Table of Contents Author Guidelines Submit a Manuscript
Clinical and Developmental Immunology
Volume 2011, Article ID 513210, 16 pages
http://dx.doi.org/10.1155/2011/513210
Review Article

T Cell Recognition of Autoantigens in Human Type 1 Diabetes: Clinical Perspectives

1INSERM, U986, Hôpital St Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France
2Université Paris Descartes, 75005 Paris, France
3Hôpital Cochin-Hôtel Dieu, Assistance Publique des Hôpitaux de Paris, 75679 Paris, France

Received 10 February 2011; Accepted 18 March 2011

Academic Editor: Vincent Geenen

Copyright © 2011 Roberto Mallone 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. B. Faideau, E. Larger, F. Lepault, J. C. Carel, and C. Boitard, “Role of β-cells in type 1 diabetes pathogenesis,” Diabetes, vol. 54, no. 2, pp. S87–S96, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. M. S. Anderson and J. A. Bluestone, “The NOD mouse: a model of immune dysregulation,” Annual Review of Immunology, vol. 23, pp. 447–485, 2005. View at Publisher · View at Google Scholar · View at Scopus
  3. U. C. Rogner, C. Boitard, J. Morin, E. Melanitou, and P. Avner, “Three loci on mouse chromosome 6 influence onset and final incidence of type I diabetes in NOD.C3H congenic strains,” Genomics, vol. 74, no. 2, pp. 163–171, 2001. View at Publisher · View at Google Scholar · View at Scopus
  4. J. A. Todd, “Etiology of type 1 diabetes,” Immunity, vol. 32, no. 4, pp. 457–467, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. N. Itoh, T. Hanafusa, A. Miyazaki et al., “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,” The Journal of Clinical Investigation, vol. 92, no. 5, pp. 2313–2322, 1993. View at Google Scholar · View at Scopus
  6. N. Somoza, F. Vargas, C. Roura-Mir et al., “Pancreas in recent onset insulin-dependent diabetes mellitus: changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor Vβ usage, and cytokine profile,” The Journal of Immunology, vol. 153, no. 3, pp. 1360–1377, 1994. View at Google Scholar · View at Scopus
  7. A. Willcox, S. J. Richardson, A. J. Bone, A. K. Foulis, and N. G. Morgan, “Analysis of islet inflammation in human type 1 diabetes,” Clinical and Experimental Immunology, vol. 155, no. 2, pp. 173–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  8. A. Hanninen, S. Jalkanen, M. Salmi, S. Toikkanen, G. Nikolakaros, and O. Simell, “Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus,” The Journal of Clinical Investigation, vol. 90, no. 5, pp. 1901–1910, 1992. View at Google Scholar · View at Scopus
  9. G. F. Bottazzo, B. M. Dean, and J. M. McNally, “In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis,” The New England Journal of Medicine, vol. 313, no. 6, pp. 353–360, 1985. View at Google Scholar · View at Scopus
  10. A. K. Foulis, M. McGill, and M. A. Farquharson, “Insulitis in type 1 (insulin-dependent) diabetes mellitus in man—macrophages, lymphocytes, and interferon-γ containing cells,” Journal of Pathology, vol. 165, no. 2, pp. 97–103, 1991. View at Google Scholar · View at Scopus
  11. A. Willcox, S. J. Richardson, A. J. Bone, A. K. Foulis, and N. G. Morgan, “Analysis of islet inflammation in human type 1 diabetes,” Clinical and Experimental Immunology, vol. 155, no. 2, pp. 173–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. B. Conrad, E. Weidmann, G. Trucco et al., “Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology,” Nature, vol. 371, no. 6495, pp. 351–355, 1994. View at Publisher · View at Google Scholar · View at Scopus
  13. S. Martin, D. Wolf-Eichbaum, G. Duinkerken et al., “Development of type 1 diabetes despite severe hereditary B-cell deficiency,” The New England Journal of Medicine, vol. 345, no. 14, pp. 1036–1040, 2001. View at Publisher · View at Google Scholar · View at Scopus
  14. A. G. Ziegler and G. T. Nepom, “Prediction and pathogenesis in type 1 diabetes,” Immunity, vol. 32, no. 4, pp. 468–478, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. R. K. Sibley, D. E. R. Sutherland, F. Goetz, and A. F. Michael, “Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases,” Laboratory Investigation, vol. 53, no. 2, pp. 132–144, 1985. View at Google Scholar · View at Scopus
  16. F. Homo-Delarche and C. Boitard, “Autoimmune diabetes: the role of the islets of Langerhans,” Immunology Today, vol. 17, no. 10, pp. 456–460, 1996. View at Publisher · View at Google Scholar · View at Scopus
