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Immune modulation in humans: implications for type 1 diabetes mellitus

Key Points

  • Reduced immune regulation seems to be a feature of a subgroup of individuals with type 1 diabetes mellitus (T1DM)

  • Several genetic risk factors for T1DM are associated with differential functionality of immune modulation

  • Most immune intervention strategies that have been assessed for their efficacy in intervening in the immunopathogenesis of T1DM suppress, rather than modulate, the autoimmune response against pancreatic islets

  • The newly appreciated heterogeneity in T1DM implies that a personalized approach could be used to treat this disease; treatments that modify the immune system might be ideally suited to this purpose

Abstract

Type 1 diabetes mellitus (T1DM) is the result of autoimmune destruction of pancreatic β cells in genetically predisposed individuals with impaired immune regulation. The insufficiency in the modulation of immune attacks on the β cells might be partly due to genetic causes; indeed, several of the genetic variants that predispose individuals to T1DM have functional features of impaired immune regulation. Whilst defects in immune regulation in patients with T1DM have been identified, many patients seem to have immune regulatory capacities that are indistinguishable from those of healthy individuals. Insight into the regulation of islet autoimmunity might enable us to restore immune imbalances with therapeutic interventions. In this Review, we discuss the current knowledge on immune regulation and dysfunction in humans that is the basis of tissue-specific immune regulation as an alternative to generalized immune suppression.

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Figure 1: Natural history of the immunopathogenesis of T1DM.
Figure 2: Imbalances between immune regulation and autoimmunity.
Figure 3: Immune modulation and therapeutic opportunities.
Figure 4: Patient heterogeneity and personalized medicine.

References

  1. 1

    Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14, 619–663 (1965).

    CAS  PubMed  Google Scholar 

  2. 2

    Itoh, N. 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. J. Clin. Invest. 92, 2313–2322 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Sibley, R., Sutherland, D. E. R., Goetz, F. & Michael, A. F. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab. Invest. 53, 132–144 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Coppieters, K. T. 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. 209, 51–60 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Keenan, H. A. et al. Residual insulin production and pancreatic β-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 59, 2846–2853 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Roep, B. O. & Peakman, M. Surrogate end points in the design of immunotherapy trials: emerging lessons from type 1 diabetes. Nat. Rev. Immunol. 10, 145–152 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Peterson, L. D., van der Keur, M., de Vries, R. R. & Roep, B. O. Autoreactive and immunoregulatory T-cell subsets in insulin-dependent diabetes mellitus. Diabetologia 42, 443–449 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Roep, B. O. et al. Autoreactive T cell responses in insulin-dependent (type 1) diabetes mellitus. Report of the first international workshop for standardization of T cell assays. J. Autoimmun. 13, 267–282 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Arif, S. et al. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J. Clin. Invest. 113, 451–463 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Tree, T. I., Duinkerken, G., Willemen, S., de Vries, R. R. & Roep, B. O. HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65. Diabetes 53, 1692–1699 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Durinovic-Bello, I. et al. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun. 11, 188–193 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Bach, J. M. et al. High affinity presentation of an autoantigenic peptide in Type I diabetes by an HLA class II protein encoded in a haplotype protecting from disease. J. Autoimmun. 10, 375–386 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Danke, N. A., Yang, J., Greenbaum, C. & Kwok, W. W. Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. J. Autoimmun. 25, 303–311 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Viglietta, V., Kent, S. C., Orban, T. & Hafler, D. A. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J. Clin. Invest. 109, 895–903 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Miyara, M. & Sakaguchi, S. Human FoxP3+CD4+ regulatory T cells: their knowns and unknowns. Immunol. Cell Biol. 89, 346–351 (2011).

