Skip to main content
SpringerLink
Log in

Immunotherapy of Type-1 Diabetes: Immunoprevention and Immunoreversal

  • Chapter
  • First Online:
Immunoendocrinology: Scientific and Clinical Aspects

Part of the book series: Contemporary Endocrinology ((COE))

  • 879 Accesses

Summary

Type-1A diabetes (T1D) is characterized by a progressive insidious loss of self-tolerance to pancreatic islet beta cells resulting in their destruction and the development of overt hyperglycemia. Immunotherapy aims either to reverse the autoimmune process thereby preventing the development of the disease (immunoprevention) or to intervene at clinical diagnosis of type-1 diabetes and preserve residual b cell function (immunoreversal). Murine models and clinical studies of patients with type-1 diabetes have provided insights into the immunopathogenesis of type-1 diabetes and have led to the development of immunomodulatory therapeutic strategies. Recent clinical trials of anti-CD3 monoclonal antibody (mAbs) and glutamic acid decarboxylase (GAD) peptide have proven successful in attenuating loss of insulin production. Current individual clinical trials are investigating the use of anti-CD3 mAb, GAD, Rituximab, and Abatacept to maintain insulin responses. These trials will lay the groundwork for future studies in which more complete metabolic correction and immunologic tolerance will be restored, possibly with the use of combinations of therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Daneman D. Type 1 diabetes. Lancet 2006;367:847–858.

    Article  PubMed  CAS  Google Scholar 

  2. Liu E, Eisenbarth GS. Type 1A diabetes mellitus-associated autoimmunity. Endocrinol Metab Clin North Am 2002;31:391–410, vii–viii.

    Article  PubMed  Google Scholar 

  3. Waldron-Lynch F, Herold K. Advances in type 1 diabetes therapeutics: immunomodulation and beta cell salvage. Endocrinol Metab Clin North Am 2009;38(2):303–317.

    Article  PubMed  CAS  Google Scholar 

  4. American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care 2008;31(Suppl 1):S12–S54.

    Article  CAS  Google Scholar 

  5. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977–986.

    Google Scholar 

  6. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653.

    Article  PubMed  Google Scholar 

  7. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285–2293.

    Article  PubMed  CAS  Google Scholar 

  8. Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997;46:271–286.

    Google Scholar 

  9. Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003;26:832–836.

    Article  PubMed  Google Scholar 

  10. Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes 2004;53:250–264.

    Article  PubMed  CAS  Google Scholar 

  11. Yoshida K, Kikutani H. Genetic and immunological basis of autoimmune diabetes in the NOD mouse. Rev Immunogenet 2000;2:140–146.

    PubMed  CAS  Google Scholar 

  12. DiLorenzo TP, Serreze DV. The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice. Immunol Rev 2005;204:250–263.

    Article  PubMed  CAS  Google Scholar 

  13. Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005;435:220–223.

    Article  PubMed  CAS  Google Scholar 

  14. Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L. Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 1995;181:817–821.

    Article  PubMed  CAS  Google Scholar 

  15. Tang Q, Henriksen KJ, Bi M, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004;199:1455–1465.

    Article  PubMed  CAS  Google Scholar 

  16. Silveira PA, Grey ST. B cells in the spotlight: innocent bystanders or major players in the pathogenesis of type 1 diabetes. Trends Endocrinol Metab 2006;17:128–135.

    Article  PubMed  CAS  Google Scholar 

  17. Chiu PP, Serreze DV, Danska JS. Development and function of diabetogenic T-cells in B-cell-deficient nonobese diabetic mice. Diabetes 2001;50:763–770.

    Article  PubMed  CAS  Google Scholar 

  18. Yang M, Charlton B, Gautam AM. Development of insulitis and diabetes in B cell-deficient NOD mice. J Autoimmun 1997;10:257–260.

    Article  PubMed  CAS  Google Scholar 

  19. Wong FS, Wen L, Tang M, et al. Investigation of the role of B-cells in type 1 diabetes in the NOD mouse. Diabetes 2004;53:2581–2587.

    Article  PubMed  CAS  Google Scholar 

  20. 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;163:743–750.

    PubMed  CAS  Google Scholar 

  21. Marino E, Grey ST. A new role for an old player: do B cells unleash the self-reactive CD8+ T cell storm necessary for the development of type 1 diabetes? J Autoimmun 2008;31:301–305.

