• 1
    Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol 2010; 160:19.
  • 2
    Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 2009; 373:20272033.
  • 3
    Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 2009; 155:173181.
  • 4
    Turley S, Poirot L, Hattori M, Benoist C, Mathis D. Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 2003; 198:15271537.
  • 5
    Wen L, Ley RE, Volchkov PY et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008; 455:11091113.
  • 6
    Noorchashm H, Lieu YK, Noorchashm N et al. I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice. J Immunol 1999; 163:743750.
  • 7
    Tian J, Zekzer D, Lu Y, Dang H, Kaufman DL. B cells are crucial for determinant spreading of T cell autoimmunity among beta cell antigens in diabetes-prone nonobese diabetic mice. J Immunol 2006; 176:26542661.
  • 8
    Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3:944950.
  • 9
    Serreze DV, Chapman HD, Varnum DS et al. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new ‘speed congenic’ stock of NOD.Ig mu null mice. J Exp Med 1996; 184:20492053.
  • 10
    Martin S, Wolf-Eichbaum D, Duinkerken G et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001; 345:10361040.
  • 11
    Hu CY, Rodriguez-Pinto D, Du W et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J Clin Invest 2007; 117:38573867.
  • 12
    Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009; 361:21432152.
  • 13
    Herold KC, Pescovitz MD, McGee P et al. Increased T cell proliferative responses to islet antigens identify clinical responders to anti-CD20 monoclonal antibody (rituximab) therapy in type 1 diabetes. J Immunol 2011; 187:19982005.
  • 14
    Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 2000; 12:471481.
  • 15
    Carvello M, Petrelli A, Vergani A et al. Inotuzumab ozogamicin murine analog-mediated B-cell depletion reduces anti-islet allo- and autoimmune responses. Diabetes 2012; 61:155165.
  • 16
    Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL. Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 2001; 167:10811089.
  • 17
    Hussain S, Delovitch TL. Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner. J Immunol 2007; 179:72257232.
  • 18
    Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care 2011; 34:20262032.
  • 19
    Roep BO, Kallan AA, De Vries RR. Beta-cell antigen-specific lysis of macrophages by CD4 T-cell clones from newly diagnosed IDDM patient. A putative mechanism of T-cell-mediated autoimmune islet cell destruction. Diabetes 1992; 41:13801384.
  • 20
    Bougneres PF, Carel JC, Castano L et al. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med 1988; 318:663670.
  • 21
    Lampeter EF, Homberg M, Quabeck K et al. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation. Lancet 1993; 341:12431244.
  • 22
    Chang JC, Linarelli LG, Laxer JA et al. Insulin-secretory-granule specific T cell clones in human IDDM. J Autoimmun 1995; 8:221234.
  • 23
    Herold KC, Hagopian W, Auger JA et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002; 346:16921698.
  • 24
    Keymeulen B, Vandemeulebroucke E, Ziegler AG et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005; 352:25982608.
  • 25
    Sherry N, Hagopian W, Ludvigsson J et al. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 2011; 378:487497.
  • 26
    AbATE Study hOKT3 1(Ala-Ala); teplizumab; treatment of type 1 diabetes – update on clinical trials [Symposia]. In: Proceedings of the 71st Scientific Sessions American Diabetes Association. San Diego, CA, 2011.
  • 27
    Christianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 1993; 42:4455.
  • 28
    Tian J, Olcott AP, Kaufman DL. Antigen-based immunotherapy drives the precocious development of autoimmunity. J Immunol 2002; 169:65646569.
  • 29
    Katz JD, Benoist C, Mathis D. T helper cell subsets in insulin-dependent diabetes. Science 1995; 268:11851188.
  • 30
    Chang CL, Chang SL, Lee YM et al. Cytopiloyne, a polyacetylenic glucoside, prevents type 1 diabetes in nonobese diabetic mice. J Immunol 2007; 178:69846993.
  • 31
    Perone MJ, Bertera S, Shufesky WJ et al. Suppression of autoimmune diabetes by soluble galectin-1. J Immunol 2009; 182:26412653.
