Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2016, Article ID 7959060, 8 pages
http://dx.doi.org/10.1155/2016/7959060
Research Article

An HLA-Transgenic Mouse Model of Type 1 Diabetes That Incorporates the Reduced but Not Abolished Thymic Insulin Expression Seen in Patients

1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
2Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY 10461, USA

Received 5 August 2015; Accepted 4 October 2015

Academic Editor: Roberto Mallone

Copyright © 2016 Jeffrey Babad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. Pociot, B. Akolkar, P. Concannon et al., “Genetics of type 1 diabetes: what's next?” Diabetes, vol. 59, no. 7, pp. 1561–1571, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. F. Cucca, R. Lampis, M. Congia et al., “A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins,” Human Molecular Genetics, vol. 10, no. 19, pp. 2025–2037, 2001. View at Publisher · View at Google Scholar · View at Scopus
  3. J. A. Todd, J. I. Bell, and H. O. McDevitt, “HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus,” Nature, vol. 329, no. 6140, pp. 599–604, 1987. View at Publisher · View at Google Scholar
  4. M. Fennessy, K. Metcalfe, G. A. Hitman et al., “A gene in the HLA class I region contributes to susceptibility to IDDM in the finnish population,” Diabetologia, vol. 37, no. 9, pp. 937–944, 1994. View at Publisher · View at Google Scholar · View at Scopus
  5. M. C. Honeyman, L. C. Harrison, B. Drummond, P. G. Colman, and B. D. Tait, “Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease,” Molecular Medicine, vol. 1, no. 5, pp. 576–582, 1995. View at Google Scholar · View at Scopus
  6. J. M. M. Howson, N. M. Walker, D. Clayton, and J. A. Todd, “Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A,” Diabetes, Obesity and Metabolism, vol. 11, supplement 1, pp. 31–45, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Nakanishi, T. Kobayashi, T. Murase, T. Naruse, Y. Nose, and H. Inoko, “Human leukocyte antigen-A24 and -DQA10301 in Japanese insulin-dependent diabetes mellitus: independent contributions to susceptibility to the disease and additive contributions to acceleration of β-cell destruction,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 10, pp. 3721–3725, 1999. View at Google Scholar · View at Scopus
  8. S. Nejentsev, J. M. Howson, N. M. Walker et al., “Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A,” Nature, vol. 450, no. 7171, pp. 887–892, 2007. View at Google Scholar
  9. S. Nejentsev, H. Reijonen, B. Adojaan et al., “The effect of HLA-B allele on the IDDM risk defined by DRB104 subtypes and DQB10302,” Diabetes, vol. 46, no. 11, pp. 1888–1892, 1997. View at Publisher · View at Google Scholar · View at Scopus
  10. J. A. Noble, A. M. Valdes, T. L. Bugawan, R. J. Apple, G. Thomson, and H. A. Erlich, “The HLA class I A locus affects susceptibility to type 1 diabetes,” Human Immunology, vol. 63, no. 8, pp. 657–664, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. J. A. Noble, A. M. Valdes, M. D. Varney et al., “HLA class I and genetic susceptibility to type 1 diabetes: results from the type 1 diabetes genetics consortium,” Diabetes, vol. 59, no. 11, pp. 2972–2979, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. D. T. Robles, G. S. Eisenbarth, T. Wang et al., “Identification of children with early onset and high incidence of anti-islet autoantibodies,” Clinical Immunology, vol. 102, no. 3, pp. 217–224, 2002. View at Publisher · View at Google Scholar · View at Scopus
  13. B. D. Tait, P. G. Colman, G. Morahan et al., “HLA genes associated with autoimmunity and progression to disease in type 1 diabetes,” Tissue Antigens, vol. 61, no. 2, pp. 146–153, 2003. View at Publisher · View at Google Scholar · View at Scopus
  14. T. P. Di Lorenzo, M. Peakman, and B. O. Roep, “Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes,” Clinical & Experimental Immunology, vol. 148, no. 1, pp. 1–16, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. S. T. Bennett, A. M. Lucassen, S. C. L. Gough et al., “Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus,” Nature Genetics, vol. 9, no. 3, pp. 284–292, 1995. View at Publisher · View at Google Scholar · View at Scopus
  16. G. I. Bell, S. Horita, and J. H. Karam, “A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus,” Diabetes, vol. 33, no. 2, pp. 176–183, 1984. View at Publisher · View at Google Scholar · View at Scopus
  17. G. A. Hitman, A. C. Tarn, R. M. Winter et al., “Type 1 (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome 11,” Diabetologia, vol. 28, no. 4, pp. 218–222, 1985. View at Publisher · View at Google Scholar · View at Scopus
  18. S. T. Bennett, A. J. Wilson, F. Cucca et al., “IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus,” Journal of Autoimmunity, vol. 9, no. 3, pp. 415–421, 1996. View at Publisher · View at Google Scholar · View at Scopus
