Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunomodulatory therapy to preserve pancreatic β-cell function in type 1 diabetes

Nature Reviews Drug Discovery volume 10, pages 439–452 (2011)Cite this article

Subjects

Key Points

  • Type 1 diabetes is a common chronic autoimmune disease that is increasing in prevalence worldwide. Immunotherapy could induce remission of autoimmunity and improve current clinical outcomes.

  • Severally agents have now entered into Phase III clinical trials.

  • This review details the preclinical models that have been used to develop these agents.

  • We comprehensively review the status and outcomes of clinical trials to date.

  • Finally, we discuss the shortcomings of the current preclinical models of immunotherapy drug development and how we can move forward to optimize treatment for patients with type 1 diabetes.

Abstract

Type 1 diabetes is a common, severe chronic autoimmune disease that is characterized by the progressive and insidious loss of self-tolerance to the insulin-producing pancreatic islet β-cells. This loss of self-tolerance leads to the destruction of β-cells and the development of overt hyperglycaemia at diagnosis. The incidence and prevalence of type 1 diabetes is rapidly increasing worldwide, and this has led to intensive efforts to develop immunotherapies to induce remission of the disease and improve clinical outcomes. Immunotherapy aims to restore self-tolerance, resulting in the downregulation of autoimmune responses to pancreatic self-antigens and arrested ongoing β-cell destruction. When combined with replacement of the lost insulin-producing cells, this may lead to the restoration of euglycaemia. In this review, we discuss the current knowledge of the immunopathogenesis of type 1 diabetes and how this information has been translated into clinical trials. We also discuss next-generation combination immunotherapies that may be administered as adjuvant therapy at time of diagnosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Aetiology of type 1 diabetes: breakdown of immune tolerance.
Figure 2: Therapeutic targets in type 1 diabetes.
Figure 3: Proposed mechanism of action of CD3-specific mAbs (teplizumab and otelixizumab).

Similar content being viewed by others

References

  1. Daneman, D. Type 1 diabetes. Lancet 367, 847–858 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Waldron-Lynch, F., von Herrath, M. & Herold, K. C. Towards a curative therapy in type 1 diabetes: remission of autoimmunity, maintenance and augmentation of β cell mass. Novartis Found. Symp. 292, 146–155; discussion 155–158, 202–203 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Patterson, C. C., Dahlquist, G. G., 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 373, 2027–2033 (2009).

    Article  PubMed  Google Scholar 

  4. Waldron-Lynch, F. & Herold, K. C. Continuous glucose monitoring: long live the revolution! Nature Clin. Pract. Endocrinol. Metab. 5, 82–83 (2009).

    Article  Google Scholar 

  5. ADA. Standards of medical care in diabetes — 2010. Diabetes Care 33 (Suppl. 1), 11–61 (2010).

  6. Shapiro, A. M. et al. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318–1330 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Morath, C. et al. Simultaneous pancreas–kidney transplantation in type 1 diabetes. Clin. Transplant. 23 (Suppl. 21), 115–120 (2009).

    Article  PubMed  Google Scholar 

  8. Liu, E. & Eisenbarth, G. S. Type 1A diabetes mellitus-associated autoimmunity. Endocrinol. Metab. Clin. North Am. 31, 391–410, vii–viii (2002).

    Article  PubMed  Google Scholar 

  9. Perkins, B. A. et al. Regression of microalbuminuria in type 1 diabetes. N. Engl. J. Med. 348, 2285–2293 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Nathan, D. M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643–2653 (2005).

    Article  PubMed  Google Scholar 

  11. [No authors listed]. Hypoglycemia in the diabetes control and complications trial. The diabetes control and complications trial research group. Diabetes 46, 271–286 (1997).

  12. Steffes, M. W., Sibley, S., Jackson, M. & Thomas, W. β-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 26, 832–836 (2003).

    Article  PubMed  Google Scholar 

  13. Barnard, K., Thomas, S., Royle, P., Noyes, K. & Waugh, N. Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. BMC Pediatr. 10, 50 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Waldron-Lynch, F. & Herold, K. C. Advances in type 1 diabetes therapeutics: immunomodulation and β-cell salvage. Endocrinol. Metab. Clin. North Am. 38, 303–317, viii (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Haller, M. J., Gottlieb, P. A. & Schatz, D. A. Type 1 diabetes intervention trials 2007: where are we and where are we going? Curr. Opin. Endocrinol. Diabetes Obes. 14, 283–287 (2007).

