Editing NOD mice

'''Non-obese diabetic''' or '''NOD''' [[house mouse|mice]], like the [[Biobreeding rat]], are used as an [[model organism|animal model]] for [[type 1 diabetes]].<ref>{{cite web | title=Non-Obese Diabetic (NOD) Mouse BAC Library | work=National Institute of Allergy and Infectious Diseases | url=http://www.niaid.nih.gov/dait/NODmice.htm | accessdate=2006-05-15}}</ref> Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the [[pancreatic islet]]s.<ref>
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</ref> 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.<ref>Eisenbarth, GS. Type 1 Diabetes: Molecular Cellular and Clinical Immunology. 2004; 552</ref> 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).<ref name="pmid1323922">{{cite journal
|vauthors=Kikutani H, Makino S |title=The murine autoimmune diabetes model: NOD and related strains
|journal=Adv. Immunol.
|volume=51
|issue=
|pages=285–322
|year=1992
|pmid=1323922
|doi=10.1016/S0065-2776(08)60490-3
}}</ref> The NOD strain and related strains were developed at Shionogi Research Laboratories in Aburahi, [[Japan]] by Makino and colleagues and first reported in 1980.<ref name="pmid6995140">{{cite journal
|vauthors=Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y |title=Breeding of a non-obese, diabetic strain of mice
|journal=Jikken Dobutsu
|volume=29
|issue=1
|pages=1–13
|year=1980
|pmid=6995140
|doi=
}}</ref>  The group developed the NOD strain by an outbreeding of the cataract-prone strain from JcI:ICR mice. 
<ref name="">
{{cite journal
|author=Leiter, Edward H
|title=The NOD Mouse: A Model for Analyzing the Interplay Between Heredity and the Environment in the Development of Autoimmune Disease
|journal= ILAR Journal
|volume=35
|issue=1
|pages=4–14
|year=1994
}}</ref>

== 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]].<ref name="pmid18806780">{{cite journal |vauthors=Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV |title=Innate immunity and intestinal microbiota in the development of Type 1 diabetes |journal=Nature |volume=455| issue = =7216 |pages=1109–13 |date=October 2008 |pmid=18806780 |doi=10.1038/nature07336 |pmc=2574766}}</ref>

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.<ref>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</ref><ref>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</ref>

== 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 histocompatibility complex class II loci I-Ag7.<ref>Serreze DV, Leiter EH. Genetic and pathogenic basis of autoimmune diabetes in NOD mice. Curr Opin Immunol. 1994; 6:900-6. PMID 7710714</ref>

NOD mice have polymorphisms in the [[Idd3]] locus which are linked to [[Interleukin 2|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.<ref name="pmid18468463">{{cite journal  |vauthors=Tang Q, Adams JY, Penaranda C, etal |title=Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction |journal=Immunity |volume=28 |issue=5 |pages=687–97 |date=May 2008 |pmid=18468463 |pmc=2394854 |doi=10.1016/j.immuni.2008.03.016 |url=}}</ref>

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.<ref name="pmid:12724780">{{cite journal |author1=Hironori Ueda |author2=Joanna M |author3=M. Howson |title=Association of the T-cell regulatory gene [[CTLA-4]] with susceptibility to autoimmune disease |journal=Nature |volume=423 |date=May 2003 |pmid=12724780 |doi=10.1038/nature01621 |issue=6939 |pages=506–11|display-authors=etal}}</ref>

== References ==
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[[Category:Laboratory mouse strains]]
[[Category:Diabetes]]
[[Category:Population genetics]]