    CAS  PubMed  Google Scholar 

  17. 17

    Bach, J. F. Regulatory T cells under scrutiny. Nat. Rev. Immunol. 3, 189–198 (2003).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Roncarolo, M. G. & Levings, M. K. The role of different subsets of T regulatory cells in controlling autoimmunity. Curr. Opin. Immunol. 12, 676–683 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Buckner, J. H. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat. Rev. Immunol. 10, 849–859 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Abbas, A. K. et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat. Immunol. 14, 307–308 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Tritt, M., Sgouroudis, E., d'Hennezel, E., Albanese, A. & Piccirillo, C. A. Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes 57, 113–123 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    D'Alise, A. M. et al. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc. Natl Acad. Sci. USA 105, 19857–19862 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Sgouroudis, E., Albanese, A. & Piccirillo, C. A. Impact of protective IL-2 allelic variants on CD4+ Foxp3+ regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice. J. Immunol. 181, 6283–6292 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Goudy, K. S. et al. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J. Immunol. 186, 3779–3786 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Grinberg-Bleyer, Y. et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Masteller, E. L. et al. Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J. Immunol. 175, 3053–3059 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Tarbell, K. V., Yamazaki, S., Olson, K., Toy, P. & Steinman, R. M. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J. Exp. Med. 199, 1467–1477 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lindley, S. et al. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes 54, 92–99 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Brusko, T. M., Wasserfall, C. H., Clare-Salzler, M. J., Schatz, D. A. & Atkinson, M. A. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 54, 1407–1414 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Glisic, S. & Jailwala, P. Interaction between Treg apoptosis pathways, Treg function and HLA risk evolves during type 1 diabetes pathogenesis. PLoS ONE 7, e36040 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Glisic-Milosavljevic, S. et al. Dynamic changes in CD4+ CD25+(high) T cell apoptosis after the diagnosis of type 1 diabetes. Clin. Exp. Immunol. 150, 75–82 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Glisic-Milosavljevic, S. et al. At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction. PLoS ONE 2, e146 (2007).

    PubMed  PubMed Central  Google Scholar 

  36. 36

    Haseda, F., Imagawa, A., Murase-Mishiba, Y., Terasaki, J. & Hanafusa, T. CD4+ CD45RA FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes. Clin. Exp. Immunol. 173, 207–216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Lawson, J. M. et al. Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin. Exp. Immunol. 154, 353–359 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Schneider, A. et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J. Immunol. 181, 7350–7355 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Tree, T. I., Roep, B. O. & Peakman, M. A mini meta-analysis of studies on CD4+CD25+ T cells in human type 1 diabetes: report of the Immunology of Diabetes Society T Cell Workshop. Ann. NY Acad. Sci. 1079, 9–18 (2006).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Garg, G. et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J. Immunol. 188, 4644–4653 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Long, S. A. 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 59, 407–415 (2010).

    CAS  PubMed  Google Scholar 

  42. 42

    Long, S. A. et al. An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells. Genes Immun. 12, 116–125 (2010).