    Article  PubMed  Google Scholar 

  16. Rewers, M. & Gottlieb, P. Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes Care 32, 1769–1782 (2009). An excellent review of clinical trials up to 2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. Roll, U. et al. 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 45, 967–973 (1996).

    Article  PubMed  Google Scholar 

  19. Mathis, D. & Benoist, C. Levees of immunological tolerance. Nature Immunol. 11, 3–6 (2010).

    Article  CAS  Google Scholar 

  20. Tsai, E. B., Sherry, N. A., Palmer, J. P. & Herold, K. C. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 49, 261–270 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Redondo, M. J., Jeffrey, J., Fain, P. R., Eisenbarth, G. S. & Orban, T. Concordance for islet autoimmunity among monozygotic twins. N. Engl. J. Med. 359, 2849–2850 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Erlich, H. et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57, 1084–1092 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Concannon, P., Rich, S. S. & Nepom, G. T. Genetics of type 1A diabetes. N. Engl. J. Med. 360, 1646–1654 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Mueller, D. L. Mechanisms maintaining peripheral tolerance. Nature Immunol. 11, 21–27 (2010).

    Article  CAS  Google Scholar 

  25. Gianani, R. & Eisenbarth, G. S. The stages of type 1A diabetes: 2005. Immunol. Rev. 204, 232–249 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Sherr, J., Sosenko, J., Skyler, J. & Herold, K. Prevention of type 1 diabetes: the time has come. Nature Clin. Pract. Endocrinol. Metab. 4, 334–343 (2008).

    Article  Google Scholar 

  27. Verge, C. F. et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45, 926–933 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Redondo, M. J. et al. Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 44, 354–362 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Yu, L. 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 50, 1735–1740 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Yu, L. et al. Antiislet autoantibodies usually develop sequentially rather than simultaneously. J. Clin. Endocrinol. Metab. 81, 4264–4267 (1996).

    CAS  PubMed  Google Scholar 

  31. Wenzlau, J. M. et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc. Natl Acad. Sci. USA 104, 17040–17045 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wenzlau, J. M. et al. Novel antigens in type 1 diabetes: the importance of ZnT8. Curr. Diab. Rep. 9, 105–112 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Bingley, P. J. et al. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 46, 1701–1710 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Mahon, J. L. et al. The TrialNet natural history study of the development of type 1 diabetes: objectives, design, and initial results. Pediatr. Diabetes 97–104 (2009).

  35. Orban, T. et al. Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 32, 2269–2274 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ferrannini, E., Mari, A., Nofrate, V., Sosenko, J. M. & Skyler, J. S. Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset. Diabetes 59, 679–685 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Sosenko, J. M. et al. Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 29, 643–649 (2006).

    Article  PubMed  Google Scholar 

  38. Sosenko, J. M. 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 30, 38–42 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Sosenko, J. M. et al. A risk score for type 1 diabetes derived from autoantibody-positive participants in the diabetes prevention trial-type 1. Diabetes Care 31, 528–533 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. von Herrath, M., Sanda, S. & Herold, K. Type 1 diabetes as a relapsing–remitting disease? Nature Rev. Immunol. 7, 988–994 (2007).

    Article  CAS  Google Scholar 

  41. Eizirik, D. L., Colli, M. L. & Ortis, F. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nature Rev. Endocrinol. 5, 219–226 (2009).

    Article  CAS  Google Scholar 

  42. Coppieters, K. T. & von Herrath, M. G. Histopathology of type 1 diabetes: old paradigms and new insights. Rev. Diabet. Stud. 6, 85–96 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14, 619–633 (1965).

    Article  CAS  PubMed  Google Scholar 

  44. Foulis, A. K., McGill, M. & Farquharson, M. A. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man—macrophages, lymphocytes, and interferon-γ containing cells. J. Pathol. 165, 97–103 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. 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). This paper shows important data on human islet inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dotta, F. et al. Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc. Natl Acad. Sci. USA 104, 5115–5120 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Imagawa, A. et al. Immunological abnormalities in islets at diagnosis paralleled further deterioration of glycaemic control in patients with recent-onset type I (insulin-dependent) diabetes mellitus. Diabetologia 42, 574–578 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Pfleger, C., Meierhoff, G., Kolb, H. & Schloot, N. C. Association of T-cell reactivity with β-cell function in recent onset type 1 diabetes patients. J. Autoimmun. 34, 127–135 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Chervonsky, A. V. Influence of microbial environment on autoimmunity. Nature Immunol. 11, 28–35 (2010).