    Article  PubMed  CAS  Google Scholar 

  22. De Aizpurua HJ, French MB, Chosich N, Harrison LC. Natural history of humoral immunity to glutamic acid decarboxylase in non-obese diabetic (NOD) mice. J Autoimmun 1994;7:643–653.

    Article  PubMed  Google Scholar 

  23. Morran MP, McInerney MF, Pietropaolo M. Innate and adaptive autoimmunity in type 1 diabetes. Pediatr Diabetes 2008;9:152–161.

    Article  PubMed  CAS  Google Scholar 

  24. Zipris D. Innate immunity and its role in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2008;15:326–331.

    Article  PubMed  CAS  Google Scholar 

  25. Hill NJ, Van Gunst K, Sarvetnick N. Th1 and Th2 pancreatic inflammation differentially affects homing of islet-reactive CD4 cells in nonobese diabetic mice. J Immunol 2003;170:1649–1658.

    PubMed  CAS  Google Scholar 

  26. Alba A, Planas R, Clemente X, et al. Natural killer cells are required for accelerated type 1 diabetes driven by interferon-beta. Clin Exp Immunol 2008;151:467–475.

    Article  PubMed  CAS  Google Scholar 

  27. Jun HS, Santamaria P, Lim HW, Zhang ML, Yoon JW. Absolute requirement of macrophages for the development and activation of beta-cell cytotoxic CD8+ T-cells in T-cell receptor transgenic NOD mice. Diabetes 1999;48:34–42.

    Article  PubMed  CAS  Google Scholar 

  28. Pearl-Yafe M, Kaminitz A, Yolcu ES, Yaniv I, Stein J, Askenasy N. Pancreatic islets under attack: cellular and molecular effectors. Curr Pharm Des 2007;13:749–760.

    Article  PubMed  CAS  Google Scholar 

  29. Wen L, Ley RE, Volchkov PY, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008;455:1109–1113.

    Article  PubMed  CAS  Google Scholar 

  30. Dotta F, Censini S, van Halteren AG, et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A 2007;104:5115–5120.

    Article  PubMed  CAS  Google Scholar 

  31. Itoh N, Hanafusa T, Miyazaki A, 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 1993;92:2313–2322.

    Article  PubMed  CAS  Google Scholar 

  32. von Herrath M, Sanda S, Herold K. Type 1 diabetes as a relapsing-remitting disease? Nat Rev Immunol 2007;7:988–994.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  34. Roll U, Christie MR, Fuchtenbusch M, Payton MA, Hawkes CJ, Ziegler AG. Perinatal autoimmunity in offspring of diabetic parents The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 1996;45:967–973.

    Article  PubMed  Google Scholar 

  35. Erlich H, Valdes AM, Noble J, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008;57:1084–1092.

    Article  PubMed  CAS  Google Scholar 

  36. Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005;435:224–228.

    Article  PubMed  CAS  Google Scholar 

  37. 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;345:1036–1040.

    Article  PubMed  CAS  Google Scholar 

  38. Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996;45:926–933.

    Article  PubMed  CAS  Google Scholar 

  39. Yu L, Rewers M, Gianani R, et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J Clin Endocrinol Metab 1996;81:4264–4267.

    Article  PubMed  CAS  Google Scholar 

  40. Yu L, Cuthbertson DD, Maclaren N, et al. Expression of GAD65 and islet cell antibody (ICA512) autoantibodies among cytoplasmic ICA+ relatives is associated with eligibility for the Diabetes Prevention Trial-Type 1. Diabetes 2001;50:1735–1740.

    Article  PubMed  CAS  Google Scholar 

  41. Bingley PJ, Bonifacio E, Williams AJ, Genovese S, Bottazzo GF, Gale EA. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 1997;46:1701–1710.

    Article  PubMed  CAS  Google Scholar 

  42. Mahon JL, Sosenko JM, Rafkin-Mervis L, et al. The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results. Pediatr Diabetes 2009;10(2):97–104.

    Article  PubMed  Google Scholar 

  43. Sosenko JM, Palmer JP, Greenbaum CJ, et al. Patterns of metabolic progression to type 1 diabetes in the diabetes prevention trial-type 1. Diabetes Care 2006;29:643–649.