  • 32
    Serreze DV, Chapman HD, Post CM, Johnson EA, Suarez-Pinzon WL, Rabinovitch A. Th1 to Th2 cytokine shifts in nonobese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation. J Immunol 2001; 166:13521359.
  • 33
    Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA 2004; 101:45724577.
  • 34
    Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007; 8:191197.
  • 35
    Salomon B, Lenschow DJ, Rhee L et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000; 12:431440.
  • 36
    Brusko T, Wasserfall C, McGrail K et al. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 2007; 56:604612.
  • 37
    Kukreja A, Cost G, Marker J et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002; 109:131140.
  • 38
    Michalek J, Vrabelova Z, Hrotekova Z et al. Immune regulatory T cells in siblings of children suffering from type 1 diabetes mellitus. Scand J Immunol 2006; 64:531535.
  • 39
    Putnam AL, Vendrame F, Dotta F, Gottlieb PA. CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 2005; 24:5562.
  • 40
    Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005; 54:9299.
  • 41
    Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, Buckner JH. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J Immunol 2008; 181:73507355.
  • 42
    Marwaha AK, Crome SQ, Panagiotopoulos C et al. Cutting edge: increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol 2010; 185:38143818.
  • 43
    Weber SE, Harbertson J, Godebu E et al. Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo. J Immunol 2006; 176:47304739.
  • 44
    Long SA, Rieck M, Sanda S et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes 2012; 61:23402348.
  • 45
    Putnam AL, Brusko TM, Lee MR et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 2009; 58:652662.
  • 46
    Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004; 199:14671477.
  • 47
    Tang Q, Henriksen KJ, Bi M et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; 199:14551465.
  • 48
    Fisson S, Djelti F, Trenado A et al. Therapeutic potential of self-antigen-specific CD4+ CD25+ regulatory T cells selected in vitro from a polyclonal repertoire. Eur J Immunol 2006; 36:817827.
  • 49
    Herold KC, Gitelman SE, Masharani U et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005; 54:17631769.
  • 50
    Martin-Orozco N, Chung Y, Chang SH, Wang YH, Dong C. Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 2009; 39:216224.
  • 51
    Bending D, De la Pena H, Veldhoen M et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 2009; 119:565572.
  • 52
    Emamaullee JA, Davis J, Merani S et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 2009; 58:13021311.
  • 53
    Van Belle TL, Esplugues E, Liao J, Juntti T, Flavell RA, von Herrath MG. Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model. J Immunol 2011; 187:29152922.
  • 54
    Arif S, Moore F, Marks K et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. Diabetes 2011; 60:21122119.
  • 55
    Honkanen J, Nieminen JK, Gao R et al. IL-17 immunity in human type 1 diabetes. J Immunol 2010; 185:19591967.
  • 56
    Ferraro A, Socci C, Stabilini A et al. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes 2011; 60:29032913.
  • 57
    Phillips JM, Parish NM, Raine T et al. Type 1 diabetes development requires both CD4+ and CD8+ T cells and can be reversed by non-depleting antibodies targeting both T cell populations. Rev Diabet Stud 2009; 6:97103.
  • 58
    Toma A, Laika T, Haddouk S 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 2009; 58:394402.
  • 59
    Coppieters KT, Dotta F, Amirian N et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 2012; 209:5160.
  • 60
    Skowera A, Ellis RJ, Varela-Calvino R 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.
  • 61
    Vincent BG, Young EF, Buntzman AS et al. Toxin-coupled MHC class I tetramers can specifically ablate autoreactive CD8+ T cells and delay diabetes in nonobese diabetic mice. J Immunol 2010; 184:41964204.
  • 62
    Brauner H, Elemans M, Lemos S et al. Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice. J Immunol 2010; 184:22722280.
  • 63
    Gur C, Porgador A, Elboim M et al. The activating receptor NKp46 is essential for the development of type 1 diabetes. Nat Immunol 2010; 11:121128.
  • 64
    Beilke JN, Kuhl NR, Van Kaer L, Gill RG. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nat Med 2005; 11:10591065.
  • 65
    Roman-Gonzalez A, Moreno ME, Alfaro JM et al. Frequency and function of circulating invariant NKT cells in autoimmune diabetes mellitus and thyroid diseases in Colombian patients. Hum Immunol 2009; 70:262268.
  • 66
    Kis J, Engelmann P, Farkas K et al. Reduced CD4+ subset and Th1 bias of the human iNKT cells in Type 1 diabetes mellitus. J Leukoc Biol 2006; 81:654662.
  • 67
    Lee PT, Putnam A, Benlagha K, Teyton L, Gottlieb PA, Bendelac A. Testing the NKT cell hypothesis of human IDDM pathogenesis. J Clin Invest 2002; 110:793800.
  • 68
    Wilson SB, Kent SC, Patton KT et al. Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes. Nature 1998; 391:177181.
  • 69
    Oikawa Y, Shimada A, Yamada S et al. High frequency of valpha24(+) vbeta11(+) T-cells observed in type 1 diabetes. Diabetes Care 2002; 25:18181823.
  • 70
    Oikawa Y, Shimada A, Yamada S et al. NKT cell frequency in Japanese type 1 diabetes. Ann NY Acad Sci 2003; 1005:230232.
  • 71
    Chatenoud L. Do NKT cells control autoimmunity? J Clin Invest 2002; 110:747748.
  • 72
    Sharif S, Arreaza GA, Zucker P et al. Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes. Nat Med 2001; 7:10571062.
  • 73
    Hong S, Wilson MT, Serizawa I et al. The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. Nat Med 2001; 7:10521056.
  • 74
    Lehuen A, Lantz O, Beaudoin L et al. Overexpression of natural killer T cells protects Valpha14- Jalpha281 transgenic nonobese diabetic mice against diabetes. J Exp Med 1998; 188:18311839.
  • 75
    Wang B, Geng YB, Wang CR. CD1-restricted NK T cells protect nonobese diabetic mice from developing diabetes. J Exp Med 2001; 194:313320.
  • 76
    Shi FD, Flodstrom M, Balasa B et al. Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse. Proc Natl Acad Sci USA 2001; 98:67776782.
  • 77
    Martin AP, Rankin S, Pitchford S, Charo IF, Furtado GC, Lira SA. Increased expression of CCL2 in insulin-producing cells of transgenic mice promotes mobilization of myeloid cells from the bone marrow, marked insulitis, and diabetes. Diabetes 2008; 57:30253033.
  • 78
    Calderon B, Suri A, Unanue ER. In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. Am J Pathol 2006; 169:21372147.
  • 79
    Bradshaw EM, Raddassi K, Elyaman W et al. Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol 2009; 183:44324439.
  • 80
    Devaraj S, Dasu MR, Rockwood J, Winter W, Griffen SC, Jialal I. Increased Toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. J Clin Endocrinol Metab 2008; 93:578583.
  • 81
    Uno S, Imagawa A, Okita K et al. Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes. Diabetologia 2007; 50:596601.
  • 82
    Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol 2008; 181:58295835.
  • 83
    Ohnmacht C, Pullner A, King SB et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 2009; 206:549559.
  • 84
    Saxena V, Ondr JK, Magnusen AF, Munn DH, Katz JD. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol 2007; 179:50415053.
  • 85
    Chen X, Makala LH, Jin Y et al. Type 1 diabetes patients have significantly lower frequency of plasmacytoid dendritic cells in the peripheral blood. Clin Immunol 2008; 129:413418.
  • 86
    Summers KL, Marleau AM, Mahon JL, McManus R, Hramiak I, Singh B. Reduced IF. N-alpha secretion by blood dendritic cells in human diabetes. Clin Immunol 2006; 121:8189.
  • 87
    Allen JS, Pang K, Skowera A et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture. Diabetes 2009; 58:138145.
  • 88
    Peng R, Li Y, Brezner K, Litherland S, Clare-Salzler MJ. Abnormal peripheral blood dendritic cell populations in type 1 diabetes. Ann NY Acad Sci 2003; 1005:222225.
  • 89
    Zhang M, Tang H, Guo Z et al. Splenic stroma drives mature dendritic cells to differentiate into regulatory dendritic cells. Nat Immunol 2004; 5:11241133.
  • 90
    Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 2002; 23:445449.
  • 91
    Perone MJ, Bertera S, Tawadrous ZS et al. Dendritic cells expressing transgenic galectin-1 delay onset of autoimmune diabetes in mice. J Immunol 2006; 177:52785289.
  • 92
    Jantsch J, Turza N, Volke M et al. Small interfering RNA (siRNA) delivery into murine bone marrow-derived dendritic cells by electroporation. J Immunol Methods 2008; 337:7177.
  • 93
    Dor Y, Brown J, Martinez OI, Melton DA. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 2004; 429:4146.
  • 94
    Maria-Engler SS, Correa-Giannella ML, Labriola L et al. Co-localization of nestin and insulin and expression of islet cell markers in long-term human pancreatic nestin-positive cell cultures. J Endocrinol 2004; 183:455467.
  • 95
    Ryan EA, Paty BW, Senior PA et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005; 54:20602069.
  • 96
    Wood K. Outlook for longer-lasting islets. Nat Med 2008; 14:11561157.
  • 97
    Emamaullee JA, Shapiro AM. Interventional strategies to prevent beta-cell apoptosis in islet transplantation. Diabetes 2006; 55:19071914.
  • 98
    Shapiro AM, Toso C, Imes A et al. Five-year results of islet-alone transplantation match pancreas-alone transplantation with alemtuzumab, Tac/MMF, with strong suppression of auto and alloreativity. Rev Diabet Stud 2011; 8:9596.
  • 99
    Yamamoto T, Mita A, Ricordi C et al. Prolactin supplementation to culture medium improves beta-cell survival. Transplantation 2010; 89:13281335.
  • 100
    Terra LF, Garay-Malpartida MH, Wailemann RA, Sogayar MC, Labriola L. Recombinant human prolactin promotes human beta cell survival via inhibition of extrinsic and intrinsic apoptosis pathways. Diabetologia 2011; 54:13881397.
  • 101
    Kroon E, Martinson LA, Kadoya K et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008; 26:443452.
  • 102
    Couri CE, Oliveira MC, Stracieri AB et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2009; 301:15731579.
  • 103
    Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. The Canadian–European Randomized Control Trial Group. Diabetes 1988; 37:15741582.
  • 104
    Saudek F, Havrdova T, Boucek P, Karasova L, Novota P, Skibova J. Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset. Rev Diabet Stud 2004; 1:8088.
  • 105
    Haller MJ, Wasserfall CH, Hulme MA et al. Autologous umbilical cord blood transfusion in young children with type 1 diabetes fails to preserve C-peptide. Diabetes Care 2011; 34:25672569.
  • 106
    Zhao Y, Jiang Z, Zhao T et al. Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med 2012; 10:112.
  • 107
    Preynat-Seauve O, Krause KH. Stem cell sources for regenerative medicine: the immunological point of view. Semin Immunopathol 2011; 33:519524.
  • 108
    Waldron-Lynch F, Henegariu O, Deng S et al. Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients. Sci Transl Med 2012; 4:118ra12.
  • 109
    GlaxoSmithKline and Tolerx announce phase III DEFEND-1 study of otelixizumab in type 1 diabetes did not meet its primary endpoint. 2011. Available at:
  • 110
    Fiorina P, Vezzulli P, Bassi R et al. Near normalization of metabolic and functional features of the central nervous system in type 1 diabetic patients with end-stage renal disease after kidney–pancreas transplantation. Diabetes Care 2012; 35:367374.
  • 111
    Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 2003; 290:28172823.