    PubMed  PubMed Central  Google Scholar 

  43. 43

    Marwaha, A. K. et al. Cutting edge: Increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J. Immunol. 185, 3814–3818 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    McClymont, S. A. et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 186, 3918–3926 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Hulme, M. A., Wasserfall, C. H., Atkinson, M. A. & Brusko, T. M. Central role for interleukin-2 in type 1 diabetes. Diabetes 61, 14–22 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Putnam, A. L. et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58, 652–662 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Ferraro, 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 60, 2903–2913 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Willcox, A., Richardson, S. J., Bone, A. J., Foulis, A. K. & Morgan, N. G. Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol. 155, 173–181 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Gregori, S., Goudy, K. S. & Roncarolo, M. G. The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front. Immunol. 3, 30 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Bacchetta, R. et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J. Exp. Med. 179, 493–502 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Roncarolo, M. G. et al. Autoreactive T cell clones specific for class I and class II HLA antigens isolated from a human chimera. J. Exp. Med. 167, 1523–1534 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Serafini, G. et al. Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia. Haematologica 94, 1415–1426 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Petrich de Marquesini, L. G. et al. IFN-γ and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes. Diabetologia 53, 1451–1460 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Sanda, S., Roep, B. O. & von Herrath, M. Islet antigen specific IL-10+ immune responses but not CD4+CD25+FoxP3+ cells at diagnosis predict glycemic control in type 1 diabetes. Clin. Immunol. 127, 138–143 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Tree, T. I. 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 59, 1451–1460 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Magnani, C. F. et al. Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur. J. Immunol. 41, 1652–1662 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Veldman, C., Hohne, A., Dieckmann, D., Schuler, G. & Hertl, M. Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J. Immunol. 172, 6468–6475 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Ward, F. J. et al. Clonal regulatory T cells specific for a red blood cell autoantigen in human autoimmune hemolytic anemia. Blood 111, 680–687 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Gianfrani, C. et al. Gliadin-specific type 1 regulatory T cells from the intestinal mucosa of treated celiac patients inhibit pathogenic T cells. J. Immunol. 177, 4178–4186 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Meiler, F. et al. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 205, 2887–2898 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Maizels, R. M. & Smith, K. A. Regulatory T cells in infection. Adv. Immunol. 112, 73–136 (2011).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    McSorley, H. J. & Maizels, R. M. Helminth infections and host immune regulation. Clin. Microbiol. Rev. 25, 585–608 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Tian, J. et al. Modulating autoimmune response to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat. Med. 12, 1348–1353 (1996).

    Google Scholar 

  64. 64

    Tisch, R., Liblau, R. S., Yang, X. D., Liblau, P. & McDevitt, H. O. Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. Diabetes 47, 894–899 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Tisch, R. et al. Antigen-specific mediated suppression of β cell autoimmunity by plasmid DNA vaccination. J. Immunol. 166, 2122–2132 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Thrower, S. L. et al. Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man phase I safety study. Clin. Exp. Immunol. 155, 156–165 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Campbell, J. D. et al. Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression. J. Exp. Med. 206, 1535–1547 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Patel, D. et al. Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. J. Allergy Clin. Immunol. 131, 103–109 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Tsai, S. et al. Reversal of autoimmunity by boosting memory-like autoregulatory T cells. Immunity 32, 568–580 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Kalampokis, I., Yoshizaki, A. & Tedder, T. F. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res. Ther. 15 (Suppl. 1), S1 (2013).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Hussain, S. & Delovitch, T. L. Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner. J. Immunol. 179, 7225–7232 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Hu, C. Y. et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J. Clin. Invest. 117, 3857–3867 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Pescovitz, M. D. et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 361, 2143–2152 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Nikolic, T. & Roep, B. O. Regulatory multitasking of tolerogenic dendritic cells—lessons taken from vitamin d3-treated tolerogenic dendritic cells. Front. Immunol. 4, 113 (2013).

    PubMed  PubMed Central  Google Scholar 

  75. 75

    Kleijwegt, F. S. & Roep, B. O. Infectious tolerance as candidate therapy for type 1 diabetes: transfer of immunoregulatory properties from human regulatory T cells to other T cells and proinflammatory dendritic cells. Crit. Rev. Immunol. 33, 415–434 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Kleijwegt, F. S. et al. Transfer of regulatory properties from tolerogenic to proinflammatory dendritic cells via induced autoreactive regulatory T cells. J. Immunol. 187, 6357–6364 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Peterson, L. D., van der Keur, M., de Vries, R. R. & Roep, B. O. Autoreactive and immunoregulatory T-cell subsets in insulin-dependent diabetes mellitus. Diabetologia 42, 443–449 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Naik, R. G. et al. Precursor frequencies of T-cells reactive to insulin in recent onset type 1 diabetes mellitus. J. Autoimmun. 23, 55–61 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Geiler, J., Buch, M. & McDermott, M. F. Anti-TNF treatment in rheumatoid arthritis. Curr. Pharm. Des. 17, 3141–3154 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Skyler, J. S. et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial–Type 1. Diabetes Care 28, 1068–1076 (2005).

    CAS  PubMed  Google Scholar 

  82. 82

    Bougneres, P. F. et al. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N. Engl. J. Med. 318, 663–670 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Silverstein, J. et al. Immunosuppression with azathioprine and prednisone in recent onset insulin-dependent diabetes mellitus. N. Engl. J. Med. 319, 599–604 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Feutren, G. & Mihatsch, M. J. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N. Engl. J. Med. 326, 1654–1660 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Couri, C. E. et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 301, 1573–1579 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Voltarelli, J. C. et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297, 1568–1576 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Gale, E. A. M. Can. we change the course of β-cell destruction in type 1 diabetes? N. Engl. J. Med. 346, 1740–1742 (2002).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Noon, L. Prophylactic inoculation against hay fever. Lancet 177, 1572–1573 (1911).

    Google Scholar 

  89. 89

    Greenbaum, C. J. et al. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes 61, 2066–2073 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Orban, T. et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412–419 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Roep, B. O. New hope for immune intervention therapy in type 1 diabetes. Lancet 378, 376–378 (2011).

    PubMed  PubMed Central  Google Scholar 

  92. 92

    Buzzetti, R. et al. C-peptide response and HLA genotypes in subjects with recent-onset type 1 diabetes after immunotherapy with DiaPep277: an exploratory study. Diabetes 60, 3067–3072 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Qu, H. Q. & Polychronakos, C. The effect of the MHC locus on autoantibodies in type 1 diabetes. J. Med. Genet. 46, 469–471 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Kobayashi, T. et al. Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care 16, 780–788 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Barker, J. M. et al. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J. Clin. Endocrinol. Metab. 89, 3896–3902 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Howson, J. M. et al. Evidence that HLA class I and II associations with type 1 diabetes, autoantibodies to GAD and autoantibodies to IA-2, are distinct. Diabetes 60, 2635–2644 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Ludvigsson, J. et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366, 433–442 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Raz, I. et al. 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. Lancet 358, 1749–1753 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Bonifacio, E., Ziegler, A., Achenbach, P., Barker, J. & Eisenbarth, G. Translating mucosal antigen based prevention of autoimmune diabetes to human. Novartis Found. Symp. 292, 187–199 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Fourlanos, S. et al. Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 60, 1237–1245 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Nanto-Salonen, K. 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. Lancet 372, 1746–1755 (2008).

    PubMed  Google Scholar 

  102. 102

    Lesterhuis, W. J. et al. Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients. Clin. Cancer Res. 17, 5725–5735 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Roep, B. O., Atkinson, M. & von Herrath, M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat. Rev. Immunol. 4, 989–997 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Huurman, V. A., Decochez, K., Mathieu, C., Cohen, I. R. & Roep, B. O. Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab. Res. Rev. 23, 269–275 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Ludvigsson, J. et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N. Engl. J. Med. 359, 1909–1920 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Roep, B. O. et al. Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabetes. Sci. Transl. Med. 5, 191ra82 (2013).

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Huurman, V. A. et al. Immunological efficacy of heat shock protein 60 peptide DiaPep277 therapy in clinical type I diabetes. Clin. Exp. Immunol. 152, 488–497 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598–2608 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Oresic, M. et al. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J. Exp. Med. 205, 2975–2984 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Diabetes Prevention Trial–Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 346, 1685–1691 (2002).

  111. 111

    Long, S. A. et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes 61, 2340–2348 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Roep, B. O. Immune intervention therapy in type 1 diabetes: safety first. Lancet Diabetes Endocrinol. 1, 263–265 (2013).

    PubMed  PubMed Central  Google Scholar 

  113. 113

    Harlan, D. M., Kenyon, N. S., Korsgren, O. & Roep, B. O. Current advances and travails in islet transplantation. Diabetes 58, 2175–2184 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Hilbrands, R. et al. Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes 58, 2267–2276 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Huurman, V. A. et al. Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS ONE 3, e2435 (2008).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Velthuis, J. H. et al. Simultaneous detection of circulating autoreactive CD8+ T-cells specific for different islet cell-associated epitopes using combinatorial MHC multimers. Diabetes 59, 1721–1730 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Gitelman, S. E. et al. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 1, 306–316 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Rigby, M. R. et al. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 1, 284–294 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Roncarolo, M. G. & Battaglia, M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat. Rev. Immunol. 7, 585–598 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Brusko, T. & Bluestone, J. Clinical application of regulatory T cells for treatment of type 1 diabetes and transplantation. Eur. J. Immunol. 38, 931–934 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Marek-Trzonkowska, N. et al. Administration of CD4+CD25highCD127 regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care 35, 1817–1820 (2012).

    PubMed  PubMed Central  Google Scholar 

  122. 122

    Welters, M. J. et al. Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses. Proc. Natl Acad. Sci. USA 107, 11895–11899 (2010).

    CAS  PubMed  Google Scholar 

  123. 123

    Sutmuller, R. P. et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J. Exp. Med. 194, 823–832 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Brusko, T. M. et al. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer. PLoS ONE 5, e11726 (2010).

    PubMed  PubMed Central  Google Scholar 

  125. 125

    Kleijwegt, F. S. et al. Critical role for TNF in the induction of human antigen-specific regulatory T cells by tolerogenic dendritic cells. J. Immunol. 185, 1412–1418 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Roep, B. O. et al. Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin. Exp. Immunol. 159, 338–343 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    van Halteren, A. G., Kardol, M. J., Mulder, A. & Roep, B. O. Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice. Diabetologia 48, 75–82 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    van Halteren, A. G., Tysma, O. M., van Etten, E., Mathieu, C. & Roep, B. O. 1α,25-dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis. J. Autoimmun. 23, 233–239 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Unger, W. W., Laban, S., Kleijwegt, F. S., van der Slik, A. R. & Roep, B. O. Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur. J. Immunol. 39, 3147–3159 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Cobbold, S. P. et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl Acad. Sci. USA 106, 12055–12060 (2009).

    CAS  PubMed  Google Scholar 

  131. 131

    Qin, S. et al. “Infectious” transplantation tolerance. Science 259, 974–977 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Sanchez-Fueyo, A. et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. 4, 1093–1101 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Sumitomo, S. et al. Transcription factor early growth response 3 is associated with the TGF-β1 expression and the regulatory activity of CD4-positive T cells in vivo. J. Immunol. 191, 2351–2359 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Matthews, J. B. et al. Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group. Clin. Exp. Immunol. 160, 176–184 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Huurman, V. A. et al. Allograft-specific cytokine profiles associate with clinical outcome after islet cell transplantation. Am. J. Transplant. 9, 382–388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Benoist, C. & Mathis, D. Treg cells, life history, and diversity. Cold Spring Harb. Perspect. Biol. 4, a007021 (2012).

    PubMed  PubMed Central  Google Scholar 

  137. 137

    Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

    CAS  Google Scholar 

  138. 138

    Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746 (2013).

    CAS  PubMed  Google Scholar 

  140. 140

    Gregori, S. et al. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 116, 935–944 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Barchet, W. et al. Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation. Blood 107, 1497–1504 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Battaglia, M. & Roncarolo, M. G. The role of cytokines (and not only) in inducing and expanding T regulatory type 1 cells. Transplantation 77 (1 Suppl.), S16–S18 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A. H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Kemper, C. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Levings, M. K. et al. IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 166, 5530–5539 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002).

    CAS  PubMed  Google Scholar 

  148. 148

    Moran, A. et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 381, 1905–1915 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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Both authors contributed equally to all aspects of the manuscript.

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Correspondence to Bart O. Roep.

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B. O. Roep has consulted for Andromeda Biotech, Diamyd Medical, GlaxoSmithKline and Lilly. B. O. Roep has performed contract research for Andromeda Biotech and Bayhill Therapeutics. T. I. M. Tree declares no competing interests.

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Roep, B., Tree, T. Immune modulation in humans: implications for type 1 diabetes mellitus. Nat Rev Endocrinol 10, 229–242 (2014). https://doi.org/10.1038/nrendo.2014.2

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