    Article  PubMed  Google Scholar 

  44. Sherr J, Sosenko J, Skyler J, Herold K. Prevention of type 1 diabetes: the time has come. Nat Clin Pract Endocrinol Metab 2008;4:334–343.

    PubMed  Google Scholar 

  45. Sosenko JM, Palmer JP, Greenbaum CJ, et al. Increasing the accuracy of oral glucose tolerance testing and extending its application to individuals with normal glucose tolerance for the prediction of type 1 diabetes: the diabetes prevention trial-type 1. Diabetes Care 2007;30:38–42.

    Article  PubMed  CAS  Google Scholar 

  46. Sosenko JM, Krischer JP, Palmer JP, et al. A risk score for type 1 diabetes derived from autoantibody-positive participants in the diabetes prevention trial-type 1. Diabetes Care 2008;31:528–533.

    Article  PubMed  CAS  Google Scholar 

  47. Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man–macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol 1991;165:97–103.

    Article  PubMed  CAS  Google Scholar 

  48. Waldron-Lynch F, von Herrath M, Herold K. Towards a curative therapy in type 1 diabetes: remission of autoimmunity, maintenance and augmentation of B cell mass. Novartis Found Symp 2008;292:146–155.

    Article  PubMed  CAS  Google Scholar 

  49. Haller MJ, Gottlieb PA, Schatz DA. Type 1 diabetes intervention trials 2007: where are we and where are we going? Curr Opin Endocrinol Diabetes Obes 2007;14:283–287.

    Article  PubMed  Google Scholar 

  50. Staeva-Vieira T, Peakman M, von Herrath M. Translational mini-review series on type 1 diabetes: immune-based therapeutic approaches for type 1 diabetes. Clin Exp Immunol 2007;148:17–31.

    Article  PubMed  CAS  Google Scholar 

  51. Waldmann H, Cobbold SP, Fairchild P, Adams E. Therapeutic aspects of tolerance. Curr Opin Pharmacol 2001;1:392–397.

    Article  PubMed  CAS  Google Scholar 

  52. Fousteri G, Bresson D, von Herrath M. Rational development of antigen-specific therapies for type 1 diabetes. Adv Exp Med Biol 2007;601:313–319.

    Article  PubMed  Google Scholar 

  53. Cobbold SP, Nolan KF, Graca L, et al. Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms. Immunol Rev 2003;196:109–124.

    Article  PubMed  CAS  Google Scholar 

  54. St Clair EW, Turka LA, Saxon A, et al. New reagents on the horizon for immune tolerance. Annu Rev Med 2007;58:329–346.

    Article  PubMed  CAS  Google Scholar 

  55. Winer S, Gunaratnam L, Astsatourov I, et al. Peptide dose, MHC affinity, and target self-antigen expression are critical for effective immunotherapy of nonobese diabetic mouse prediabetes. J Immunol 2000;165:4086–4094.

    PubMed  CAS  Google Scholar 

  56. Martinez NR, Augstein P, Moustakas AK, et al. Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J Clin Invest 2003;111:1365–1371.

    PubMed  CAS  Google Scholar 

  57. Graca L, Chen TC, Le Moine A, Cobbold SP, Howie D, Waldmann H. Dominant tolerance: activation thresholds for peripheral generation of regulatory T cells. Trends Immunol 2005;26:130–135.

    Article  PubMed  CAS  Google Scholar 

  58. Horvath L, Cervenak L, Oroszlan M, et al. Antibodies against different epitopes of heat-shock protein 60 in children with type 1 diabetes mellitus. Immunol Lett 2002;80:155–162.

    Article  PubMed  CAS  Google Scholar 

  59. Brugman S, Klatter FA, Visser J, Bos NA, Elias D, Rozing J. Neonatal oral administration of DiaPep277, combined with hydrolysed casein diet, protects against type 1 diabetes in BB-DP rats. An experimental study. Diabetologia 2004;47:1331–1333.

    Article  PubMed  CAS  Google Scholar 

  60. Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A 1991;88:10252–10256.

    Article  PubMed  CAS  Google Scholar 

  61. Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet 1993;341:927–928.