  17. D. Daniel, R. G. Gill, N. Schloot, and D. Wegmann, “Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice,” European Journal of Immunology, vol. 25, no. 4, pp. 1056–1062, 1995. View at Google Scholar · View at Scopus
  18. 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
  19. 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
  20. M. Nakayama, J. N. Beilke, J. M. Jasinski et al., “Priming and effector dependence on insulin B:9-23 peptide in NOD islet autoimmunity,” The Journal of Clinical Investigation, vol. 117, no. 7, pp. 1835–1843, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. T. Yamamoto, E. Yamato, F. Tashiro et al., “Development of autoimmune diabetes in glutamic acid decarboxylase 65 (GAD65) knockout NOD mice,” Diabetologia, vol. 47, no. 2, pp. 221–224, 2004. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Kubosaki, J. Miura, and A. L. Notkins, “IA-2 is not required for the development of diabetes in NOD mice,” Diabetologia, vol. 47, no. 1, pp. 149–150, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. D. Zekzer, F. S. Wong, O. Ayalon et al., “GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice,” The Journal of Clinical Investigation, vol. 101, no. 1, pp. 68–73, 1998. View at Google Scholar · View at Scopus
  24. S. M. Lieberman, A. M. Evans, B. Han et al., “Identification of the β cell antigen targeted by a prevalent population of pathogenic CD8 T cells in autoimmune diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8384–8388, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Haskins and M. McDuffie, “Acceleration of diabetes in young NOD mice with a CD4 islet-specific T cell clone,” Science, vol. 249, no. 4975, pp. 1433–1436, 1990. View at Google Scholar · View at Scopus
  26. B. D. Stadinski, T. Delong, N. Reisdorph et al., “Chromogranin A is an autoantigen in type 1 diabetes,” Nature Immunology, vol. 11, no. 3, pp. 225–231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. L. Yu, D. T. Robles, N. Abiru et al., “Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1701–1706, 2000. View at Publisher · View at Google Scholar · View at Scopus
  28. A. G. Ziegler, M. Hummel, M. Schenker, and E. Bonifacio, “Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study,” Diabetes, vol. 48, no. 3, pp. 460–468, 1999. View at Google Scholar · View at Scopus
  29. R. J. Keller, “Cellular immunity to human insulin in individuals at high risk for the development of type I diabetes mellitus,” Journal of Autoimmunity, vol. 3, no. 3, pp. 321–327, 1990. View at Publisher · View at Google Scholar · View at Scopus
  30. D. Dubois-LaForgue, J. C. Carel, P. F. Bougnères, J. G. Guillet, and C. Boitard, “T-cell response to proinsulin and insulin in type 1 and pretype 1 diabetes,” Journal of Clinical Immunology, vol. 19, no. 2, pp. 127–134, 1999. View at Google Scholar · View at Scopus
  31. N. C. Schloot, B. O. Roep, D. Wegmann et al., “Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects,” Diabetologia, vol. 40, no. 5, pp. 564–572, 1997. View at Publisher · View at Google Scholar · View at Scopus
  32. E. Martinuzzi, G. Novelli, M. Scotto et al., “The frequency and immunodominance of islet-specific CD8 T-cell responses change after type 1 diabetes diagnosis and treatment,” Diabetes, vol. 57, no. 5, pp. 1312–1320, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Rudy, N. Stone, L. C. Harrison et al., “Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes,” Molecular Medicine, vol. 1, no. 6, pp. 625–633, 1995. View at Google Scholar · View at Scopus
  34. D. G. Alleva, P. D. Crowe, L. Jin et al., “A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin,” The Journal of Clinical Investigation, vol. 107, no. 2, pp. 173–180, 2001. View at Google Scholar · View at Scopus
  35. L. D. Petersen, G. Duinkerken, G. J. Bruining, R. A. W. Van Lier, R. R. P. De Vries, and B. O. Roep, “Increased numbers of in vivo activated T cells in patients with recent onset insulin-dependent diabetes mellitus,” Journal of Autoimmunity, vol. 9, no. 6, pp. 731–737, 1996. View at Publisher · View at Google Scholar · View at Scopus
