NOD mice
{{Short description|Strain of mice genetically prone to developing diabetes}}
Non-obese diabetic or NOD mice, like biobreeding rats, are used as an animal model for type 1 diabetes.{{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 | access-date=2006-05-15}} Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets.{{cite journal | author = Delovitch TL, Singh B | year = 1997 | title = The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD | journal = Immunity | volume = 7 | issue = 6 | pages = 727–38 | pmid = 9430219 | doi=10.1016/s1074-7613(00)80392-1| doi-access = free }} The onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycemia. 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.{{cite book | vauthors = Eisenbarth GS | title = Type 1 diabetes: molecular, cellular and clinical immunology | series = Adv Exp Med Biol | volume = 552 | pages = 306–10 | date = 2004 | pmid = 15622970 }} 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 mice (as well as C57BL/6 and SJL) are known to carry IgG2c allele.{{cite journal | vauthors = Zhang Z, Goldschmidt T, Salter H | title = Possible allelic structure of IgG2a and IgG2c in mice | journal = Mol Immunol | volume = 50 | issue = 3 | pages = 169–71 | date = March 2012 | pmid = 22177661 | doi = 10.1016/j.molimm.2011.11.006 }}{{cite book | year=2015 | edition=3 | page=70 | publication-place=Amsterdam | first5=Mark | first1=James | first4=Kathleen | first2=Lynn | last1=Fox | first3=Glen | last4=Corning | last2=Anderson | last3=Otto | publisher=Elsevier Inc (American College of Laboratory Animal Medicine) | last5=Whary | oclc=913513718 | doi=10.1016/B978-0-12-409527-4.00003-1 | id={{isbn|978-0-12-409527-4}} | isbn=978-0-12-416613-4 | title=Laboratory Animal Medicine | s2cid=88753861 }}
History
Non-obese diabetic (NOD) mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus (IDDM).{{cite book
|vauthors=Kikutani H, Makino S |chapter=The Murine Autoimmune Diabetes Model: NOD and Related Strains
|title=Advances in Immunology Volume 51
|volume=51
|pages=285–322
|year=1992
|pmid=1323922
|doi=10.1016/S0065-2776(08)60490-3
|isbn=9780120224517
}} The NOD strain and related strains were developed at Shionogi Research Laboratories in Aburahi, Japan by Makino and colleagues and first reported in 1980.{{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=10.1538/expanim1978.29.1_1
|doi-access=free
}} The group developed the NOD strain by an outbreeding of the cataract-prone strain from JcI:ICR mice.
{{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
|doi=10.1093/ilar.35.1.4
|doi-access=free
}}
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. The incidence of disease is linked to the microbiome.{{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|bibcode=2008Natur.455.1109W }}
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 (BCG) vaccine.{{cite journal | vauthors = Sadelain MW, Qin HY, Lauzon J, Singh B | year = 1990 | title = Prevention of type I diabetes in NOD mice by adjuvant immunotherapy | journal = Diabetes | volume = 39 | issue = 5 | pages = 583–9 | pmid = 2139617 | doi=10.2337/diabetes.39.5.583}}{{cite journal | vauthors = Qin HY, Sadelain MW, Hitchon C, Lauzon J, Singh B | year = 1993 | title = Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice | journal = J Immunol | volume = 150 | issue = 5 | pages = 2072–80 | doi = 10.4049/jimmunol.150.5.2072 | pmid = 8436836 | s2cid = 9779509 | doi-access = free }}
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 idd1 which is the major histocompatibility complex class II loci I-Ag7.{{cite journal | vauthors = Serreze DV, Leiter EH | year = 1994 | title = Genetic and pathogenic basis of autoimmune diabetes in NOD mice | journal = Curr Opin Immunol | volume = 6 | issue = 6 | pages = 900–6 | pmid = 7710714 | doi = 10.1016/0952-7915(94)90011-6 }}
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.{{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 }}
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.{{cite journal | vauthors = Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Rønningen KS, Guja C, Ionescu-Tîrgovişte C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC |display-authors=6| title = Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease | journal = Nature | volume = 423 | issue = 6939 | pages = 506–11 | date = May 2003 | pmid = 12724780 | doi = 10.1038/nature01621 | doi-access = free|bibcode=2003Natur.423..506U}}