    Article  PubMed  CAS  Google Scholar 

  62. Bergerot I, Fabien N, Maguer V, Thivolet C. Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. J Autoimmun 1994;7:655–663.

    Article  PubMed  CAS  Google Scholar 

  63. Sercarz EE. Driver clones and determinant spreading. J Autoimmun 2000;14:275–277.

    Article  PubMed  CAS  Google Scholar 

  64. 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;346:1685–1691.

    Article  Google Scholar 

  65. Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial – Type 1. Diabetes Care 2005;28:1068–1076.

    Article  PubMed  CAS  Google Scholar 

  66. Näntö-Salonen K, Kupila A, Simell S, 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 2008;372:1746–1755.

    Article  PubMed  CAS  Google Scholar 

  67. Polanski M, Melican NS, Zhang J, Weiner HL. Oral administration of the immunodominant B-chain of insulin reduces diabetes in a co-transfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines. J Autoimmun 1997;10:339–346.

    Article  PubMed  CAS  Google Scholar 

  68. Bergerot I, Fabien N, Mayer A, Thivolet C. Active suppression of diabetes after oral administration of insulin is determined by antigen dosage. Ann N Y Acad Sci 1996;778:362–367.

    Article  PubMed  CAS  Google Scholar 

  69. Di Lorenzo TP, Peakman M, Roep BO. Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 2007;148:1–16.

    Article  PubMed  Google Scholar 

  70. Achenbach P, Barker J, Bonifacio E, Pre PSG. Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. Curr Diab Rep 2008;8:87–93.

    Article  PubMed  CAS  Google Scholar 

  71. Trialnet. The oral insulin for the prevention of type 1 diabetes study. In: 2008.

    Google Scholar 

  72. Sloan-Lancaster J, Allen PM. Altered peptide ligand-induced partial T cell activation: molecular mechanisms and role in T cell biology. Annu Rev Immunol 1996;14:1–27.

    Article  PubMed  CAS  Google Scholar 

  73. Alleva DG, Gaur A, Jin L, et al. Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide. Diabetes 2002;51:2126–2134.

    Article  PubMed  CAS  Google Scholar 

  74. Alleva DG, Maki RA, Putnam AL, et al. Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B epitope. Scand J Immunol 2006;63:59–69.

    Article  PubMed  CAS  Google Scholar 

  75. Fenalti G, Rowley M. GAD65 as a prototypic autoantigen. J Autoimmun 2008;31(3):228–232.

    Article  PubMed  CAS  Google Scholar 

  76. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990;347:151–156.

    Article  PubMed  CAS  Google Scholar 

  77. Skorstad G, Hestvik AL, Vartdal F, Holmoy T. Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65 in patients with stiff person syndrome. J Autoimmun 2009;32(1):24–32.

    Article  PubMed  CAS  Google Scholar 

  78. Oling V, Marttila J, Ilonen J, 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. J Autoimmun 2005;25:235–243.

    Article  PubMed  CAS  Google Scholar 

  79. Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993;366:72–75.

    Article  PubMed  CAS  Google Scholar 

  80. Tian J, Clare-Salzler M, Herschenfeld A, et al. Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat Med 1996;2:1348–1353.

    Article  PubMed  CAS  Google Scholar 

  81. Tian J, Atkinson MA, Clare-Salzler M, et al. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med 1996;183:1561–1567.

    Article  PubMed  CAS  Google Scholar 

  82. Tisch R, Liblau RS, Yang XD, Liblau P, McDevitt HO. Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. Diabetes 1998;47:894–899.

    Article  PubMed  CAS  Google Scholar 

  83. Agardh CD, Cilio CM, Lethagen A, et al. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications 2005;19:238–246.

    Article  PubMed  Google Scholar 

  84. Ludvigsson J, Faresjo M, Hjorth M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med 2008;359:1909–1920.

    Article  PubMed  CAS  Google Scholar 

  85. Ludvigsson J. Immune intervention at diagnosis–should we treat children to preserve beta-cell function? Pediatr Diabetes 2007;8(Suppl 6):34–39.

    Article  PubMed  Google Scholar 

  86. Brudzynski K, Martinez V, Gupta RS. Secretory granule autoantigen in insulin-dependent diabetes mellitus is related to 62 kDa heat-shock protein (hsp60). J Autoimmun 1992;5:453–463.

