Non-obese diabetic (NOD) mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus (IDDM). The NOD strain and related strains were developed at Shionogi Research Laboratories in Aburahi, Japan by Makino and colleagues and first reported in 1980. The group developed the NOD strain by selecting cataract-prone strains. The strain was then established by inbreeding.
Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. Onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycaemia. It is recommended to monitor for development of glycosuria from 10 weeks of age; this can be carried out using urine glucose dipsticks. The incidence of spontaneous diabetes in the NOD mouse is 60-80% in females and 20-30% in males. Onset of diabetes also varies between males and females: commonly, onset is delayed in males by several weeks.
The susceptibility to IDDM is polygenic and environment exerts a strong effect on gene penetrances. Environment including housing conditions, health status, and diet all affect development of diabetes in the mice. For instance, NOD mice maintained in different laboratories can have different levels of incidence. Interestingly, the incidence of disease is much higher if the mice are maintained in a relatively germ-free environment.
NOD mice are also susceptible to developing other autoimmune syndromes, including autoimmunine sialitis, autoimmune thyroiditis, autoimmune peripheral polyneuropathy, a systemic lupus erythematosus-like disease that develops if mice are exposed to killed mycobacterium, and prostatitis.
Identifying IDDM susceptibility loci
Genetic Loci associated with susceptibility to IDDM have been identified in the NOD mouse strain through the development of congenic mouse strains, which have identified several insulin dependent diabetes (Idd) loci.
NOD mice have polymorphisms in the Idd3 locus which are linked to IL-2 production. IL-2 promotes either immunity or tolerance in a concentration dependent fashion by acting on T helper cells, CTL and NK cells. Low amounts of IL-2 may be needed to promote survival of Treg in mice. Loss of IL-2 can thereby contribute to the development of autoimmunity in NOD mice.
NOD mice have a mutation in exon 2 of the CTLA-4 gene, which causes it to be spliced incorrectly. CTLA-4 plays a major role in suppressing the T-cell immune response. Without the proper functioning of CTLA-4 T-cells attack the insulin producing cells. This results in Type 1 Diabetes.
- "Non-Obese Diabetic (NOD) Mouse BAC Library". National Institute of Allergy and Infectious Diseases. Retrieved 2006-05-15.
- Kikutani H, Makino S (1992). "The murine autoimmune diabetes model: NOD and related strains". Adv. Immunol. 51: 285–322. doi:10.1016/S0065-2776(08)60490-3. PMID 1323922.
- Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y (1980). "Breeding of a non-obese, diabetic strain of mice". Jikken Dobutsu 29 (1): 1–13. PMID 6995140.
- Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV (October 2008). "Innate immunity and intestinal microbiota in the development of Type 1 diabetes". Nature 455 (7216): 1109–13. doi:10.1038/nature07336. PMC 2574766. PMID 18806780.
- Tang Q, Adams JY, Penaranda C, et al. (May 2008). "Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction". Immunity 28 (5): 687–97. doi:10.1016/j.immuni.2008.03.016. PMC 2394854. PMID 18468463.
- Hironori Ueda, Joanna M, M. Howson et al. (May 2003). "Association of the T-cell regulatory gene CTLA-4 with susceptibility to autoimmune disease". Nature 423 (6939): 506–11. doi:10.1038/nature01621. PMID 12724780.