    Article  CAS  Google Scholar 

  51. Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nakayama, M. et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435, 220–223 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. French, M. B. et al. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 46, 34–39 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nature Genet. 15, 293–297 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Kent, S. C. et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435, 224–228 (2005). This research provides evidence to support insulin as an antigen in humans.

    Article  CAS  PubMed  Google Scholar 

  57. Mannering, S. I. et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J. Exp. Med. 202, 1191–1197 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Knip, M. et al. Prediction of type 1 diabetes in the general population. Diabetes Care 33, 1206–1212 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Tang, Q. & Bluestone, J. A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nature Immunol. 9, 239–244 (2008).

    CAS  Google Scholar 

  61. Waldron-Lynch, F. & Herold, K. C. in Immunoendocrinology: Scientific and Clinical Aspects Ch. 18 (ed. Eisenbarth, G. S.) 293–314 (Humana, New York, 2010).

    Google Scholar 

  62. Mackay, I. R. Autoimmunity since the 1957 clonal selection theory: a little acorn to a large oak. Immunol. Cell Biol. 86, 67–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Isaacs, J. D. T cell immunomodulation — the Holy Grail of therapeutic tolerance. Curr. Opin. Pharmacol. 7, 418–425 (2007). A comprehensive review explaining the importance of tolerance in treatment of autoimmune disease.

    Article  CAS  PubMed  Google Scholar 

  64. Buse, J. B. et al. How do we define cure of diabetes? Diabetes Care 32, 2133–2135 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Palmer, J. P. et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve β-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes 53, 250–264 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Cernea, S. et al. Challenges in developing endpoints for type 1 diabetes intervention studies. Diabetes Metab. Res. Rev. 25, 694–704 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Herold, K. C. Treatment of type 1 diabetes mellitus to preserve insulin secretion. Endocrinol. Metab. Clin. North Am. 33, 93–111, ix (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Luopajarvi, K. et al. Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr. Diabetes 9, 434–441 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schmid, S., Buuck, D., Knopff, A., Bonifacio, E. & Ziegler, A. G. BABYDIET, a feasibility study to prevent the appearance of islet autoantibodies in relatives of patients with type 1 diabetes by delaying exposure to gluten. Diabetologia 47, 1130–1131 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Norris, J. M. et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 298, 1420–1428 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. [No authors listed]. Vitamin D supplement in early childhood and risk for type I (insulin-dependent) diabetes mellitus. The EURODIAB substudy 2 study group. Diabetologia 42, 51–54 (1999).

  72. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Teplizumab for Prevention of Type 1 Diabetes In Relatives “At-Risk”. ClinicalTrials.gov [online], (2011).

  73. Hagopian, W. A. et al. Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J. Clin. Invest. 95, 1505–1511 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. TEDDY Study Group. The environmental determinants of diabetes in the young (TEDDY) study: study design. Pediatr. Diabetes 8, 286–298 (2007).

  75. 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. 148, 17–31 (2007). An excellent review of clinical trials up to 2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Achenbach, P., Barker, J. & Bonifacio, E. Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization. Curr. Diab. Rep. 8, 87–93 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. 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).

  78. Di Lorenzo, T. P., Peakman, M. & Roep, B. O. Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin. Exp. Immunol. 148, 1–16 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 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).

    Article  CAS  PubMed  Google Scholar 

  80. Harrison, L. C. et al. Pancreatic β-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care 27, 2348–2355 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Näntö-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).

    Article  CAS  PubMed  Google Scholar 

  82. Tian, J. & Kaufman, D. L. Antigen-based therapy for the treatment of type 1 diabetes. Diabetes 58, 1939–1946 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bergerot, I., Fabien, N., Mayer, A. & Thivolet, C. Active suppression of diabetes after oral administration of insulin is determined by antigen dosage. Ann. NY Acad. Sci. 778, 362–367 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bayhill Therapeutics. BHT-3021. Phase 1 Study of BHT-3021 in Subjects With Type 1 Diabetes Mellitus. ClinicalTrials.gov [online], (2011).

  88. Buddhala, C., Hsu, C. C. & Wu, J. Y. A novel mechanism for GABA synthesis and packaging into synaptic vesicles. Neurochem. Int. 55, 9–12 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Baekkeskov, S. et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347, 151–156 (1990).