  19. P. Vafiadis, S. T. Bennett, J. A. Todd et al., “Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus,” Nature Genetics, vol. 15, no. 3, pp. 289–292, 1997. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Pugliese, M. Zeller, A. Fernandez Jr. et al., “The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes,” Nature Genetics, vol. 15, no. 3, pp. 293–297, 1997. View at Publisher · View at Google Scholar · View at Scopus
  21. I. Durinovic-Belló, R. P. Wu, V. H. Gersuk, S. Sanda, H. G. Shilling, and G. T. Nepom, “Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin,” Genes and Immunity, vol. 11, no. 2, pp. 188–193, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. J. P. Driver, D. V. Serreze, and Y.-G. Chen, “Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease,” Seminars in Immunopathology, vol. 33, no. 1, pp. 67–87, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. B. M. Wentworth, I. M. Schaefer, L. Villa-Komaroff, and J. M. Chirgwin, “Characterization of the two nonallelic genes encoding mouse preproinsulin,” Journal of Molecular Evolution, vol. 23, no. 4, pp. 305–312, 1986. View at Publisher · View at Google Scholar · View at Scopus
  24. A. A. Chentoufi and C. Polychronakos, “Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes,” Diabetes, vol. 51, no. 5, pp. 1383–1390, 2002. View at Publisher · View at Google Scholar · View at Scopus
  25. V. L. Heath, N. C. Moore, S. M. Parnell, and D. W. Mason, “Intrathymic expression of genes involved in organ specific autoimmune disease,” Journal of Autoimmunity, vol. 11, no. 4, pp. 309–318, 1998. View at Publisher · View at Google Scholar · View at Scopus
  26. M. Nakayama, N. Babaya, D. Miao, K. Sikora, J. F. Elliott, and G. S. Eisenbarth, “Thymic expression of mutated B16:a preproinsulin messenger RNA does not reverse acceleration of NOD diabetes associated with insulin 2 (thymic expressed insulin) knockout,” Journal of Autoimmunity, vol. 25, no. 3, pp. 193–198, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. J.-M. Pléau, A. Esling, S. Geutkens, M. Dardenne, and F. Homo-Delarche, “Pancreatic hormone and glutamic acid decarboxylase expression in the mouse thymus: a real-time PCR study,” Biochemical and Biophysical Research Communications, vol. 283, no. 4, pp. 843–848, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. I. Jarchum and T. P. DiLorenzo, “Ins2 deficiency augments spontaneous HLA-A0201-restricted T cell responses to insulin,” Journal of Immunology, vol. 185, no. 2, pp. 658–665, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Moriyama, N. Abiru, J. Paronen et al., “Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 18, pp. 10376–10381, 2003. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Thébault-Baumont, D. Dubois-Laforgue, P. Krief et al., “Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice,” The Journal of Clinical Investigation, vol. 111, no. 6, pp. 851–857, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Takaki, M. P. Marron, C. E. Mathews et al., “HLA-A0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes,” The Journal of Immunology, vol. 176, no. 5, pp. 3257–3265, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. M. W. Pfaffl, “A new mathematical model for relative quantification in real-time RT-PCR,” Nucleic Acids Research, vol. 29, no. 9, article e45, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. M. W. Pfaffl, G. W. Horgan, and L. Dempfle, “Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR,” Nucleic Acids Research, vol. 30, no. 9, article e36, 2002. View at Publisher · View at Google Scholar · View at Scopus
  34. D. V. Serreze, H. D. Chapman, D. S. Varnum et al., “B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new ‘speed congenic’ stock of NOD.Igμ(null) mice,” Journal of Experimental Medicine, vol. 184, no. 5, pp. 2049–2053, 1996. View at Publisher · View at Google Scholar · View at Scopus
  35. I. Jarchum, T. Takaki, and T. P. DiLorenzo, “Efficient culture of CD8+ T cells from the islets of NOD mice and their use for the study of autoreactive specificities,” Journal of Immunological Methods, vol. 339, no. 1, pp. 66–73, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. R. D. Salter, D. N. Howell, and P. Cresswell, “Genes regulating HLA class I antigen expression in T-B lymphoblast hybrids,” Immunogenetics, vol. 21, no. 3, pp. 235–246, 1985. View at Publisher · View at Google Scholar · View at Scopus
  37. T. J. Tsomides, A. Aldovini, R. P. Johnson, B. D. Walker, R. A. Young, and H. N. Eisen, “Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1,” Journal of Experimental Medicine, vol. 180, no. 4, pp. 1283–1293, 1994. View at Publisher · View at Google Scholar · View at Scopus
  38. Z. Moodie, L. Price, C. Gouttefangeas et al., “Response definition criteria for ELISPOT assays revisited,” Cancer Immunology, Immunotherapy, vol. 59, no. 10, pp. 1489–1501, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. J. G. M. Markle, D. N. Frank, S. Mortin-Toth et al., “Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity,” Science, vol. 339, no. 6123, pp. 1084–1088, 2013. View at Publisher · View at Google Scholar · View at Scopus
