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Non-obese diabetic transgenic mouse

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Conclusions

Several important conclusions can be drawn from these experiments and are as follows. First, not only the lack of I-E but also the presence of unique I-A are involved in the development of autoimmune insulitis in a NOD mouse. Second, the mechanism of prevention in I-Ak transgenic mice might be different from that in I-E transgenic mice, although the negative selection of autoreactive T cells in thymus has been suggested in I-E transgenic mice. Third, the single amino acid substitution from Asp to Ser at position 57 of the Aβ chain is not sufficient for development of insulitis. Other amino acids including residue 56 of the Aβ chain as well as Aα chain are important in the development of insulitis and diabetes. However, the amino acid at position 57 may be involved in the conformational change of I-A molecule in such a way as to alter the interaction with the T cell receptor, leading to the positive or negative selection of autoreactive T cells. Fourth, the ectopic expression of class II molecules on β cells may not be the initial event for the generation of insulitis.

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References

  1. Acha-Orbea H, McDevitt HO (1987) The first external domain of the nonobese diabetic mouse class II I-A β chain is unique. Proc Natl Acad Sci USA 84: 2435

    Google Scholar 

  2. Allison J, Campbell IL, Morahan TE, Harrison LC, Miller JFAP (1988) Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic β cells. Nature 333: 529

    Google Scholar 

  3. Allison J, Malcolm L, Culvenor J, Bartholomeusz RK, Holmberg K, Miller JFAP (1991) Overexpression of β2-microglobulin in transgenic mouse islet β cells results in defective insulin secretion. Proc Natl Acad Sci USA 88: 2070

    Google Scholar 

  4. Baekkeskov S, Aanstoot H-J, Christogau S, Reetz A, Solimena M, Folli F, Richter-Olesen H, Camilli P-D (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347: 151

    Google Scholar 

  5. Baxevanis CN, Nagy ZA, Klein J (1981) A novel type of T-T cell interaction removes the requirement for I-B region in the H-2 complex. Proc Natl Acad Sci USA 78: 3809

    Google Scholar 

  6. Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates —Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med 166: 823

    Google Scholar 

  7. Bohme J, Stecha P, van Ewijk W, LeMeur M, Gerlinger P, Benoist C, Mathis D (1989) Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant. Science 244: 1179

    Google Scholar 

  8. Bohme J, Schuhbaur B, Kanagawa O, Benoist C, Mathis D (1990) MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science 249: 293

    Google Scholar 

  9. Boitard C, Bendelac A, Richard MF, Carnaud C, Bach JF (1988) Prevention of diabetes in nonobese diabetic mice by anti-I-A monoclonal antibodies: transfer of protection by splenic T cells. Proc Natl Acad Sci USA 85: 9719

    Google Scholar 

  10. Bottazzo GF, Dean BM, McNally JM, MacKay EM, Swift PGF, Gamble DR (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 313: 353

    CAS  PubMed  Google Scholar 

  11. Candeias S, Katz J, Benoist C, Mathis D, Haskins K (1991) Islet-specific T cell clones from nonobese diabetic mice express heterogeneous T-cell receptors. Proc Natl Acad Sci USA 88: 6167

    Google Scholar 

  12. Charlton B, Mandel TE (1988) Progression from insulitis to β-cell destruction in NOD mouse requires L3T4+ T-lymphocytes. Diabetes 37: 1108

    Google Scholar 

  13. Charlton B, Bacelj A, Mandel TE (1988) Administration of silica particles or anti-Lyt 2 antibody prevents b-cell destruction in NOD mice given cyclophophamide. Diabetes 37: 930

    Google Scholar 

  14. Dean BM, Walker R, Bone AJ, Baird JD, Cooke A (1985) Pre-diabetes in the spontaneously diabetic BB/E rat: lymphocyte subpopulations in the pancreatic infiltrate and expression of rat MHC class II molecules in endocrine cells. Diabetologia 28: 464

    Google Scholar 

  15. Formby B, Miller N (1990) Autologous CD4 T-cell responses to ectopic class II major histocompatibility complex antigen-expressing single-cell islet cells: an in vitro insight into the pathogenesis of lymphocytic insulitis in nonobese diabetic mice. Proc Natl Acad Sci USA 87: 2438

    Google Scholar 

  16. Garchon H-J, Bedossa P, Eloy L, Bach J-F (1991) Identification and mapping to chromosome 1 of a susceptibility locus for preinsulitis in non-obese diabetic mice. Nature 353: 260

