NOD mice

Non-obese diabetic or NOD mice, like the Biobreeding rat, are used as an animal model for type 1 diabetes.[1] Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets.[2] 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. NOD mice will develop spontaneous diabetes when left in a sterile environment. [3] 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.

History

Non-obese diabetic (NOD) mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus (IDDM).[4] The NOD strain and related strains were developed at Shionogi Research Laboratories in Aburahi, Japan by Makino and colleagues and first reported in 1980.[5] The group developed the NOD strain by an outbreeding of the cataract-prone strain from JcI:ICR mice. [6]

Susceptibility

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 linked to Microbiome.[7]

NOD mice are also susceptible to developing other autoimmune syndromes, including autoimmunine sialitis, autoimmune thyroiditis, autoimmune peripheral polyneuropathy etc. Diabetes in these mice can be prevented by a single injection of mycobacterial adjuvants such as complete Freund's adjuvant (FCA) or Bacille de Calmette et Guérin or BCG vaccine.[8][9]

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. The most important is idd1which is the major histocompatibilty complex class II loci I-Ag7.[10]

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.[11]

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.[12]

References

  1. ↑ "Non-Obese Diabetic (NOD) Mouse BAC Library". National Institute of Allergy and Infectious Diseases. Retrieved 2006-05-15.
  2. ↑ Delovitch TL, Singh B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity. 1997; 7:727-38. PMID 9430219
  3. ↑ Eisenbarth, GS. Type 1 Diabetes: Molecular Cellular and Clinical Immunology. 2004; 552
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Leiter, Edward H (1994). "The NOD Mouse: A Model for Analyzing the Interplay Between Heredity and the Environment in the Development of Autoimmune Disease". ILAR Journal 35 (1): 4–14.
  7. ↑ 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.
  8. ↑ Sadelain MW, Qin HY, Lauzon J, Singh B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes. 1990;39:583-9. PMID 2139617
  9. ↑ Qin HY, Sadelain MW, Hitchon C, Lauzon J, Singh B. Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice. J Immunol. 1993;150:2072-80. PMID 8436836
  10. ↑ Serreze DV, Leiter EH. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr Opin Immunol. 1994; 6:900-6. PMID 7710714
  11. ↑ 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.
  12. ↑ 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.


This article is issued from Wikipedia - version of the Saturday, September 26, 2015. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.