing pharmaceutical or environmental agents that repress the disease process. In NOD/LtJ females, leukocyte accumulation in and around pancreatic islets begins as early as 3 weeks, with precipitous declines in pancreatic insulin levels and development of overt hyperglycemia evident by 12 weeks of age.

The early development of insulitis in females leaves little time to manipulate the course of disease by the time purchased female mice are received then acclimated to a new vivarium. In this regard, NOD/LtJ males also offer an advantage as recipients in islet transplantation studies. Note: NOD/LtSz-Prkdcscid/J males are ideal syngeneic islet donors for transplantation studies into male recipients since they are free of T- and B-lymphocyte infiltrates.

• NOD/LtJ males may be used for "accelerated transfer" of IDDM. Young, pre-diabetic irradiated males may be used as hosts in adoptive transfer experiments by intravenously or intraperitoneally injecting populations of leukocytes or purified T lymphocytes from diabetic or pre-diabetic donor NOD mice.

Please note: splenic leukocytes from female donors should not be transferred into male recipients because female T lymphocytes will respond to male sex-limited (H-Y) antigen. However, syngeneic T cell lines and clones without anti-H-Y specificities can be used in accelerated transfer studies into males.

• NOD/LtJ males are as useful as NOD/LtJ females for some in vitro studies. For example, immune functions of leukocyte subpopulations (e.g. macrophages or B-lymphocytes) isolated from NOD/LtJ males generally show the same deficiencies as those from females.

SELECTED REVIEWS

Leiter EH. 1998. NOD mice and related strains: research applications in diabetes, AIDS, cancer, and other diseases. In: Medical Intelligence Unit, Leiter EH, Atkinson MA (eds), Landes, Austin, pp. 208.

Leiter EH. 1997. The NOD mouse: a model for insulin-dependent diabetes mellitis. Current Protocols in Immunology 24(Suppl):15.9.1-15.9.23.

Serreze DV, Leiter EH. 1995. Insulin-dependent diabetes mellitus in NOD mice and BB rats: origins in hematopoietic stem cell defects and implications for therapy. In: Lessons From Animal Diabetes, Shafrir E (ed), Smith Gordon Press, pp. 59-73.

Serreze DV, Leiter EH. 1994. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr Opin Immunol 6:900-906.