    Google Scholar 

  17. Germain R, Bently DM, Quill H (1985) Influence of allelic polymorphism on the assembly and surface expression of class II MHC (Ia) molecules. Cell 43: 233

    Google Scholar 

  18. Hanafusa T, Fujino-Kurihara H, Miyazaki A, Yamada K, Nakajima H, Miyagawa J, Kono N, Tarui S (1987) Expression of class II major histocompatibility complex antigens on pancreatic b-cells in the NOD mouse. Diabetologia 30: 104

    Google Scholar 

  19. Haskins K, McDuffie M (1990) Acceleration of diabetes in young NOD mice with a CD4+ isletspecific T cell clone. Science 249: 1433

    Google Scholar 

  20. Hattori M, Buse JB, Jackson RA, Glimcher L, Dorf ME, Minami M, Makino S, Moriwaki K, Kuzuya H, Imura H, Straus WM, Seidman JG, Eisenbarth GS (1986) The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science 231: 733

    Google Scholar 

  21. Kanazawa Y, Komeda K, Sato S, Mori S, Akanuma K, Takaku F (1984) Non-obese-diabetic mice: immune mechanisms of pancreatic beta-cell destruction. Diabetologia 27: 113

    Google Scholar 

  22. Kikutani H, Nakano N, Kurner T, Yamamura K, Nishimoto H, Kishimoto T (1990) Generation and inactivation of autoreactive T cells in NOD and I-E transgenic NOD mice. In: Shafrir E (ed) Frontier in diabetic research: lessons from animal diabetes, vol 3. Smith-Gordon, London, pp 590–593

    Google Scholar 

  23. Koike T, Itoh Y, Ishii T, Ito I, Takabayashi K, Maruyama N, Tomioka H, Yoshida S (1987) Preventive effect of monoclonal anti-L3T4 antibody on development of diabetes in NOD mice. Diabetes 36: 539

    Google Scholar 

  24. Lo D, Burkly LC, Widera G, Cowing C, Flavell RA, Palmiter RD, Brinster RL (1988) Diabetes and tolerance in transgenic mice expressing class II molecules in pancreatic beta cells. Cell 53: 159

    Google Scholar 

  25. Lund T, O'Reilly L, Hutings P, Kanagawa O, Simpson E, Kioussis D, Cooke A (1990) Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain. Nature 345: 727

    Google Scholar 

  26. Makino S, Kunimoto K, Muraoka Y, Katagiri K, Tochino Y (1980) Breeding of a non-obese diabetic strain of mice. Exp Anim 29: 1

    Google Scholar 

  27. Makino S, Muraoka Y, Kishimoto Y, Hayashi Y (1985) Genetic analysis for insulitis in NOD mice. Exp Anim 34: 425

    Google Scholar 

  28. Makino S, Harada M, Kishimoto Y, Hayashi Y (1986) Absence of insulitis and overt diabetes in athymic nude mice with NOD genetic background. Exp Anim 35: 495

    Google Scholar 

  29. Markmann J, Lo D, Naji A, Palmiter RD, Brinster RL, Heber-Katz E (1988) Antigen-presenting function of class II MHC expressing pancreatic beta cells. Nature 336: 476

    Google Scholar 

  30. Miller BJ, Appel MC, O'Neil JJ, Wicker LS (1988) Lyt-2+ and L3T4+ T cell are required for the transfer of diabetes in non-obese diabetic mice. J Immunol 140: 52

    CAS  PubMed  Google Scholar 

  31. Miyazaki T, Uno M, Uehira M, Kikutani H, Kishimoto T, Yamamura K (1990) Direct evidence for the contribution of the unique I-ANOD to the development of insulitis in non-obese diabetic mice. Nature 345: 722

    Google Scholar 

  32. Morahan G, Allison J, Miller JFAP (1989) Tolerance of class I histocompatibility antigens expressed extrathymically. Nature 339: 622

    Google Scholar 

  33. Nagata M, Yokono K, Hayakawa M, Kawase Y, Hatamori N, Ogawa W, Yonezawa K, Shii K, Baba S (1989) Destruction of pancreatic islet cells by cytotoxic T lymphocytes in nonobese diabetic mice. J Immunol 143: 1155