    Article  PubMed  CAS  Google Scholar 

  87. Brudzynski K, Cunningham IA, Martinez V. A family of hsp60-related proteins in pancreatic beta cells of non-obese diabetic (NOD) mice. J Autoimmun 1995;8:859–874.

    Article  PubMed  CAS  Google Scholar 

  88. Zanin-Zhorov A, Tal G, Shivtiel S, et al. Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. J Immunol 2005;175:276–285.

    PubMed  CAS  Google Scholar 

  89. Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR. Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest 2006;116:2022–2032.

    Article  PubMed  CAS  Google Scholar 

  90. Raz I, Avron A, Tamir M, et al. Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab Res Rev 2007;23:292–298.

    Article  PubMed  CAS  Google Scholar 

  91. Huurman VA, Decochez K, Mathieu C, Cohen IR, Roep BO. Therapy with the hsp60 peptide DiaPep277 in C-peptide positive type 1 diabetes patients. Diabetes Metab Res Rev 2007;23:269–275.

    Article  PubMed  CAS  Google Scholar 

  92. Schloot NC, Meierhoff G, Lengyel C, et al. Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: two prospective, randomized, double-blind phase II trials. Diabetes Metab Res Rev 2007;23:276–285.

    Article  PubMed  CAS  Google Scholar 

  93. Lazar L, Ofan R, Weintrob N, et al. Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study. Diabetes Metab Res Rev 2007;23:286–291.

    Article  PubMed  CAS  Google Scholar 

  94. Cernea S, Pozzilli P. New potential treatments for protection of pancreatic B-cell function in type 1 diabetes. Diabet Med 2008;25:1259–1267.

    PubMed  CAS  Google Scholar 

  95. Bisikirska B, Colgan J, Luban J, Bluestone JA, Herold KC. TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin Invest 2005;115:2904–2913.

    Article  PubMed  CAS  Google Scholar 

  96. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 2007;7:622–632.

    Article  PubMed  CAS  Google Scholar 

  97. Gale EA, Bingley PJ, Emmett CL, Collier T, European Nicotinamide Diabetes Intervention Trial Group. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004;363:925–931.

    Article  PubMed  CAS  Google Scholar 

  98. Stiller CR, Dupre J, Gent M, et al. Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 1984;223:1362–1367.

    Article  PubMed  CAS  Google Scholar 

  99. Stiller CR, Dupre J, Gent M, et al. Effects of cyclosporine in recent-onset juvenile type 1 diabetes: impact of age and duration of disease. J Pediatr 1987;111:1069–1072.

    Article  PubMed  CAS  Google Scholar 

  100. 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;318:663–670.

    Article  PubMed  CAS  Google Scholar 

  101. Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988;319:599–604.

    Article  PubMed  CAS  Google Scholar 

  102. Bougneres PF, Landais P, Boisson C, et al. Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin. Diabetes 1990;39:1264–1272.

    Article  PubMed  CAS  Google Scholar 

  103. Cook JJ, Hudson I, Harrison LC, et al. Double-blind controlled trial of azathioprine in children with newly diagnosed type I diabetes. Diabetes 1989;38:779–783.

    Article  PubMed  CAS  Google Scholar 

  104. Parving HH, Tarnow L, Nielsen FS, et al. Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes Care 1999;22:478–483.

    Article  PubMed  CAS  Google Scholar 

  105. Bingley PJ, Mahon JL, Gale EA, European Nicotinamide Diabetes Intervention Trial Group. Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetes Care 2008;31:146–150.

    Article  PubMed  CAS  Google Scholar 

  106. Rother KI, Wijewickrama RC, Digon BJ, et al. Effect of exenatide alone or in combination with daclizumab on endogenous insulin secretion in patients with long-standing type 1 diabetes. In: 68th Scientific Sessions of the American Diabetes Associations. 2008;471-P.

    Google Scholar 

  107. Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 1981;32:535–539.

    Article  PubMed  CAS  Google Scholar 

  108. Friend PJ, Hale G, Chatenoud L, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 1999;68:1632–1637.

    Article  PubMed  CAS  Google Scholar 

  109. Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 1989;47:606–608.

    Article  PubMed  CAS  Google Scholar 

  110. Chatenoud L, Ferran C, Reuter A, et al. Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-gamma [corrected]. N Engl J Med 1989;320:1420–1421.

