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. 1994 Nov 1;180(5):1705–1713. doi: 10.1084/jem.180.5.1705

Resistance alleles at two non-major histocompatibility complex-linked insulin-dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect nonobese diabetic mice from diabetes

PMCID: PMC2191746  PMID: 7964456

Abstract

Development of diabetes in NOD mice is polygenic and dependent on both major histocompatibility complex (MHC)-linked and non-MHC-linked insulin-dependent diabetes (Idd) genes. In (F1 x NOD) backcross analyses using the B10.H-2g7 or B6.PL-Thy1a strains as the outcross partner, we previously identified several non-MHC Idd loci, including two located on chromosome 3 (Idd3 and Idd10). In the current study, we report that protection from diabetes is observed in NOD congenic strains having B6.PL-Thy1a- or B10-derived alleles at Idd3 or Idd10. It is important to note that only partial protection is provided by two doses of the resistance allele at either Idd3 or Idd10. However, nearly complete protection from diabetes is achieved when resistance alleles are expressed at both loci. Development of these congenic strains has allowed Idd3 to be localized between Glut2 and D3Mit6, close to the Il2 locus.

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Selected References

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  1. Acha-Orbea H., McDevitt H. O. The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2435–2439. doi: 10.1073/pnas.84.8.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atkinson M. A., Kaufman D. L., Campbell L., Gibbs K. A., Shah S. C., Bu D. F., Erlander M. G., Tobin A. J., Maclaren N. K. Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet. 1992 Feb 22;339(8791):458–459. doi: 10.1016/0140-6736(92)91061-c. [DOI] [PubMed] [Google Scholar]
  3. Bain S. C., Prins J. B., Hearne C. M., Rodrigues N. R., Rowe B. R., Pritchard L. E., Ritchie R. J., Hall J. R., Undlien D. E., Ronningen K. S. Insulin gene region-encoded susceptibility to type 1 diabetes is not restricted to HLA-DR4-positive individuals. Nat Genet. 1992 Nov;2(3):212–215. doi: 10.1038/ng1192-212. [DOI] [PubMed] [Google Scholar]
  4. Chesnut K., She J. X., Cheng I., Muralidharan K., Wakeland E. K. Characterizations of candidate genes for IDD susceptibility from the diabetes-prone NOD mouse strain. Mamm Genome. 1993;4(10):549–554. doi: 10.1007/BF00361383. [DOI] [PubMed] [Google Scholar]
  5. Cornall R. J., Prins J. B., Todd J. A., Pressey A., DeLarato N. H., Wicker L. S., Peterson L. B. Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1. Nature. 1991 Sep 19;353(6341):262–265. doi: 10.1038/353262a0. [DOI] [PubMed] [Google Scholar]
  6. Dietrich W., Katz H., Lincoln S. E., Shin H. S., Friedman J., Dracopoli N. C., Lander E. S. A genetic map of the mouse suitable for typing intraspecific crosses. Genetics. 1992 Jun;131(2):423–447. doi: 10.1093/genetics/131.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ghosh S., Palmer S. M., Rodrigues N. R., Cordell H. J., Hearne C. M., Cornall R. J., Prins J. B., McShane P., Lathrop G. M., Peterson L. B. Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet. 1993 Aug;4(4):404–409. doi: 10.1038/ng0893-404. [DOI] [PubMed] [Google Scholar]
  8. Haskins K., McDuffie M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science. 1990 Sep 21;249(4975):1433–1436. doi: 10.1126/science.2205920. [DOI] [PubMed] [Google Scholar]
  9. Hattori M., Buse J. B., Jackson R. A., Glimcher L., Dorf M. E., Minami M., Makino S., Moriwaki K., Kuzuya H., Imura H. The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science. 1986 Feb 14;231(4739):733–735. doi: 10.1126/science.3003909. [DOI] [PubMed] [Google Scholar]
  10. Hänninen A., Jalkanen S., Salmi M., Toikkanen S., Nikolakaros G., Simell O. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest. 1992 Nov;90(5):1901–1910. doi: 10.1172/JCI116067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Itoh N., Hanafusa T., Miyazaki A., Miyagawa J., Yamagata K., Yamamoto K., Waguri M., Imagawa A., Tamura S., Inada M. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest. 1993 Nov;92(5):2313–2322. doi: 10.1172/JCI116835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Julier C., Hyer R. N., Davies J., Merlin F., Soularue P., Briant L., Cathelineau G., Deschamps I., Rotter J. I., Froguel P. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature. 1991 Nov 14;354(6349):155–159. doi: 10.1038/354155a0. [DOI] [PubMed] [Google Scholar]
  13. Kaufman D. L., Clare-Salzler M., Tian J., Forsthuber T., Ting G. S., Robinson P., Atkinson M. A., Sercarz E. E., Tobin A. J., Lehmann P. V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993 Nov 4;366(6450):69–72. doi: 10.1038/366069a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kikutani H., Makino S. The murine autoimmune diabetes model: NOD and related strains. Adv Immunol. 1992;51:285–322. doi: 10.1016/s0065-2776(08)60490-3. [DOI] [PubMed] [Google Scholar]
  15. Lund T., O'Reilly L., Hutchings P., Kanagawa O., Simpson E., Gravely R., Chandler P., Dyson J., Picard J. K., Edwards A. Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature. 1990 Jun 21;345(6277):727–729. doi: 10.1038/345727a0. [DOI] [PubMed] [Google Scholar]
