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. 2004 Aug 23;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X

Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma

Nora Sarvetnick , Denny Liggitt , Sharon L Pitts , Stanley E Hansen , Timothy A Stewart
PMCID: PMC7133464  PMID: 2449974

Abstract

We have produced transgenic mouse strains harboring class II major histocompatibility complex or interferon-gamma genes linked to the human insulin promoter. These experiments were designed to investigate the consequences of the expression of immunological effector molecules by nonimmunological cells. In both of these studies we observed the disappearance from the pancreas of the insulin-producing β cells coinciding with the development of insulin-dependent diabetes mellitus. Transgenic mice expressing both chains of the I-A gene showed progressive atrophy of the islets of Langerhans, whereas mice expressing interferon-gamma suffered an inflammatory destruction of the islets.

References

  1. Acha-Orbea H., McDevitt H.O. Vol. 84. 1987. The first external domain of the nonobese diabetic mouse class II I-A β chain is unique; pp. 2435–2439. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adams E.E., Alpert S., Hanahan D. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature. 1987;325:223–228. doi: 10.1038/325223a0. [DOI] [PubMed] [Google Scholar]
  3. Bendtzen K., Mandrup-Poulsen T., Nerup J., Nielsen J.H., Dinarello C.A., Svenson M. Cytotoxicity of human pl7 interleukin-1 for pancreatic islets of Langerhans. Science. 1986;232:1545–1547. doi: 10.1126/science.3086977. [DOI] [PubMed] [Google Scholar]
  4. Bhattacharya A., Dorf M.E., Springer T.A. A shared alloantigenic determinant on la antigens encoded by the I-A and I-E subregions evidence for I refions gene duplication. J. Immunol. 1981;127:2488–2495. [PubMed] [Google Scholar]
  5. Bottazzo G.F., Pujol-Borrell R., Hanfusa T. Hypothesis: role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet. 1983;ii:1115–1119. doi: 10.1016/s0140-6736(83)90629-3. [DOI] [PubMed] [Google Scholar]
  6. Bottazzo G.F., Dean B.M., McNally J.M., MacKay E.H., Swift P.G.F., Gamble D.R. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. New Eng. J. Med. 1985;313:353–360. doi: 10.1056/NEJM198508083130604. [DOI] [PubMed] [Google Scholar]
  7. Bucchini D., Ripoche M.-A., Stinnakre M.-G., Desbois P., Lores P., Monthioux E., Absil J., Lepesant J.-A., Pictet R., Jami J. Vol. 83. 1986. Pancreatic expression of human insulin gene in transgenic mice; pp. 2511–2515. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Campbell I.L., Wong G.W.H., Schrader J.W., Harrison L.C. Interferon-gamma enhances the expression of the mahor histocompatibility class I antigens on mouse pancreatic beta cells. Diabetes. 1985;34:1205–1209. doi: 10.2337/diab.34.11.1205. [DOI] [PubMed] [Google Scholar]
  9. Campbell I.L., Bizilj K., Colman P.G., Tuch B.E., Harrison L.C. Interferon-γ induces the expression of HLA-A,B,C but not HLA-DR on human pancreatic β-cells. J. Clin. Endocrin. Metab. 1986;62:1101–1109. doi: 10.1210/jcem-62-6-1101. [DOI] [PubMed] [Google Scholar]
  10. Chirgwin J.M., Przbyia A.E., MacDonald R.J., Rutter W.J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979;18:5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  11. Choi E., McIntyre K., Germain R.N., Seidman J.G. Murine I-Aβ chain polymorphism: nucleotides sequences of three allelic I-Aβ genes. Science. 1983;221:283–286. doi: 10.1126/science.6407114. [DOI] [PubMed] [Google Scholar]
  12. Davignon D., Martz E., Reynolds T., Kurzinger K., Springer T.A. Vol. 78. 1981. Lymphocyte function-associated antigen 1 (LFA-1): a surface antigen distinct from Lyt-2,3 that participates in T lymphocyte-mediated killing; pp. 4535–4539. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Eisenbarth G.S. Type I diabetes mellitus: a chronic autoimmune disease. New Engl. J. Med. 1986;314:1360–1368. doi: 10.1056/NEJM198605223142106. [DOI] [PubMed] [Google Scholar]
  14. Estess P., Begovich A.B., Koo M., Jones P.P., McDevitt H.O. Vol. 83. 1986. Sequence analysis and structure-function correlates of mutine k, u, s, and f haplotype I-Aβ cDNA clones; pp. 3594–3598. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Figari I.S., Mori N.A., Palladino M.A., Jr. Regulation of neutrophil migration and superoxide production by recombinant neutrophil migration and superoxide production by recombinant tumor necrosis factors-α and β: comparison to recombinant interferon-γ and interleukin-1α. Blood. 1987;70:979–984. [PubMed] [Google Scholar]
