NOD mice

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Non-obese diabetic or NOD mice, like biobreeding rats, 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] 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. [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. The mice (as well as C57BL/6 and SJL) are known to carry IgG2c allele. [4] [5]

Contents

History

Non-obese diabetic (NOD) mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus (IDDM). [6] The NOD strain and related strains were developed at Shionogi Research Laboratories in Aburahi, Japan by Makino and colleagues and first reported in 1980. [7] The group developed the NOD strain by an outbreeding of the cataract-prone strain from JcI:ICR mice. [8]

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. [9]

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. [10] [11]

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. [12]

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. [13]

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. [14]

Related Research Articles

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

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<span class="mw-page-title-main">Resistin</span> Mammalian protein found in Homo sapiens

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Denise Louise Faustman is an American physician and medical researcher. An associate professor of medicine at Harvard University and director of the Immunobiology Laboratory at Massachusetts General Hospital, her work specializes in diabetes mellitus type 1 and other autoimmune diseases. She has worked at Massachusetts General Hospital in Boston since 1985.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when pancreatic cells are destroyed by the body's immune system. In healthy persons, beta cells produce insulin. Insulin is a hormone required by the body to store and convert blood sugar into energy. T1D results in high blood sugar levels in the body prior to treatment. Common symptoms include frequent urination, increased thirst, increased hunger, weight loss, and other complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. While some cases take longer, symptoms usually appear within weeks or a few months.

Slowly evolving immune-mediated diabetes, or latent autoimmune diabetes in adults (LADA), is a form of diabetes that exhibits clinical features similar to both type 1 diabetes (T1D) and type 2 diabetes (T2D), and is sometimes referred to as type 1.5 diabetes. It is an autoimmune form of diabetes, similar to T1D, but patients with LADA often show insulin resistance, similar to T2D, and share some risk factors for the disease with T2D. Studies have shown that LADA patients have certain types of antibodies against the insulin-producing cells, and that these cells stop producing insulin more slowly than in T1D patients. Since many people develop the disease later in life, it is often misdiagnosed as type 2 diabetes.

<span class="mw-page-title-main">CD1D</span> Protein-coding gene in humans

CD1D is the human gene that encodes the protein CD1d, a member of the CD1 family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.

Biobreeding rat, also known as the BB or BBDP rat, is an inbred laboratory rat strain that spontaneously develops autoimmune Type 1 Diabetes. Like the NOD mice, BB rats are used as an animal model for Type 1 diabetes. The strain re-capitulates many of the features of human type 1 diabetes, and has contributed greatly to the research of T1D pathogenesis.

<span class="mw-page-title-main">PD-L1</span> Mammalian protein found in humans

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<span class="mw-page-title-main">Free fatty acid receptor 2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ICA1</span> Gene of the species Homo sapiens

Islet cell autoantigen 1 is a protein that in humans is encoded by the ICA1 gene.

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<span class="mw-page-title-main">Insulitis</span> Medical condition

Insulitis is an inflammation of the islets of Langerhans, a collection of endocrine tissue located in the pancreas that helps regulate glucose levels, and is classified by specific targeting of immune cell infiltration in the islets of Langerhans. This immune cell infiltration can result in the destruction of insulin-producing beta cells of the islets, which plays a major role in the pathogenesis, the disease development, of type 1 and type 2 diabetes. Insulitis is present in 19% of individuals with type 1 diabetes and 28% of individuals with type 2 diabetes. It is known that genetic and environmental factors contribute to insulitis initiation, however, the exact process that causes it is unknown. Insulitis is often studied using the non-obese diabetic (NOD) mouse model of type 1 diabetes. The chemokine family of proteins may play a key role in promoting leukocytic infiltration into the pancreas prior to pancreatic beta-cell destruction.

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<span class="mw-page-title-main">CDKAL1</span> Protein-coding gene in humans

CDKAL1 is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1. This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells. CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.

<span class="mw-page-title-main">Pancreatic islet macrophage</span>

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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 (1997). "The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD". Immunity. 7 (6): 727–38. doi: 10.1016/s1074-7613(00)80392-1 . PMID   9430219.
  3. ↑ Eisenbarth GS (2004). "Type 1 diabetes: molecular, cellular and clinical immunology". Adv Exp Med Biol. 552: 306–10. PMID   15622970.
  4. ↑ Zhang Z, Goldschmidt T, Salter H (March 2012). "Possible allelic structure of IgG2a and IgG2c in mice". Mol Immunol. 50 (3): 169–71. doi:10.1016/j.molimm.2011.11.006. PMID   22177661.
  5. ↑ Fox, James; Anderson, Lynn; Otto, Glen; Corning, Kathleen; Whary, Mark (2015). Laboratory Animal Medicine (3 ed.). Amsterdam: Elsevier Inc (American College of Laboratory Animal Medicine). p. 70. doi:10.1016/B978-0-12-409527-4.00003-1. ISBN   978-0-12-416613-4. OCLC   913513718. S2CID   88753861. ISBN   978-0-12-409527-4.
  6. ↑ Kikutani H, Makino S (1992). "The murine autoimmune diabetes model: NOD and related strains". Adv. Immunol. Advances in Immunology. 51: 285–322. doi:10.1016/S0065-2776(08)60490-3. ISBN   9780120224517. PMID   1323922.
  7. ↑ 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. doi: 10.1538/expanim1978.29.1_1 . PMID   6995140.
  8. ↑ 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. doi: 10.1093/ilar.35.1.4 .
  9. ↑ 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.
  10. ↑ Sadelain MW, Qin HY, Lauzon J, Singh B (1990). "Prevention of type I diabetes in NOD mice by adjuvant immunotherapy". Diabetes. 39 (5): 583–9. doi:10.2337/diabetes.39.5.583. PMID   2139617.
  11. ↑ Qin HY, Sadelain MW, Hitchon C, Lauzon J, Singh B (1993). "Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice". J Immunol. 150 (5): 2072–80. doi: 10.4049/jimmunol.150.5.2072 . PMID   8436836. S2CID   9779509.
  12. ↑ Serreze DV, Leiter EH (1994). "Genetic and pathogenic basis of autoimmune diabetes in NOD mice". Curr Opin Immunol. 6 (6): 900–6. doi:10.1016/0952-7915(94)90011-6. PMID   7710714.
  13. ↑ 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.
  14. ↑ Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. (May 2003). "Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease". Nature. 423 (6939): 506–11. doi: 10.1038/nature01621 . PMID   12724780.
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