  36. I. Durinovic-Belló, M. Schlosser, M. Riedl et al., “Pro- and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB104, DQ8 Type 1 diabetes,” Diabetologia, vol. 47, no. 3, pp. 439–450, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. P. Naquet, J. Ellis, D. Tibensky et al., “T cell autoreactivity to insulin in diabetic and related non-diabetic individuals,” The Journal of Immunology, vol. 140, no. 8, pp. 2569–2578, 1988. View at Google Scholar · View at Scopus
  38. P. Panina-Bordignon, R. Lang, P. M. Van Endert et al., “Cytotoxic T cells specific for glutamic acid decarboxylase in autoimmune diabetes,” Journal of Experimental Medicine, vol. 181, no. 5, pp. 1923–1927, 1995. View at Google Scholar · View at Scopus
  39. S. E. Fineberg, T. T. Kawabata, D. Finco-Kent, R. J. Fountaine, G. L. Finch, and A. S. Krasner, “Immunological responses to exogenous insulin,” Endocrine Reviews, vol. 28, no. 6, pp. 625–652, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. I. Durinovic-Bellò, M. Hummel, and A. G. Ziegler, “Cellular immune response to diverse islet cell antigens in IDDM,” Diabetes, vol. 45, no. 6, pp. 795–800, 1996. View at Google Scholar · View at Scopus
  41. I. Durinovic-Bellò, M. Hummel, and A. G. Ziegler, “Cellular immune response to diverse islet cell antigens in IDDM,” Diabetes, vol. 45, no. 6, pp. 795–800, 1996. View at Google Scholar · View at Scopus
  42. T. I. M. Tree, G. Duinkerken, S. Willemen, R. R. P. De Vries, and B. O. Roep, “HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65,” Diabetes, vol. 53, no. 7, pp. 1692–1699, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. 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 and Experimental Immunology, vol. 148, no. 1, pp. 1–16, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. R. Raju, S. R. Munn, and C. S. David, “T cell recognition of human pre-proinsulin peptides depends on the polymorphism at HLA DQ locus: a study using HLA DQ8 and DQ6 transgenic mice,” Human Immunology, vol. 58, no. 1, pp. 21–29, 1997. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Congia, S. Patel, A. P. Cope, S. De Virgiliis, and G. Sønderstrup, “T cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 7, pp. 3833–3838, 1998. View at Publisher · View at Google Scholar · View at Scopus
  46. K. H. Lee, K. W. Wucherpfennig, and D. C. Wiley, “Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type I diabetes,” Nature Immunology, vol. 2, no. 6, pp. 501–507, 2001. View at Publisher · View at Google Scholar · View at Scopus
  47. E. Havari, A. M. Lennon-Dumenil, L. Klein et al., “Expression of the B7.1 costimulatory molecule on pancreatic β cells abrogates the requirement for CD4 T cells in the development, of type 1 diabetes,” The Journal of Immunology, vol. 173, no. 2, pp. 787–796, 2004. View at Google Scholar · View at Scopus
  48. S. Arif, T. I. Tree, T. P. Astill et al., “Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health,” The Journal of Clinical Investigation, vol. 113, no. 3, pp. 451–463, 2004. View at Publisher · View at Google Scholar · View at Scopus
  49. S. I. Mannering, L. C. Harrison, N. A. Williamson et al., “The insulin A-chain epitope recognized by human T cells is posttranslationally modified,” Journal of Experimental Medicine, vol. 202, no. 9, pp. 1191–1197, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. S. C. Kent, Y. Chen, L. Bregoli et al., “Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope,” Nature, vol. 435, no. 7039, pp. 224–228, 2005. View at Publisher · View at Google Scholar · View at Scopus
  51. P. E. Jensen, “Reduction of disulfide bonds during antigen processing: evidence from a thiol-dependent insulin determinant,” Journal of Experimental Medicine, vol. 174, no. 5, pp. 1121–1130, 1991. View at Google Scholar · View at Scopus
  52. G. G. Miller, J. F. Hoy, L. J. Nell, and J. W. Thomas, “Antigen processing and the human T cell receptor repertoire for insulin,” The Journal of Immunology, vol. 141, no. 10, pp. 3293–3298, 1988. View at Google Scholar · View at Scopus
  53. L. Chang, L. Kjer-Nielsen, S. Flynn et al., “Novel strategy for identification of candidate cytotoxic T-cell epitopes from human preproinsulin,” Tissue Antigens, vol. 62, no. 5, pp. 408–417, 2003. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Hassainya, F. Garcia-Pons, R. Kratzer et al., “Identification of naturally processed HLA-A2—restricted proinsulin epitopes by reversed immunology,” Diabetes, vol. 54, no. 7, pp. 2053–2059, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. A. Toma, S. Haddouk, J. P. Briand et al., “Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 30, pp. 10581–10586, 2005. View at Publisher · View at Google Scholar · View at Scopus