  16. Foulis A.K., Farquharson M.A. Aberrant expression of HLA-DR antigens by insulin-containing β-cells in recent-onset type I diabetes mellitus. Diabetes. 1986;35:1215–1224. doi: 10.2337/diab.35.11.1215. [DOI] [PubMed] [Google Scholar]
  17. Foulis A.K., Farquharson M.A., Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in Type I (insulin-dependent) diabetes mellitus. Diabetologia. 1987;30:333–343. doi: 10.1007/BF00299027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gepts W., LeCompte P.M. The pathology of type (juvenile) diabetes. In: Volk B.W., Arguilla E.R., editors. The Diabetic Pancreas. Plenum; New York: 1985. pp. 337–365. [Google Scholar]
  19. Germain R.N., Malissen B. Analysis of the expression and function of class-II major histocompatibility complex-encoded molecules by DNA-mediated gene transfer. Annu. Rev. Immunol. 1986;4:281–315. doi: 10.1146/annurev.iy.04.040186.001433. [DOI] [PubMed] [Google Scholar]
  20. Gray P.W., Goeddel D.V. Vol. 80. 1983. Cloning and expression of murine immune interferon cDNA; pp. 5842–5846. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hanahan D. Heritable formation of pancreatic β-cell tumors in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985;315:115–122. doi: 10.1038/315115a0. [DOI] [PubMed] [Google Scholar]
  22. Hanafusa T., Pujol-Borrell R., Chiovato L., Russell R.C.G., Doniach D., Bottazzo G.F. Aberrant expression of HLA-DR antigen on thyrocytes in Graves disease: relevance for autoimmunity. Lancet. 1983;ii:1111–1115. doi: 10.1016/s0140-6736(83)90628-1. [DOI] [PubMed] [Google Scholar]
  23. Lechler R.I., Norcross M.A., Germain R.N. Qualitative and quantitative studies of antigen-presenting cell function by using I-A-expressing L cells. J. Immunol. 1985;135:2292–2914. [PubMed] [Google Scholar]
  24. Le Meur M., Gerlinger P., Benoist C., Mathis D. Correcting an immune-response deficiency by creating Eα gene transgenic mice. Nature. 1985;316:38–42. doi: 10.1038/316038a0. [DOI] [PubMed] [Google Scholar]
  25. Londei M., Lamb J.R., Bottazzo G.F., Feldmann M. Epithelial cells expressing aberrant MHC class II determinants can present antigen to cloned human T cells. Nature. 1984;312:639–641. doi: 10.1038/312639a0. [DOI] [PubMed] [Google Scholar]
  26. Londei M., Bottazzo G.F., Feldmann M. Human T-cell clones from autoimmune thyroid glands: specific recognition of autologous thyroid cells. Science. 1985;228:85–89. doi: 10.1126/science.3871967. [DOI] [PubMed] [Google Scholar]
  27. Malissen M., Hunkapiller T., Hood L. Nucleotide sequence of a light chain gene of the mouse I-A subregion, Aβd. Science. 1983;221:750–754. doi: 10.1126/science.6410508. [DOI] [PubMed] [Google Scholar]
  28. Malissen B., Peele Price M., Goverman J.M., McMillan M., White J., Kappler J., Marrack P., Pierres A., Pierres M., Hood L. Gene transfer of H-2 class II genes: antigen presentation by mouse fibroblast and hamster B-cell lines. Cell. 1984;36:319–327. doi: 10.1016/0092-8674(84)90225-3. [DOI] [PubMed] [Google Scholar]
  29. Nomikos I.N., Prowse S.J., Carotenuto P., Lafferty K.J. Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice. Diabetes. 1986;35:1302–1304. doi: 10.2337/diab.35.11.1302. [DOI] [PubMed] [Google Scholar]
  30. Nocross M.A., Bentley D.M., Margulies D.H., Germain R.N. Membrane la expression and antigen-presenting accessory cell function of L-cells transfected with class II major histocompatibility genes. J. Exp. Med. 1984;160:1316–1337. doi: 10.1084/jem.160.5.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pinkert C.A., Widera G., Cowing C., Heber-Katz E., Palmiter R.D., Flavell R.A., Brinster R.L. Tissue-specific, inducible and functional expression of the Eαd MHC class II gene in transgenic mice. EMBO J. 1985;4:2225–2230. doi: 10.1002/j.1460-2075.1985.tb03918.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Prowse S.J., Lafferly K.J., Nonikos I.N., Carotenuto P. The pathogenesis of spontaneous diabetes. Ann. Inst. Pasteur/Immunology. 1986;137:459–462. [Google Scholar]
  33. Pujol-Borrell R., Todd I., Doshi M., Gray D., Feldmann M., Bottazzo G.F. Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas. Clin. Exp. Immunol. 1986;65:128–139. [PMC free article] [PubMed] [Google Scholar]