  16. Makino S., Muraoka Y., Kishimoto Y., Hayashi Y. Genetic analysis for insulitis in NOD mice. Jikken Dobutsu. 1985 Oct;34(4):425–431. doi: 10.1538/expanim1978.34.4_425. [DOI] [PubMed] [Google Scholar]
  17. Miller B. J., Appel M. C., O'Neil J. J., Wicker L. S. Both the Lyt-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol. 1988 Jan 1;140(1):52–58. [PubMed] [Google Scholar]
  18. Miyazaki T., Uno M., Uehira M., Kikutani H., Kishimoto T., Kimoto M., Nishimoto H., Miyazaki J., Yamamura K. Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. Nature. 1990 Jun 21;345(6277):722–724. doi: 10.1038/345722a0. [DOI] [PubMed] [Google Scholar]
  19. Nepom G. T. A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes. 1990 Oct;39(10):1153–1157. doi: 10.2337/diab.39.10.1153. [DOI] [PubMed] [Google Scholar]
  20. Nishimoto H., Kikutani H., Yamamura K., Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. 1987 Jul 30-Aug 5Nature. 328(6129):432–434. doi: 10.1038/328432a0. [DOI] [PubMed] [Google Scholar]
  21. Podolin P. L., Pressey A., DeLarato N. H., Fischer P. A., Peterson L. B., Wicker L. S. I-E+ nonobese diabetic mice develop insulitis and diabetes. J Exp Med. 1993 Sep 1;178(3):793–803. doi: 10.1084/jem.178.3.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Prins J. B., Todd J. A., Rodrigues N. R., Ghosh S., Hogarth P. M., Wicker L. S., Gaffney E., Podolin P. L., Fischer P. A., Sirotina A. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice. Science. 1993 Apr 30;260(5108):695–698. doi: 10.1126/science.8480181. [DOI] [PubMed] [Google Scholar]
  23. Prochazka M., Leiter E. H., Serreze D. V., Coleman D. L. Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science. 1987 Jul 17;237(4812):286–289. doi: 10.1126/science.2885918. [DOI] [PubMed] [Google Scholar]
  24. Prochazka M., Serreze D. V., Worthen S. M., Leiter E. H. Genetic control of diabetogenesis in NOD/Lt mice. Development and analysis of congenic stocks. Diabetes. 1989 Nov;38(11):1446–1455. doi: 10.2337/diab.38.11.1446. [DOI] [PubMed] [Google Scholar]
  25. Risch N., Ghosh S., Todd J. A. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Sep;53(3):702–714. [PMC free article] [PubMed] [Google Scholar]
  26. Rodrigues N. R., Cornall R. J., Chandler P., Simpson E., Wicker L. S., Peterson L. B., Todd J. A. Mapping of an insulin-dependent diabetes locus, Idd9, in NOD mice to chromosome 4. Mamm Genome. 1994 Mar;5(3):167–170. doi: 10.1007/BF00352349. [DOI] [PubMed] [Google Scholar]
  27. Roep B. O., Arden S. D., de Vries R. R., Hutton J. C. T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature. 1990 Jun 14;345(6276):632–634. doi: 10.1038/345632a0. [DOI] [PubMed] [Google Scholar]
  28. Rotella C. M., Dotta F., Mannucci E., Di Mario U. Autoantigens in thyroid and islet autoimmunity: similarities and differences. Autoimmunity. 1992;12(3):223–237. doi: 10.3109/08916939209148463. [DOI] [PubMed] [Google Scholar]
  29. Slattery R. M., Kjer-Nielsen L., Allison J., Charlton B., Mandel T. E., Miller J. F. Prevention of diabetes in non-obese diabetic I-Ak transgenic mice. Nature. 1990 Jun 21;345(6277):724–726. doi: 10.1038/345724a0. [DOI] [PubMed] [Google Scholar]
  30. Srikanta S., Ganda O. P., Rabizadeh A., Soeldner J. S., Eisenbarth G. S. First-degree relatives of patients with type I diabetes mellitus. Islet-cell antibodies and abnormal insulin secretion. N Engl J Med. 1985 Aug 22;313(8):461–464. doi: 10.1056/NEJM198508223130801. [DOI] [PubMed] [Google Scholar]
  31. Tisch R., Yang X. D., Singer S. M., Liblau R. S., Fugger L., McDevitt H. O. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993 Nov 4;366(6450):72–75. doi: 10.1038/366072a0. [DOI] [PubMed] [Google Scholar]
  32. Tochino Y. The NOD mouse as a model of type I diabetes. Crit Rev Immunol. 1987;8(1):49–81. [PubMed] [Google Scholar]
  33. Todd J. A., Aitman T. J., Cornall R. J., Ghosh S., Hall J. R., Hearne C. M., Knight A. M., Love J. M., McAleer M. A., Prins J. B. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. doi: 10.1038/351542a0. [DOI] [PubMed] [Google Scholar]
  34. Wicker L. S., Appel M. C., Dotta F., Pressey A., Miller B. J., DeLarato N. H., Fischer P. A., Boltz R. C., Jr, Peterson L. B. Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes. J Exp Med. 1992 Jul 1;176(1):67–77. doi: 10.1084/jem.176.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wicker L. S., Miller B. J., Coker L. Z., McNally S. E., Scott S., Mullen Y., Appel M. C. Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J Exp Med. 1987 Jun 1;165(6):1639–1654. doi: 10.1084/jem.165.6.1639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wicker L. S., Miller B. J., Fischer P. A., Pressey A., Peterson L. B. Genetic control of diabetes and insulitis in the nonobese diabetic mouse. Pedigree analysis of a diabetic H-2nod/b heterozygote. J Immunol. 1989 Feb 1;142(3):781–784. [PubMed] [Google Scholar]
  37. Wicker L. S., Miller B. J., Mullen Y. Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes. 1986 Aug;35(8):855–860. doi: 10.2337/diab.35.8.855. [DOI] [PubMed] [Google Scholar]

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