    Article  PubMed  CAS  Google Scholar 

  111. Chatenoud L. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 2003;3:123–132.

    Article  PubMed  CAS  Google Scholar 

  112. Hirsch R, Bluestone JA, DeNenno L, Gress RE. Anti-CD3 F(ab’)2 fragments are immunosuppressive in vivo without evoking either the strong humoral response or morbidity associated with whole mAb. Transplantation 1990;49:1117–1123.

    Article  PubMed  CAS  Google Scholar 

  113. Bolt S, Routledge E, Lloyd I, et al. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 1993;23:403–411.

    Article  PubMed  CAS  Google Scholar 

  114. Alegre ML, Peterson LJ, Xu D, et al. A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 1994;57:1537–1543.

    PubMed  CAS  Google Scholar 

  115. Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci U S A 1994;91:123–127.

    Article  PubMed  CAS  Google Scholar 

  116. Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003;9:1202–1208.

    Article  PubMed  CAS  Google Scholar 

  117. Chatenoud L, Primo J, Bach JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 1997;158:2947–2954.

    PubMed  CAS  Google Scholar 

  118. Herold KC, Burton JB, Francois F, Poumian-Ruiz E, Glandt M, Bluestone JA. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest 2003;111:409–418.

    PubMed  CAS  Google Scholar 

  119. Plain KM, Chen J, Merten S, He XY, Hall BM. Induction of specific tolerance to allografts in rats by therapy with non-mitogenic, non-depleting anti-CD3 monoclonal antibody: association with TH2 cytokines not anergy. Transplantation 1999;67:605–613.

    Article  PubMed  CAS  Google Scholar 

  120. Chatenoud L. The use of CD3-specific antibodies in autoimmune diabetes: a step toward the induction of immune tolerance in the clinic. Handb Exp Pharmacol 2008;181:221–236.

    Article  PubMed  CAS  Google Scholar 

  121. Smith JA, Tso JY, Clark MR, Cole MS, Bluestone JA. Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy. J Exp Med 1997;185:1413–1422.

    Article  PubMed  CAS  Google Scholar 

  122. 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;54:1763–1769.

    Article  PubMed  CAS  Google Scholar 

  123. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692–1698.

    Article  PubMed  CAS  Google Scholar 

  124. 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;352:2598–2608.

    Article  PubMed  CAS  Google Scholar 

  125. Monti P, Scirpoli M, Maffi P, et al. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 2008;118:1806–1814.

    PubMed  CAS  Google Scholar 

  126. Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 2006;24:467–496.

    Article  PubMed  CAS  Google Scholar 

  127. Molina A. A decade of rituximab: improving survival outcomes in non-Hodgkin’s lymphoma. Annu Rev Med 2008;59:237–250.

    Article  PubMed  CAS  Google Scholar 

  128. Looney RJ. B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis. Rheumatology (Oxford) 2005;44(Suppl 2):ii13–ii17.

    Article  CAS  Google Scholar 

  129. Kazkaz H, Isenberg D. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases. Curr Opin Pharmacol 2004;4:398–402.

    Article  PubMed  CAS  Google Scholar 

  130. Uchida J, Lee Y, Hasegawa M, et al. Mouse CD20 expression and function. Int Immunol 2004;16:119–129.

    Article  PubMed  CAS  Google Scholar 

  131. 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;117:3857–3867.

    Article  PubMed  CAS  Google Scholar 

  132. Xiu Y, Wong CP, Bouaziz JD, et al. B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions. J Immunol 2008;180:2863–2875.

    PubMed  CAS  Google Scholar 

  133. Rituximab. 2008. (Accessed at http://www.diabetestrialnet.org/patientinfo/studies/rituximab.htm.)

  134. Vincenti F. Costimulation blockade in autoimmunity and transplantation. J Allergy Clin Immunol 2008;121:299–306.

    Article  PubMed  CAS  Google Scholar 

  135. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 2008;224:166–182.

    Article  PubMed  CAS  Google Scholar 

  136. Schneider H, Downey J, Smith A, et al. Reversal of the TCR stop signal by CTLA-4. Science 2006;313:1972–1975.

    Article  PubMed  CAS  Google Scholar 

  137. Bluestone JA, St Clair EW, Turka LA. CTLA4Ig: bridging the basic immunology with clinical application. Immunity 2006;24:233–238.