  40. P. Pozzilli, A. Signore, A. J. K. Williams, and P. E. Beales, “NOD mouse colonies around the world—recent facts and figures,” Immunology Today, vol. 14, no. 5, pp. 193–196, 1993. View at Publisher · View at Google Scholar · View at Scopus
  41. L. Leroux, P. Desbois, L. Lamotte et al., “Compensatory responses in mice carrying a null mutation for Ins1 or Ins2,” Diabetes, vol. 50, supplement 1, pp. S150–S153, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. I. Jarchum, J. C. Baker, T. Yamada et al., “In vivo cytotoxicity of insulin-specific CD8+ T-cells in HLA-A0201 transgenic NOD mice,” Diabetes, vol. 56, no. 10, pp. 2551–2560, 2007. View at Publisher · View at Google Scholar · View at Scopus
  43. E. Énée, E. Martinuzzi, P. Blancou, J.-M. Bach, R. Mallone, and P. V. Endert, “Equivalent specificity of peripheral blood and islet-infiltrating CD8+ T lymphocytes in spontaneously diabetic HLA-A2 transgenic NOD mice,” Journal of Immunology, vol. 180, no. 8, pp. 5430–5438, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. I. Jarchum, L. Nichol, M. Trucco, P. Santamaria, and T. P. DiLorenzo, “Identification of novel IGRP epitopes targeted in type 1 diabetes patients,” Clinical Immunology, vol. 127, no. 3, pp. 359–365, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. R. Mallone, E. Martinuzzi, P. Blancou et al., “CD8+ T-cell responses identify β-cell autoimmunity in human type 1 diabetes,” Diabetes, vol. 56, no. 3, pp. 613–621, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. W. W. J. Unger, T. Pearson, J. R. F. Abreu et al., “Islet-specific CTL cloned from a type 1 diabetes patient cause beta-cell destruction after engraftment into HLA-A2 transgenic NOD/scid/IL2RG null mice,” PLoS ONE, vol. 7, no. 11, Article ID e49213, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. M. Nakayama, “Insulin as a key autoantigen in the development of type 1 diabetes,” Diabetes/Metabolism Research and Reviews, vol. 27, no. 8, pp. 773–777, 2011. View at Publisher · View at Google Scholar · View at Scopus
  48. K. E. Pauken, J. L. Linehan, J. A. Spanier et al., “Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice,” Journal of Immunology, vol. 191, no. 10, pp. 4913–4917, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. M. B. French, J. Allison, D. S. Cram et al., “Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice,” Diabetes, vol. 46, no. 1, pp. 34–39, 1997. View at Publisher · View at Google Scholar · View at Scopus
  50. E. Jaeckel, M. A. Lipes, and H. von Boehmer, “Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes,” Nature Immunology, vol. 5, no. 10, pp. 1028–1035, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. B. Krishnamurthy, N. L. Dudek, M. D. McKenzie et al., “Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP,” Journal of Clinical Investigation, vol. 116, no. 12, pp. 3258–3265, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. B. T. Fife, I. Guleria, M. Gubbels Bupp et al., “Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway,” Journal of Experimental Medicine, vol. 203, no. 12, pp. 2737–2747, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. L. C. Harrison, J. M. Wentworth, Y. Zhang et al., “Antigen-based vaccination and prevention of type 1 diabetes,” Current Diabetes Reports, vol. 13, no. 5, pp. 616–623, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. D. Kronenberg, R. R. Knight, M. Estorninho et al., “Circulating preproinsulin signal peptide-specific CD8 T cells restricted by the susceptibility molecule HLA-A24 are expanded at onset of type 1 diabetes and kill β-cells,” Diabetes, vol. 61, no. 7, pp. 1752–1759, 2012. View at Publisher · View at Google Scholar · View at Scopus
  55. A. L. Corper, T. Stratmann, V. Apostolopoulos et al., “A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes,” Science, vol. 288, no. 5465, pp. 505–511, 2000. View at Publisher · View at Google Scholar
  56. K. H. Lee, K. W. Wucherpfennig, and D. C. Wiley, “Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes,” Nature Immunology, vol. 2, no. 6, pp. 501–507, 2001. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Nakayama, K. McDaniel, L. Fitzgerald-Miller et al., “Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 14, pp. 4429–4434, 2015. View at Google Scholar
  58. A. Suri, J. J. Walters, M. L. Gross, and E. R. Unanue, “Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity,” Journal of Clinical Investigation, vol. 115, no. 8, pp. 2268–2276, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. L. Wen, F. S. Wong, R. Sherwin, and C. Mora, “Human DQ8 can substitute for murine I-Ag7 in the selection of diabetogenic T cells restricted to I-Ag7,” The Journal of Immunology, vol. 168, no. 7, pp. 3635–3640, 2002. View at Publisher · View at Google Scholar · View at Scopus