  56. A. Toma, T. Laïka, S. Haddouk et al., “Recognition of human proinsulin leader sequence by class I-restricted T-cells in HLA-A*0201 transgenic mice and in human type 1 diabetes,” Diabetes, vol. 58, no. 2, pp. 394–402, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. A. Skowera, R. J. Ellis, R. Varela-Calviño et al., “CTLs are targeted to kill β cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope,” The Journal of Clinical Investigation, vol. 118, no. 10, pp. 3390–3402, 2008. View at Publisher · View at Google Scholar
  58. G. G. M. Pinkse, O. H. M. Tysma, C. A. M. Bergen et al., “Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18425–18430, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Larger, C. Becourt, J. F. Bach, and C. Boitard, “Pancreatic islet β cells drive T cell-immune responses in the nonobese diabetic mouse model,” Journal of Experimental Medicine, vol. 181, no. 5, pp. 1635–1642, 1995. View at Google Scholar · View at Scopus
  60. J. H. Velthuis, W. W. Unger, J. R. F. Abreu et al., “Simultaneous detection of circulating autoreactive CD8+ T-cells specific for different islet cell-associated epitopes using combinatorial MHC multimers,” Diabetes, vol. 59, no. 7, pp. 1721–1730, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. M. Peakman, T. I. Tree, J. Endl, P. Van Endert, M. A. Atkinson, and B. O. Roep, “Characterization of preparations of GAD65, proinsulin, and the islet tyrosine phosphatase IA-2 for use in detection of autoreactive T-cells in type 1 diabetes: report of phase II of the second international immunology of diabetes society workshop for standardization of T-cell assays in type 1 diabetes,” Diabetes, vol. 50, no. 8, pp. 1749–1754, 2001. View at Google Scholar · View at Scopus
  62. M. S. Lan, J. Lu, Y. Goto, and A. L. Notkins, “Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma,” DNA and Cell Biology, vol. 13, no. 5, pp. 505–514, 1994. View at Google Scholar · View at Scopus
  63. D. U. Rabin, S. M. Pleasic, J. A. Shapiro et al., “Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases,” The Journal of Immunology, vol. 152, no. 6, pp. 3183–3188, 1994. View at Google Scholar · View at Scopus
  64. H. J. DeAizpurua, M. C. Honeyman, L. C. Harrison et al., “Glutamic acid decarboxylase (GAD) in fetal pig proislets is recognised by antibodies and stimulates T cells from humans with pre-clinical insulindependent diabetes mellitus,” Journal of Autoimmunity, vol. 5, pp. 759–770, 1992. View at Google Scholar
  65. L. C. Harrison, M. C. Honeyman, H. J. DeAizpurua et al., “Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes,” The Lancet, vol. 341, no. 8857, pp. 1365–1369, 1993. View at Publisher · View at Google Scholar · View at Scopus
  66. T. Lohmann, R. D. G. Leslie, M. Hawa, M. Geysen, S. Rodda, and M. Londei, “Immunodominant epitopes of glutamic acid decarboxylase 65 and 67 in insulin-dependent diabetes mellitus,” The Lancet, vol. 343, no. 8913, pp. 1607–1608, 1994. View at Publisher · View at Google Scholar · View at Scopus
  67. M. C. Honeyman, D. S. Cram, and L. C. Harrison, “Glutamic acid decarboxylase 67-reactive T cells: a marker of insulin- dependent diabetes,” Journal of Experimental Medicine, vol. 177, no. 2, pp. 535–540, 1993. View at Google Scholar · View at Scopus
  68. M. A. Atkinson, D. L. Kaufman, L. Campbell et al., “Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes,” The Lancet, vol. 339, no. 8791, pp. 458–459, 1992. View at Publisher · View at Google Scholar · View at Scopus
  69. L. C. Harrison, M. C. Honeyman, H. J. DeAizpurua et al., “Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes,” The Lancet, vol. 341, no. 8857, pp. 1365–1369, 1993. View at Publisher · View at Google Scholar · View at Scopus
  70. M. A. Atkinson, M. A. Bowman, L. Campbell, B. L. Darrow, D. L. Kaufman, and N. K. Maclaren, “Cellular immunity to a determinant common to glutamate decarboxylase and Coxsackie virus in insulin-dependent diabetes,” The Journal of Clinical Investigation, vol. 94, no. 5, pp. 2125–2129, 1994. View at Google Scholar · View at Scopus
  71. L. C. Harrison, “Antigen-specific therapy for autoimmune disease: prospects for the prevention of insulin-dependent diabetes,” Molecular Medecine, vol. 1, no. 7, pp. 722–727, 1995. View at Google Scholar
  72. M. C. Honeyman, N. L. Stone, and L. C. Harrison, “T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA- 2: potential for mimicry with rotavirus and other environmental agents,” Molecular Medicine, vol. 4, no. 4, pp. 231–239, 1998. View at Google Scholar · View at Scopus
  73. P. A. Ott, B. A. Herzog, S. Quast et al., “Islet-cell antigen-reactive T cells show different expansion rates and Th1/Th2 differentiation in type 1 diabetic patients and healthy controls,” Clinical Immunology, vol. 115, no. 1, pp. 102–114, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. L. S. Wicker, S. L. Chen, G. T. Nepom et al., “Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes- associated human MHC class II allele, DRB10401,” The Journal of Clinical Investigation, vol. 98, no. 11, pp. 2597–2603, 1996. View at Google Scholar · View at Scopus
  75. S. D. Patel, A. P. Cope, M. Congia et al., “Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(α10101,β10401) transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 15, pp. 8082–8087, 1997. View at Publisher · View at Google Scholar · View at Scopus
  76. G. T. Nepom, J. D. Lippolis, F. M. White et al., “Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65),” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 4, pp. 1763–1768, 2001. View at Publisher · View at Google Scholar · View at Scopus
  77. L. I. Wen, F. S. Wong, L. Burkly et al., “Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4 T cells from human DQ transgenic mice,” The Journal of Clinical Investigation, vol. 102, no. 5, pp. 947–957, 1998. View at Google Scholar · View at Scopus
  78. R. S. Abraham, S. B. Wilson, N. F. De Souza, J. L. Strominger, S. R. Munn, and C. S. David, “NOD background genes influence T cell responses to GAD 65 in HLA-DQ8 transgenic mice,” Human Immunology, vol. 60, no. 7, pp. 583–590, 1999. View at Publisher · View at Google Scholar · View at Scopus
  79. H. Reijonen, E. J. Novak, S. Kochik et al., “Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects,” Diabetes, vol. 51, no. 5, pp. 1375–1382, 2002. View at Google Scholar · View at Scopus
  80. V. Öling, J. Marttila, J. Ilonen et al., “GAD65- and proinsulin-specific CD4 T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects,” Journal of Autoimmunity, vol. 25, no. 3, pp. 235–243, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. J. Endl, H. Otto, G. Jung et al., “Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients,” The Journal of Clinical Investigation, vol. 99, no. 10, pp. 2405–2415, 1997. View at Google Scholar · View at Scopus
  82. J. A. Gebe, K. A. Unrath, B. B. Yue, T. Miyake, B. A. Falk, and G. T. Nepom, “Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice,” Journal of Autoimmunity, vol. 30, no. 4, pp. 197–206, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. J. A. Gebe, B. B. Yue, K. A. Unrath, B. A. Falk, and G. T. Nepom, “Restricted autoantigen recognition associated with deletional and adaptive regulatory mechanisms,” The Journal of Immunology, vol. 183, no. 1, pp. 59–65, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. N. E. Standifer, E. A. Burwell, V. H. Gersuk, C. J. Greenbaum, and G. T. Nepom, “Changes in autoreactive T cell avidity during type 1 diabetes development,” Clinical Immunology, vol. 132, no. 3, pp. 312–320, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. A. Geluk, K. E. Van Meijgaarden, N. C. Schloot, J. W. Drijfhout, T. H. M. Ottenhoff, and B. O. Roep, “HLA-DR binding analysis of peptides from islet antigens in IDDM,” Diabetes, vol. 47, no. 10, pp. 1594–1601, 1998. View at Publisher · View at Google Scholar · View at Scopus
  86. E. Harfouch-Hammoud, T. Walk, H. Otto et al., “Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes,” Diabetes, vol. 48, no. 10, pp. 1937–1947, 1999. View at Publisher · View at Google Scholar · View at Scopus
  87. G. Fenalti, C. S. Hampe, Y. Arafat et al., “COOH-terminal clustering of autoantibody and T-cell determinants on the structure of GAD65 provide insights into the molecular basis of autoreactivity,” Diabetes, vol. 57, no. 5, pp. 1293–1301, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. X. Ge, J. D. Piganelli, H. M. Tse et al., “Modulatory role of DR4- to DQ8-restricted CD4 T-cell responses and type 1 diabetes susceptibility,” Diabetes, vol. 55, no. 12, pp. 3455–3462, 2006. View at Publisher · View at Google Scholar · View at Scopus
  89. K. Y. Chang and E. R. Unanue, “Prediction of HLA-DQ8 β cell peptidome using a computational program and its relationship to autoreactive T cells,” International Immunology, vol. 21, no. 6, pp. 705–713, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. M. C. Honeyman, N. L. Stone, and L. C. Harrison, “T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA- 2: potential for mimicry with rotavirus and other environmental agents,” Molecular Medicine, vol. 4, no. 4, pp. 231–239, 1998. View at Google Scholar · View at Scopus
  91. K. Kelemen, P. A. Gottlieb, A. L. Putnam, H. W. Davidson, D. R. Wegmann, and J. C. Hutton, “HLA-DQ8-associated T cell responses to the diabetes autoantigen phogrin (IA-2β) in human prediabetes,” The Journal of Immunology, vol. 172, no. 6, pp. 3955–3962, 2004. View at Google Scholar · View at Scopus
  92. M. C. Honeyman, N. L. Stone, B. A. Falk, G. Nepom, and L. C. Harrison, “Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens,” The Journal of Immunology, vol. 184, no. 4, pp. 2204–2210, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. S. M. Weenink, J. Lo, C. R. Stephenson et al., “Autoantibodies and associated T-cell responses to determinants within the 831-860 region of the autoantigen IA-2 in Type 1 diabetes,” Journal of Autoimmunity, vol. 33, no. 2, pp. 147–154, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. J. Yang, N. A. Danke, D. Berger et al., “Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects,” The Journal of Immunology, vol. 176, no. 5, pp. 2781–2789, 2006. View at Google Scholar · View at Scopus
  95. F. Vendrame, A. Pileggi, E. Laughlin et al., “Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells,” Diabetes, vol. 59, no. 4, pp. 947–957, 2010. View at Publisher · View at Google Scholar · View at Scopus
  96. 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
  97. K. Takahashi, M. C. Honeyman, and L. C. Harrison, “Cytotoxic T cells to an epitope in the islet autoantigen IA-2 are not disease-specific,” Clinical Immunology, vol. 99, no. 3, pp. 360–364, 2001. View at Publisher · View at Google Scholar · View at Scopus
  98. C. Panagiotopoulos, H. Qin, R. Tan, and C. B. Verchere, “Identification of a β-cell-specific HLA class I restricted epitope in type 1 diabetes,” Diabetes, vol. 52, no. 11, pp. 2647–2651, 2003. View at Publisher · View at Google Scholar · View at Scopus
  99. N. E. Standifer, Q. Ouyang, C. Panagiotopoulos et al., “Identification of novel HLA-A0201-restricted epitopes in recent-onset type 1 diabetic subjects and antibody-positive relatives,” Diabetes, vol. 55, no. 11, pp. 3061–3067, 2006. View at Publisher · View at Google Scholar · View at Scopus
  100. Q. Ouyang, N. E. Standifer, H. Qin et al., “Recognition of HLA class I-restricted β-cell epitopes in type 1 diabetes,” Diabetes, vol. 55, no. 11, pp. 3068–3074, 2006. View at Publisher · View at Google Scholar · View at Scopus
  101. P. Monti, M. Scirpoli, A. Rigamonti et al., “Evidence for in vivo primed and expanded autoreactive T cells as a specific feature of patients with type 1 diabetes,” The Journal of Immunology, vol. 179, no. 9, pp. 5785–5792, 2007. View at Google Scholar · View at Scopus
  102. 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 Google Scholar · View at Scopus
  103. P. Blancou, R. Mallone, E. Martinuzzi et al., “Immunization of HLA class I transgenic mice identifies autoantigenic epitopes eliciting dominant responses in type 1 diabetes patients,” The Journal of Immunology, vol. 178, no. 11, pp. 7458–7466, 2007. View at Google Scholar · View at Scopus
  104. C. Boitard, R. Yasunami, M. Dardenne et al., “T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice,” The Journal of Experimental Medecine, vol. 169, no. 5, pp. 1669–1680, 1989. View at Google Scholar
  105. A. Kukreja, G. Cost, J. Marker et al., “Multiple immuno-regulatory defects in type-1 diabetes,” The Journal of Clinical Investigation, vol. 109, no. 1, pp. 131–140, 2002. View at Publisher · View at Google Scholar · View at Scopus
  106. W. Liu, A. L. Putnam, Z. Xu-yu et al., “CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells,” Journal of Experimental Medicine, vol. 203, no. 7, pp. 1701–1711, 2006. View at Publisher · View at Google Scholar
  107. T. I. M. Tree, J. Lawson, H. Edwards et al., “Naturally arising human CD4+ T-cells that recognize islet autoantigens and secrete interleukin-10 regulate proinflammatory T-cell responses via linked suppression,” Diabetes, vol. 59, no. 6, pp. 1451–1460, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. R. Mallone, S. A. Kochik, H. Reijonen et al., “Functional avidity directs T-cell fate in autoreactive CD4+ T cells,” Blood, vol. 106, no. 8, pp. 2798–2805, 2005. View at Publisher · View at Google Scholar
  109. I. Durinovic-Belló, E. Jelinek, M. Schlosser et al., “Class III alleles at the insulin VNTR polymorphism are associated with regulatory T-cell responses to proinsulin epitopes in HLA-DR4, DQ8 individuals,” Diabetes, vol. 54, supplement 2, pp. S18–S24, 2005. View at Publisher · View at Google Scholar
  110. I. Durinovic-Belló, S. Rosinger, J. A. Olson et al., “DRB10401-restricted human T cell clone specific for the major proinsulin 73-90 epitope expresses a down-regulatory T helper 2 phenotype,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 31, pp. 11683–11688, 2006. View at Publisher · View at Google Scholar · View at Scopus
  111. N. A. Danke, J. Yang, C. Greenbaum, and W. W. Kwok, “Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects,” Journal of Autoimmunity, vol. 25, no. 4, pp. 303–311, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. N. A. Danke, D. M. Koelle, C. Yee, S. Beheray, and W. W. Kwok, “Autoreactive T cells in healthy individuals,” The Journal of Immunology, vol. 172, no. 10, pp. 5967–5972, 2004. View at Google Scholar · View at Scopus
  113. J. A. Dromey, B. H. Lee, H. Yu et al., “Generation and expansion of regulatory human CD4(+) T-cell clones specific for pancreatic islet autoantigens,” Journal of Autoimmunity, vol. 36, no. 1, pp. 47–55, 2011. View at Publisher · View at Google Scholar
  114. S. A. Long, K. Cerosaletti, P. L. Bollyky et al., “Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects,” Diabetes, vol. 59, no. 2, pp. 407–415, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. V. Viglietta, S. C. Kent, T. Orban, and D. A. Hafler, “GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes,” The Journal of Clinical Investigation, vol. 109, no. 7, pp. 895–903, 2002. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Endl, S. Rosinger, B. Schwarz et al., “Coexpression of CD25 and OX40 (CD134) receptors delineates autoreactive T-cells in type 1 diabetes,” Diabetes, vol. 55, no. 1, pp. 50–60, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. E. A. James and W. W. Kwok, “CD8 suppressor-mediated regulation of human CD4+ T cell responses to glutamic acid decarboxylase 65,” European Journal of Immunology, vol. 37, no. 1, pp. 78–86, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. C. Boitard, G. Feutren, L. Castano et al., “Effect of cyclosporin A treatment on the production of antibody in insulin-dependent (type I) diabetic patients,” The Journal of Clinical Investigation, vol. 80, no. 6, pp. 1607–1612, 1987. View at Google Scholar · View at Scopus
  119. B. O. Roep and M. Peakman, “Surrogate end points in the design of immunotherapy trials: emerging lessons from type 1 diabetes,” Nature Reviews Immunology, vol. 10, no. 2, pp. 145–152, 2010. View at Publisher · View at Google Scholar · View at Scopus
  120. A. M. Secrest, D. J. Becker, S. F. Kelsey, R. E. LaPorte, and T. J. Orchard, “Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes,” Diabetes, vol. 59, no. 12, pp. 3216–3222, 2010. View at Publisher · View at Google Scholar
  121. J. Tian and D. L. Kaufman, “Antigen-based therapy for the treatment of type 1 diabetes,” Diabetes, vol. 58, no. 9, pp. 1939–1946, 2009. View at Publisher · View at Google Scholar · View at Scopus
  122. S. D. Miller, D. M. Turley, and J. R. Podojil, “Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease,” Nature Reviews Immunology, vol. 7, no. 9, pp. 665–677, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. B. Salomon, L. Rhee, H. Bour-Jordan et al., “Development of spontaneous autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice,” Journal of Experimental Medicine, vol. 194, no. 5, pp. 677–684, 2001. View at Publisher · View at Google Scholar · View at Scopus
  124. N. Prevot, C. Briet, and H. Lassmann, “Abrogation of ICOS/ICOSL costimulation in NOD mice results in autoimmune deviation towards the neuromuscular system,” European Journal of Immunology, vol. 40, pp. 2267–2276, 2010. View at Google Scholar
  125. S. C. Shah, J. I. Malone, and N. E. Simpson, “A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 320, no. 9, pp. 550–554, 1989. View at Google Scholar · View at Scopus
  126. O. Schnell, B. Eisfelder, E. Standl et al., “High-dose intravenous insulin infusion versus intensive insulin treatment in newly diagnosed IDDM,” Diabetes, vol. 46, no. 10, pp. 1607–1611, 1997. View at Google Scholar
  127. The Diabetes Control and Complications Trial, “Effect of intensive therapy on residual β-cell function in patients with type 1 diabetes in the Diabetes Control and Complications Trial,” Annals of Internal Medecine, vol. 128, pp. 517–523, 1998. View at Google Scholar
  128. L. C. Harrison, M. C. Honeyman, C. E. Steele et al., “Pancreatic β-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes,” Diabetes Care, vol. 27, no. 10, pp. 2348–2355, 2004. View at Publisher · View at Google Scholar
  129. diabetes Prevention Trial–Type 1 Diabetes Study Group, “Effects of insulin in relatives of patients with Type 1 Diabetes Mellitus,” The New England Journal of Medecine, vol. 346, pp. 1685–1691, 2002. View at Google Scholar
  130. J. S. Skyler, J. P. Krischer, and J. Wolfsdorf, “Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial-type 1,” Diabetes Care, vol. 28, no. 5, pp. 1068–1076, 2005. View at Publisher · View at Google Scholar
  131. K. Näntö-Salonen, A. Kupila, S. Simell et al., “Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial,” The Lancet, vol. 372, no. 9651, pp. 1746–1755, 2008. View at Publisher · View at Google Scholar · View at Scopus
  132. L. Chaillous, H. Lefèvre, C. Thivolet et al., “Oral insulin administration and residual β-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial,” The Lancet, vol. 356, no. 9229, pp. 545–549, 2000. View at Google Scholar
  133. P. Pozzilli, D. Pitocco, N. Visalli et al., “No effect of oral insulin on residual beta-cell function in recent-onset Type I diabetes (the IMDIAB VII),” Diabetologia, vol. 43, no. 8, pp. 1000–1004, 2000. View at Publisher · View at Google Scholar · View at Scopus
  134. T. Orban, K. Farkas, H. Jalahej et al., “Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy,” Journal of Autoimmunity, vol. 34, no. 4, pp. 408–415, 2010. View at Publisher · View at Google Scholar · View at Scopus
  135. T. Maruyama, S. Tanaka, A. Shimada et al., “Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 6, pp. 2115–2121, 2008. View at Publisher · View at Google Scholar · View at Scopus
  136. M. Alvarsson, G. Sundkvist, I. Lager et al., “Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up,” Diabetes, Obesity and Metabolism, vol. 10, no. 5, pp. 421–429, 2008. View at Publisher · View at Google Scholar
  137. C. D. Agardh, C. M. Cilio, A. Lethagen et al., “Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes,” Journal of Diabetes and its Complications, vol. 19, no. 4, pp. 238–246, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. J. Ludvigsson, M. Faresjö, M. Hjorth et al., “GAD treatment and insulin secretion in recent-onset type 1 diabetes,” The New England Journal of Medicine, vol. 359, no. 18, pp. 1909–1920, 2008. View at Publisher · View at Google Scholar · View at Scopus
  139. I. Raz, D. Elias, A. Avron, M. Tamir, M. Metzger, and I. R. Cohen, “β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial,” The Lancet, vol. 358, no. 9295, pp. 1749–1753, 2001. View at Publisher · View at Google Scholar
  140. G. Semana, R. Gausling, R. A. Jackson, and D. A. Hafler, “T cell autoreactivity to proinsulin epitopes in diabetic patients and healthy subjects,” Journal of Autoimmunity, vol. 12, no. 4, pp. 259–267, 1999. View at Publisher · View at Google Scholar · View at Scopus
  141. I. Durinovic-Belló, B. O. Boehm, and A. G. Ziegler, “Predominantly recognized ProInsulin T helper cell epitopes in individuals with and without islet cell autoimmunity,” Journal of Autoimmunity, vol. 18, no. 1, pp. 55–66, 2002. View at Publisher · View at Google Scholar · View at Scopus
  142. K. Kimura, T. Kawamura, S. Kadotani, H. Inada, S. Niihira, and T. Yamano, “Peptide-specific cytotoxicity of T lymphocytes against glutamic acid decarboxylase and insulin in type 1 diabetes mellitus,” Diabetes Research and Clinical Practice, vol. 51, no. 3, pp. 173–179, 2001. View at Publisher · View at Google Scholar · View at Scopus