    Google Scholar 

  34. Nakano N, Kikutani H, Nishimoto H, Kishimoto T (1991) T cell receptor V gene usage of islet beta cell-reactive T cells is not restricted in non-obese diabetic mice. J Exp Med 173: 1091

    Google Scholar 

  35. Nishimoto H, Kikutani H, Yamamura K, Kishimoto T (1987) Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 328: 432

    Google Scholar 

  36. Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H (1991) Ablation of tolerance and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65: 305

    Google Scholar 

  37. Oldstone MBA, Nerenberg M, Southern P, Price J, Lewicki H (1991) Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65: 319

    Google Scholar 

  38. Oliveria DBG, Blackwell N, Virchis AE, Axelirod RA (1985) T helper and T suppressor cells are restricted by the A and E molecules, respectively, in the F antigen system. Immunogenetics 22: 169.

    Google Scholar 

  39. Prochazka MEHL, Serreze DV, Coleman DL (1987) Three recessive loci required for insulindependent diabetes in nonobese diabetic mice. Science 237: 286

    CAS  PubMed  Google Scholar 

  40. Pujol-Borrell R, Todd I, Doshi M, Bottazzo GF, Sutton R, Gray D, Adolf GR, Feldmann M (1987) HLA class II induction in human islet cells by interferon-γ plus tumor necrosis factor or lymphotoxin. Nature 326: 304

    Google Scholar 

  41. Roep BO, Arden SD, deVries RRP, Hutton JC (1990) T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature 345: 632

    Google Scholar 

  42. Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA (1988) Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52: 773

    Google Scholar 

  43. Serreze DV, Leiter EH, Worthen SM, Schultz LD (1988) NOD marrow stem cells adoptively transfer diabetes to resistent (NOD X NOD) F1 mice. Diabetes 37: 252

    Google Scholar 

  44. Shizuru JA, Taylor-Edwards C, Banks BA, Gregory AK, Fathmann G (1988) Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science 240: 659

    CAS  PubMed  Google Scholar 

  45. Slattery RM, Kjer-Nielsen L, Allison J, Charlton B, Mandel TE, Miller JFAP (1990) Prevention of diabetes in non-obese diabetic I-Ak transgenic mice. Nature 345: 724

    Google Scholar 

  46. Todd JA, Bell JI, McDevitt HO (1987) HIA-DQβ gene contributes to susceptibility and resistence to insulin-dependent diabetes. Nature 329: 599

    Google Scholar 

  47. Todd JA, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH (1989) Identification of susceptibility loci for insulin-dependent diabetes by trans-racial gene mapping. Nature 338: 587

    Article  CAS  PubMed  Google Scholar 

  48. Todd JA, Aitman TJ, Cornall RJ, Ghosh S, Hall JRS, Hearne CM, Knight AM, Love JM, McAleer MA, Prins J-B, Godgigeus N, Lathrop M, Pressey A, DeLarato NH, Peterson LB, Wicker LS (1991) Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 351: 542

    Google Scholar 

  49. Uehira MMU, Kurner T, Kikutani H, Mori K, Inomoto T, Uede T, Miyazaki J, Nishimoto H, Kishimoto T, Yamamura K (1989) Development of autoimmune insulitis is prevented in Eα but not in Aαk NOD transgenic mice. Int Immunol 1: 209

    Google Scholar 

  50. Wikker LS, Miller BJ, Mullen Y (1986) Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes 35: 855

    CAS  PubMed  Google Scholar 

  51. Yamamura K, Kikutani H, Folsom V, Clayton L, Kimoto M, Akira S, Kashiwamura S, Tonegawa S, Kishimoto T (1985) Functional expression of a microinjected Eαd gene in transgenic mice. Nature 316: 67

    Google Scholar 

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Author notes

  1. Jun-ichi Miyazaki

    Present address: Department of Disease-Related Gene Regulation Research (Saodoz), Faculty of Medicine, The University of Tokyo, Kongo 7-3-1, Bunkyo-ku, 113, Tokyo, Japan

Authors and Affiliations

  1. Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kuhonji, 862, Kumamoto, Japan

    Ken-ichi Yamamura, Toru Miyazaki, Masashi Uno, Tetsushi Toyonaga & Jun-ichi Miyazaki

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Yamamura, Ki., Miyazaki, T., Uno, M. et al. Non-obese diabetic transgenic mouse. Springer Semin Immunopathol 14, 115–125 (1992). https://doi.org/10.1007/BF00195289

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