  34. Pujol-Borrell R., Londei M., Foulis A., Feldmann M., Bottazzo G.F. Inappropriate major histocompability complex class II expression by thyroid folliclar cells in thyroid autoimmune disease and by pancreatic beta cells in type I diabetes. Mol. Biol. Med. 1986;3:159–165. [PubMed] [Google Scholar]
  35. Pujol-Borrell R., Todd I., Doshi M., Bottazzo G.F., Sutton R., Gray D., Adolf G.R., Feldmann M. HLA class II induction in human inset cells by interferon-γ plus tumor necrosis factor or lymphotoxi. Nature. 1987;326:304–306. doi: 10.1038/326304a0. [DOI] [PubMed] [Google Scholar]
  36. Quinn P., Barros C., Whittingham D.G. Preservation of hamster oocytes to assay the fertilizing capacity of human spermatozoa. J. Reprod. Fertil. 1982;66:161–168. doi: 10.1530/jrf.0.0660161. [DOI] [PubMed] [Google Scholar]
  37. Robbins S.L., Cotran R.S., Kumar V. Saunders; Philadelphia: 1984. Pathologic Basis of Disease; pp. 61–68. [Google Scholar]; Robbins S.L., Cotran R.S., Kumar V. Saunders; Philadelphia: 1984. Pathologic Basis of Disease; pp. 171–176. [Google Scholar]
  38. Rosa F., Fellous M. The effect of γ-interferon on MHC antigens. Immunology Today. 1984;5:261–262. doi: 10.1016/0167-5699(84)90135-X. [DOI] [PubMed] [Google Scholar]
  39. Rossini A.A., Mordes J.P., Like A.A. Immunology of insulin-dependent diabetes mellitus. Annu. Rev. Immunol. 1985;3:289–320. doi: 10.1146/annurev.iy.03.040185.001445. [DOI] [PubMed] [Google Scholar]
  40. Selden R.F., Skoskiewicz M.J., Howie K.B., Russell P.S., Goodman H.M. Regulation of human insulin gene expression in transgenic mice. Nature. 1986;321:525–528. doi: 10.1038/321525a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Suzumura A., Lavi E., Weiss S.R., Silberberg D.H. Coronavirus infection induces H-2 antigen expression on oligodendrocytes and astrocytes. Science. 1986;232:991–993. doi: 10.1126/science.3010460. [DOI] [PubMed] [Google Scholar]
  42. Tishon A., Oldstone M.B.A. Persistent virus infection associated with chemical manifestations of diabetes. Am. J. Pathol. 1987;126:61–72. [PMC free article] [PubMed] [Google Scholar]
  43. Todd J.A., Bell J.I., McDevitt H.O. HLA-DQβ gene conttibutes to susceptability and resistance to insulin-dependent diabetes mellitus. Nature. 1987;329:599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]
  44. Tsymimoto M., Yokota S., Vilcek J., Weissman G. Tumor necrosis provoked superoxide anion generation from neutrophils. Biochem. Biophys. Res. Commun. 1986;137:1094–1100. doi: 10.1016/0006-291x(86)90337-2. [DOI] [PubMed] [Google Scholar]
  45. Ullrich A., Dull T.J., Gray A., Brosius J., Sures I. Genetic variation in the human insulin gene. Science. 1980;209:612–615. doi: 10.1126/science.6248962. [DOI] [PubMed] [Google Scholar]
  46. Ullrich A., Dull T.J., Gray A., Philips J.A., Peter S. Variation in the sequence and modification state of the human insulin gene flanking regions. Nucl. Acids Res. 1982;10:2225–2240. doi: 10.1093/nar/10.7.2225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Unanue E.R. Antigen-presenting function of the macriphage. Annu. Rev. Immunol. 1984;2:395–428. doi: 10.1146/annurev.iy.02.040184.002143. [DOI] [PubMed] [Google Scholar]
  48. Walden P., Nagy Z.A., Klein J. Induction of regulatory T-lymphocyte responses by liposomes carrying major histocompatibility complex molecules and foreign antigen. Nature. 1985;315:327–329. doi: 10.1038/315327a0. [DOI] [PubMed] [Google Scholar]
  49. Watts T.H., Brian A.A., Kappler J.W., Marracj P., McConnell H.M. Vol. 81. 1984. Antigen presentation by supported planar membranes containing affinity-purified I-Ad; pp. 7564–7568. (Proc. Natl. Acad. Sci. USA). [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wright J.R., Lacy P.E., Unanue E.R., Muszynski C., Hauptfeld V. Interferon-mediated induction of la antigen expression on isolated murine whole islets and dispersed islet cells. Diabetes. 1986;35:1174–1177. doi: 10.2337/diab.35.10.1174. [DOI] [PubMed] [Google Scholar]
  51. Yamamura K.I., Kikutani H., Folson V., Clayton L.K., Kimoto M., Akira S., Kashiwamura S., Tonegawa S., Kishimoto T. Functional expression of a microinjected Eαd gene in C57BL/6 transgenic mice. Nature. 1985;316:67–69. doi: 10.1038/316067a0. [DOI] [PubMed] [Google Scholar]

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