    Article  CAS  PubMed  Google Scholar 

  90. Skorstad, G., Hestvik, A. L., Vartdal, F. & Holmoy, T. Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65 in patients with stiff person syndrome. J. Autoimmun. 32, 24–32 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Fenalti, G. & Rowley, M. GAD65 as a prototypic autoantigen. J. Autoimmun. 32, 228–232 (2008).

    Article  CAS  Google Scholar 

  92. Tisch, R. et al. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366, 72–75 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Tian, J. et al. Nasal administration of glutamate decarboxylase (GAD65) peptides induces TH2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 183, 1561–1567 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  Google Scholar 

  95. Agardh, C. D. et al. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J. Diabetes Complicat. 19, 238–246 (2005).

    Article  Google Scholar 

  96. Ludvigsson, J. Immune intervention at diagnosis — should we treat children to preserve β-cell function? Pediatr. Diabetes 8 (Suppl. 6), 34–39 (2007).

    Article  PubMed  Google Scholar 

  97. Horvath, L. et al. Antibodies against different epitopes of heat-shock protein 60 in children with type 1 diabetes mellitus. Immunol. Lett. 80, 155–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  99. Raz, I. et al. Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved β-cell function: extension of a randomized, double-blind, phase II trial. Diabetes Metab. Res. Rev. 23, 292–298 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  CAS  PubMed  Google Scholar 

  101. Schloot, N. C. et al. Effect of heat shock protein peptide DiaPep277 on β-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. 23, 276–285 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Lazar, L. 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. 23, 286–291 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Andromeda Biotech Ltd. DIA-AID2. Efficacy and Safety Study of DiaPep277 in Newly Diagnosed Type 1 Diabetes Adults (DIA-AID2). ClinicalTrials.gov [online], (2011).

  104. Stiller, C. R. et al. Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 223, 1362–1367 (1984). The first proof of principle that immunotherapy works in humans with type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  105. Stiller, C. R. et al. Effects of cyclosporine in recent-onset juvenile type 1 diabetes: impact of age and duration of disease. J. Pediatr. 111, 1069–1072 (1987).

    Article  CAS  PubMed  Google Scholar 

  106. Feutren, G. et al. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet 2, 119–124 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  108. Bougneres, P. F. et al. Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin. Diabetes 39, 1264–1272 (1990).

    Article  CAS  PubMed  Google Scholar 

  109. Parving, H. H. et al. Cyclosporine nephrotoxicity in type 1 diabetic patients. A 7-year follow-up study. Diabetes Care 22, 478–483 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Bingley, P. J., Mahon, J. L., Gale, E. A. & European Nicotinamide Diabetes Intervention Trial Group. Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetes Care 31, 146–150 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  Google Scholar 

  112. Monti, P. et al. Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J. Clin. Invest. 118, 1806–1814 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Chatenoud, L. & Bluestone, J. A. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nature Rev. Immunol. 7, 622–632 (2007). An excellent review of anti-CD3 therapy.

    Article  CAS  Google Scholar 

  114. Cosimi, A. B. et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation 32, 535–539 (1981).

    Article  CAS  PubMed  Google Scholar 

  115. Friend, P. J. et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 68, 1632–1637 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Abramowicz, D. et al. Release of tumor necrosis factor, interleukin-2, and γ-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 47, 606–608 (1989).

    Article  CAS  PubMed  Google Scholar 

  117. Chatenoud, L. et al. Systemic reaction to the anti-T-cell monoclonal antibody OKT3 in relation to serum levels of tumor necrosis factor and interferon-γ [corrected]. N. Engl. J. Med. 320, 1420–1421 (1989).

    Article  CAS  PubMed  Google Scholar 

  118. Bolt, S. et al. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur. J. Immunol. 23, 403–411 (1993).

    Article  CAS  PubMed  Google Scholar 

  119. Alegre, M. L. et al. A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 57, 1537–1543 (1994).

    Article  CAS  PubMed  Google Scholar 

  120. Gandhi, G. Y. et al. Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials. Clin. Endocrinol. (Oxf.) 69, 244–252 (2008).

    Article  CAS  Google Scholar 

  121. Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J. Immunol. 158, 2947–2954 (1997).

    CAS  PubMed  Google Scholar 

  122. Chatenoud, L., Thervet, E., Primo, J. & Bach, J. F. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 91, 123–127 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Belghith, M. et al. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nature Med. 9, 1202–1208 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Bisikirska, B. C. & Herold, K. C. Regulatory T cells and type 1 diabetes. Curr. Diab. Rep. 5, 104–109 (2005).

    Article  PubMed  Google Scholar 

  125. Herold, K. C. et al. A single course of anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54, 1763–1769 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Herold, K. C. et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692–1698 (2002). A positive trial of teplizumab with a primary end point of preservation of C peptide.

    Article  CAS  PubMed  Google Scholar 

  127. Keymeulen, B. et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598–2608 (2005). A positive trial of otelixizumab with a primary end point of preservation of C peptide.

    Article  CAS  PubMed  Google Scholar 

  128. Herold, K. C. et al. Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years. Clin. Immunol. 132, 166–173 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Keymeulen, B. et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual β cell mass. Diabetologia 53, 614–623 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Keymeulen, B. et al. Transient Epstein–Barr virus reactivation in CD3 monoclonal antibody-treated patients. Blood 115, 1145–1155 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Chatenoud, L. Immune therapy for type 1 diabetes mellitus-what is unique about anti-CD3 antibodies? Nature Rev. Endocrinol. 6, 149–157 (2010).

    Article  CAS  Google Scholar 

  132. Hirsch, R., Gress, R. E., Pluznik, D. H., Eckhaus, M. & Bluestone, J. A. Effects of in vivo administration of anti-CD3 monoclonal antibody on T cell function in mice. II. In vivo activation of T cells. J. Immunol. 142, 737–743 (1989).

    CAS  PubMed  Google Scholar 

  133. Kaufman, A. & Herold, K. C. Anti-CD3 mAbs for treatment of type 1 diabetes. Diabetes Metab. Res. Rev. 25, 302–306 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. National Institute of Allergy and Infectious Diseases (NIAID). Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes (AbATE). ClinicalTrials.gov [online], (2009).

  135. Yale University. Anti-CD3 mAb Treatment of Recent Onset Type 1 Diabetes. ClinicalTrials.gov [online], (2010).

  136. MacroGenics. Press release: MacroGenics and Lilly announce pivotal clinical trial of teplizumab did not meet primary efficacy endpoint. MacroGenics [online], (2010).

  137. Linsley, P. S. & Nadler, S. G. The clinical utility of inhibiting CD28-mediated costimulation. Immunol. Rev. 229, 307–321 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Bluestone, J. A., St Clair, E. W. & Turka, L. A. CTLA4Ig: bridging the basic immunology with clinical application. Immunity 24, 233–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043–6053 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rudd, C. E., Taylor, A. & Schneider, H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol. Rev. 229, 12–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Herold, K. C. et al. CD28/B7 costimulation regulates autoimmune diabetes induced with multiple low doses of streptozotocin. J. Immunol. 158, 984–991 (1997).

    CAS  PubMed  Google Scholar 

  143. Herold, K. C. et al. Regulation of C-C chemokine production by murine T cells by CD28/B7 costimulation. J. Immunol. 159, 4150–4153 (1997).

    CAS  PubMed  Google Scholar 

  144. Lenschow, D. J. et al. CD28/B7 regulation of TH1 and TH2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996).

    Article  CAS  PubMed  Google Scholar 

  145. Abrams, J. R. et al. CTLA4 Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J. Clin. Invest. 103, 1243–1252 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kremer, J. M. 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. 52, 2263–2271 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. Kremer, J. M. et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 144, 865–876 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Russell, A. S. 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. 66, 189–194 (2007).

    Article  CAS  PubMed  Google Scholar 

  149. Kremer, J. M. et al. Results of a two-year followup study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum. 58, 953–963 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Intravenous CTLA4-lg Treatment in Recent Onset Type 1 Diabetes Mellitus. ClinicalTrials.gov [online], (2011). This trial will report at the ADA meeting in 2011.

  151. Cruzado, J. M., Bestard, O. & Grinyo, J. M. New immunosuppressive protocols with the advent of novel biological drugs. Transplantation 88, S20–S23 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. Hardinger, K. L. Rabbit antithymocyte globulin induction therapy in adult renal transplantation. Pharmacotherapy 26, 1771–1783 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Ormrod, D. & Jarvis, B. Antithymocyte globulin (rabbit): a review of the use of thymoglobulin in the prevention and treatment of acute renal allograft rejection. BioDrugs 14, 255–273 (2000).

    Article  CAS  Google Scholar 

  154. Perico, N. & Remuzzi, G. Prevention of transplant rejection: current treatment guidelines and future developments. Drugs 54, 533–570 (1997).

    Article  CAS  PubMed  Google Scholar 

  155. Deeks, E. D. & Keating, G. M. Rabbit antithymocyte globulin (thymoglobulin): a review of its use in the prevention and treatment of acute renal allograft rejection. Drugs 69, 1483–1512 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Preville, X. et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation 71, 460–468 (2001).

    Article  CAS  PubMed  Google Scholar 

  157. LaCorcia, G. et al. Polyclonal rabbit antithymocyte globulin exhibits consistent immunosuppressive capabilities beyond cell depletion. Transplantation 87, 966–974 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Lopez, M., Clarkson, M. R., Albin, M., Sayegh, M. H. & Najafian, N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. J. Am. Soc. Nephrol. 17, 2844–2853 (2006).

    Article  CAS  PubMed  Google Scholar 

  159. Eisenbarth, G. S. et al. Anti-thymocyte globulin and prednisone immunotherapy of recent onset type 1 diabetes mellitus. Diabetes Res. 2, 271–276 (1985).

    CAS  PubMed  Google Scholar 

  160. Saudek, F. et al. Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset. Rev. Diabet. Stud. 1, 80–88 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Institute for Clinical and Experimental Medicine. Polyclonal Anti-T-Lymphocyte Globulin (ATG) in Type 1 Diabetes. ClinicalTrials.gov [online], (2007).

  162. National Institute of Allergy and Infectious Diseases (NIAID). Study of Thymoglobulin to Arrest Newly Diagnosed Type 1 Diabetes (START). ClinicalTrials.gov [online], (2011).

  163. Parker, M. J. et al. Immune depletion with cellular mobilization imparts immunoregulation and reverses autoimmune diabetes in nonobese diabetic mice. Diabetes 58, 2277–2284 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. University of Florida. Reversing Type 1 Diabetes After it is Established. ClinicalTrials.gov [online], (2011).

  165. Martin, S. et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N. Engl. J. Med. 345, 1036–1040 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Uchida, J. et al. Mouse CD20 expression and function. Int. Immunol. 16, 119–129 (2004).

    Article  CAS  PubMed  Google Scholar 

  168. Xiu, Y. et al. B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in FcγR effector functions. J. Immunol. 180, 2863–2875 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Martin, F. & Chan, A. C. B cell immunobiology in disease: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Molina, A. A decade of rituximab: improving survival outcomes in non-Hodgkin's lymphoma. Annu. Rev. Med. 59, 237–250 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Looney, R. J. B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis. Rheumatology (Oxf.) 44 (Suppl. 2), ii13–ii17 (2005).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Pescovitz, M. Webcast: Treatment of Type 1 diabetes with Rituxumab — 2 year follow up. DiabetesPro [online], (2010).

  175. Bendtzen, K. et al. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 232, 1545–1547 (1986).

    Article  CAS  PubMed  Google Scholar 

  176. Cain, J. A., Smith, J. A., Ondr, J. K., Wang, B. & Katz, J. D. NKT cells and IFN-γ establish the regulatory environment for the control of diabetogenic T cells in the nonobese diabetic mouse. J. Immunol. 176, 1645–1654 (2006).

    Article  CAS  Google Scholar 

  177. Katz, J. D., Wang, B., Haskins, K., Benoist, C. & Mathis, D. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74, 1089–1100 (1993).

    Article  CAS  PubMed  Google Scholar 

  178. Rother, K. I. et al. Effect of ingested interferon-α on β-cell function in children with new-onset type 1 diabetes. Diabetes Care 32, 1250–1255 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  180. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. McDermott, D. F. Immunotherapy of metastatic renal cell carcinoma. Cancer 115, 2298–2305 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Bhatia, S., Tykodi, S. S. & Thompson, J. A. Treatment of metastatic melanoma: an overview. Oncology (Williston Park, NY) 23, 488–496 (2009).

    Google Scholar 

  183. Kodama, S., Davis, M. & Faustman, D. L. The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis. Cell. Mol. Life Sci. 62, 1850–1862 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Yang, X. D. et al. Effect of tumor necrosis factor α on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J. Exp. Med. 180, 995–1004 (1994).

    Article  CAS  PubMed  Google Scholar 

  185. Feldmann, M., Williams, R. O. & Paleolog, E. What have we learnt from targeted anti-TNF therapy? Ann. Rheum. Dis. 69 (Suppl. 1), i97–i99 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Tack, C. J., Kleijwegt, F. S., Van Riel, P. L. & Roep, B. O. Development of type 1 diabetes in a patient treated with anti-TNF-α therapy for active rheumatoid arthritis. Diabetologia 52, 1442–1444 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Bloom, B. J. Development of diabetes mellitus during etanercept therapy in a child with systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum. 43, 2606–2608 (2000).

    Article  CAS  PubMed  Google Scholar 

  188. Mastrandrea, L. et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 32, 1244–1249 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Nuki, G., Bresnihan, B., Bear, M. B. & McCabe, D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 2838–2846 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007). A good study demonstrating the use of anti-IL1 therapy in type 2 diabetes. Anti-IL-1 therapy could be used in combination with other immunotherapies in type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  191. Larsen, C. M. et al. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 32, 1663–1668 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Mandrup-Poulsen, T., Pickersgill, L. & Donath, M. Y. Blockade of interleukin 1 in type 1 diabetes mellitus. Nature Rev. Endocrinol. 6, 158–166 (2010).

    Article  CAS  Google Scholar 

  193. Thomas, H. E. et al. IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. Diabetes 53, 113–121 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Dinarello, C. A., Donath, M. Y. & Mandrup-Poulsen, T. Role of IL-1β in type 2 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 17, 314–321 (2010).

    CAS  PubMed  Google Scholar 

  195. Nicoletti, F. et al. Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor. Eur. J. Immunol. 24, 1843–1847 (1994).

    Article  CAS  PubMed  Google Scholar 

  196. Pfleger, C. et al. Association of IL-1ra and adiponectin with C-peptide and remission in patients with type 1 diabetes. Diabetes 57, 929–937 (2008).

    Article  CAS  PubMed  Google Scholar 

  197. Pickersgill, L. M. & Mandrup-Poulsen, T. R. The anti-interleukin-1 in type 1 diabetes action trial — background and rationale. Diabetes Metab. Res. Rev. 25, 321–324 (2009).

    Article  CAS  PubMed  Google Scholar 

  198. Steno Diabetes Center. Anti-Interleukin-1 in Diabetes Action (AIDA). ClinicalTrials.gov [online], (2010).

  199. von Herrath, M. & Nepom, G. T. Remodeling rodent models to mimic human type 1 diabetes. Eur. J. Immunol. 39, 2049–2054 (2009).

    Article  CAS  PubMed  Google Scholar 

  200. Maecker, H. T. et al. A model for harmonizing flow cytometry in clinical trials. Nature Immunol. 11, 975–978 (2010).

    Article  CAS  Google Scholar 

  201. Lepus, C. M. et al. Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc−/−, Balb/c-Rag1−/−γc−/−, and C.B-17-scid/bg immunodeficient mice. Hum. Immunol. 70, 790–802 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Shultz, L. D., Ishikawa, F. & Greiner, D. L. Humanized mice in translational biomedical research. Nature Rev. Immunol. 7, 118–130 (2007). A positive trial of otelixizumab with a primary end point of preservation of C peptide.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  204. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).

    Article  CAS  PubMed  Google Scholar 

  205. Stebbings, R., Poole, S. & Thorpe, R. Safety of biologics, lessons learnt from TGN1412. Curr. Opin. Biotechnol. 20, 673–677 (2009).

    Article  CAS  PubMed  Google Scholar 

  206. Kuhn, C. et al. Human CD3 transgenic mice: preclinical testing of antibodies promoting immune tolerance. Sci. Transl. Med. 3, 68ra10 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. Bresson, D. et al. Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing TRegs . J. Clin. Invest. 116, 1371–1381 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Yoshida, K. & Kikutani, H. Genetic and immunological basis of autoimmune diabetes in the NOD mouse. Rev. Immunogenet. 2, 140–146 (2000).

    CAS  PubMed  Google Scholar 

  209. De Aizpurua, H. J., French, M. B., Chosich, N. & Harrison, L. C. Natural history of humoral immunity to glutamic acid decarboxylase in non-obese diabetic (NOD) mice. J. Autoimmun. 7, 643–653 (1994).

    Article  CAS  PubMed  Google Scholar 

  210. Marino, E. & