• 1
    Mallone, R., Martinuzzi, E., Blancou, P., Novelli, G., Afonso, G., Dolz, M., Bruno, G. et al., CD8+T-cell responses identify beta-cell autoimmunity in human type 1 diabetes. Diabetes 2007. 56: 613621.
  • 2
    Brezar, V., Carel, J. C., Boitard, C. and Mallone, R., Beyond the hormone: insulin as an autoimmune target in type 1 diabetes. Endocr. Rev. 2011. 32: 623669.
  • 3
    Chandra, J., Zhivotovsky, B., Zaitsev, S., Juntti-Berggren, L., Berggren, P. O. and Orrenius, S., Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes 2001. 50(Suppl 1): S44S47.
  • 4
    Skowera, A., Ellis, R. J., Varela-Calvino, R., Arif, S., Huang, G. C., Van-Krinks, C., Zaremba, A. et al., CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope. J. Clin. Invest. 2008. 118: 33903402.
  • 5
    Miller, S. D., Turley, D. M. and Podojil, J. R., Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease. Nat. Rev. Immunol. 2007. 7: 665677.
  • 6
    Atkinson, M. A., Maclaren, N. K. and Luchetta, R., Insulitis and diabetes in NOD mice reduced by prophylactic insulin therapy. Diabetes 1990. 39: 933937.
  • 7
    Diabetes Prevention Trial-Type 1 Diabetes Study Group, Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 2002. 346: 16851691.
  • 8
    Carel, J. C., Landais, P. and Bougneres, P., Therapy to prevent type 1 diabetes mellitus. N. Engl. J. Med. 2002. 347: 11151116.
  • 9
    Mallone, R. and van Endert, P., T cells in the pathogenesis of type 1 diabetes. Curr. Diab. Rep. 2008. 8: 101106.
  • 10
    Nagata, M., Santamaria, P., Kawamura, T., Utsugi, T. and Yoon, J. W., Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice. J. Immunol. 1994. 152: 20422050.
  • 11
    Wong, F. S., Visintin, I., Wen, L., Flavell, R. A. and Janeway, C. A., Jr., CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J. Exp. Med. 1996. 183: 6776.
  • 12
    Verdaguer, J., Schmidt, D., Amrani, A., Anderson, B., Averill, N. and Santamaria, P., Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J. Exp. Med. 1997. 186: 16631676.
  • 13
    Wong, F. S., Siew, L. K., Scott, G., Thomas, I. J., Chapman, S., Viret, C. and Wen, L., Activation of insulin-reactive CD8 T cells for development of autoimmune diabetes. Diabetes 2009. 58: 11561164.
  • 14
    Trudeau, J. D., Kelly-Smith, C., Verchere, C. B., Elliott, J. F., Dutz, J. P., Finegood, D. T., Santamaria, P. et al., Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood. J. Clin. Invest. 2003. 111: 217223.
  • 15
    Fourlanos, S., Perry, C., Gellert, S. A., Martinuzzi, E., Mallone, R., Butler, J., Colman, P. G. et al., Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 2011. 60: 12371245.
  • 16
    Achenbach, P., Barker, J. and Bonifacio, E., Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. Curr. Diab. Rep. 2008. 8: 8793.
  • 17
    Atkinson, M. A., ADA Outstanding Scientific Achievement Lecture 2004. Thirty years of investigating the autoimmune basis for type 1 diabetes: why can't we prevent or reverse this disease? Diabetes 2005. 54: 12531263.
  • 18
    Pozzilli, P., Pitocco, D., Visalli, N., Cavallo, M. G., Buzzetti, R., Crino, A., Spera, S. et al., No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 2000. 43: 10001004.
  • 19
    Skyler, J. S., Krischer, J. P., Wolfsdorf, J., Cowie, C., Palmer, J. P., Greenbaum, C., Cuthbertson, D. et al., Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial-Type 1. Diabetes Care 2005. 28: 10681076.
  • 20
    Culina, S., Boitard, C. and Mallone, R., Antigen-based immune therapeutics for type 1 diabetes: magic bullets or ordinary blanks? Clin. Dev. Immunol. 2011. 2011: 286248.
  • 21
    Vehik, K., Cuthbertson, D., Ruhlig, H., Schatz, D. A., Peakman, M. and Krischer, J. P., Long-term outcome of individuals treated with oral insulin: Diabetes Prevention Trial-Type 1 (DPT-1) oral insulin trial. Diabetes Care 2011. 34: 15851590.
  • 22
    Guery, J. C., Galbiati, F., Smiroldo, S. and Adorini, L., Selective development of T helper (Th)2 cells induced by continuous administration of low dose soluble proteins to normal and beta(2)-microglobulin-deficient BALB/c mice. J. Exp. Med. 1996. 183: 485497.
  • 23
    Karounos, D. G., Bryson, J. S. and Cohen, D. A., Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice. J. Clin. Invest. 1997. 100: 13441348.
  • 24
    Volund, A., Brange, J., Drejer, K., Jensen, I., Markussen, J., Ribel, U., Sorensen, A. R. et al., In vitro and in vivo potency of insulin analogues designed for clinical use. Diabet. Med. 1991. 8: 839847.
  • 25
    Bowman, M. A., Campbell, L., Darrow, B. L., Ellis, T. M., Suresh, A. and Atkinson, M. A., Immunological and metabolic effects of prophylactic insulin therapy in the NOD-scid/scid adoptive transfer model of IDDM. Diabetes 1996. 45: 205208.
  • 26
    Thivolet, C. H., Goillot, E., Bedossa, P., Durand, A., Bonnard, M. and Orgiazzi, J., Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse. Diabetologia 1991. 34: 314319.
  • 27
    Muir, A., Peck, A., Clare-Salzler, M., Song, Y. H., Cornelius, J., Luchetta, R., Krischer, J. et al., Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J. Clin. Invest. 1995. 95: 628634.
  • 28
    Daniel, D. and Wegmann, D. R., Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23). Proc. Natl. Acad. Sci. USA 1996. 93: 956960.
  • 29
    Abiru, N., Maniatis, A. K., Yu, L., Miao, D., Moriyama, H., Wegmann, D. and Eisenbarth, G. S., Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice. Diabetes 2001. 50: 12741281.
  • 30
    Orban, T., Farkas, K., Jalahej, H., Kis, J., Treszl, A., Falk, B., Reijonen, H. et al., Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy. J. Autoimmun. 2010. 34: 408415.
  • 31
    Zhang, Z. J., Davidson, L., Eisenbarth, G. and Weiner, H. L., Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc. Natl. Acad. Sci. USA 1991. 88: 1025210256.
  • 32
    Harrison, L. C., Dempsey-Collier, M., Kramer, D. R. and Takahashi, K., Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J. Exp. Med. 1996. 184: 21672174.
  • 33
    Diana, J., Brezar, V., Beaudoin, L., Dalod, M., Mellor, A., Tafuri, A., von Herrath, M. et al., Viral infection prevents diabetes by inducing regulatory T cells through NKT cell-plasmacytoid dendritic cell interplay. J. Exp. Med. 2011. 208: 729745.
  • 34
    Jarchum, I., Takaki, T. and DiLorenzo, T. P., Efficient culture of CD8(+) T cells from the islets of NOD mice and their use for the study of autoreactive specificities. J. Immunol. Methods 2008. 339: 6673.