    Article  PubMed  CAS  Google Scholar 

  138. Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423:506–511.

    Article  PubMed  CAS  Google Scholar 

  139. Abrams JR, Lebwohl MG, Guzzo CA, et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999;103:1243–1252.

    Article  PubMed  CAS  Google Scholar 

  140. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263–2271.

    Article  PubMed  CAS  Google Scholar 

  141. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865–876.

    PubMed  CAS  Google Scholar 

  142. Russell AS, Wallenstein GV, Li T, et al. Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. Ann Rheum Dis 2007;66:189–194.

    Article  PubMed  CAS  Google Scholar 

  143. Kremer JM, Genant HK, Moreland LW, et al. Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum 2008;58:953–963.

    Article  PubMed  CAS  Google Scholar 

  144. Lenschow DJ, Herold KC, Rhee L, et al. CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 1996;5:285–293.

    Article  PubMed  CAS  Google Scholar 

  145. 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;12:431–440.

    Article  PubMed  CAS  Google Scholar 

  146. Trialnet. CTLA4-Ig. In: 2008.

    Google Scholar 

  147. Shevach EM. Immunology. Regulating suppression. Science 2008;322:202–203.

    Article  PubMed  CAS  Google Scholar 

  148. Cobbold SP, Adams E, Graca L, et al. Immune privilege induced by regulatory T cells in transplantation tolerance. Immunol Rev 2006;213:239–255.

    Article  PubMed  CAS  Google Scholar 

  149. Bresson D, Togher L, Rodrigo E, et al. Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs. J Clin Invest 2006;116:1371–1381.

    Article  PubMed  CAS  Google Scholar 

  150. Sherry NA, Chen W, Kushner JA, et al. Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells. Endocrinology 2007;148:5136–5144.

    Article  PubMed  CAS  Google Scholar 

  151. 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;50:596–601.

    Article  PubMed  CAS  Google Scholar 

  152. Kaizer EC, Glaser CL, Chaussabel D, Banchereau J, Pascual V, White PC. Gene expression in peripheral blood mononuclear cells from children with diabetes. J Clin Endocrinol Metab 2007;92:3705–3711.

    Article  PubMed  CAS  Google Scholar 

  153. Bilgic S, Aktas E, Salman F, et al. Intracytoplasmic cytokine levels and neutrophil functions in early clinical stage of type 1 diabetes. Diabetes Res Clin Pract 2008;79:31–36.

    Article  PubMed  CAS  Google Scholar 

  154. Pfleger C, Mortensen HB, Hansen L, et al. Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes. Diabetes 2008;57:929–937.

    Article  PubMed  CAS  Google Scholar 

  155. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007;356:1517–1526.

    Article  PubMed  CAS  Google Scholar 

  156. Skyler JS. Prediction and prevention of type 1 diabetes: progress, problems, and prospects. Clin Pharmacol Ther 2007;81:768–771.

    Article  PubMed  CAS  Google Scholar 

  157. Gandhi GY, Murad MH, Flynn DN, et al. Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials. Clin Endocrinol (Oxf) 2008;69:244–252.

    Article  CAS  Google Scholar 

  158. Strand V, Kimberly R, Isaacs JD. Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev Drug Discov 2007;6:75–92.

    Article  PubMed  CAS  Google Scholar 

  159. Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity. Nature 2005;435:612–619.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT, USA

    Frank Waldron-Lynch & Kevan C. Herold

Authors
  1. Frank Waldron-Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevan C. Herold
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Health Sciences Center, Children's Hospital, University of Colorado, East 9th Avenue 4200, Denver, 80262, Colorado, USA

    George S. Eisenbarth

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Waldron-Lynch, F., Herold, K.C. (2011). Immunotherapy of Type-1 Diabetes: Immunoprevention and Immunoreversal. In: Eisenbarth, G. (eds) Immunoendocrinology: Scientific and Clinical Aspects. Contemporary Endocrinology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-478-4_18

Download citation

  • DOI: https://doi.org/10.1007/978-1-60327-478-4_18

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60327-477-7

  • Online ISBN: 978-1-60327-478-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation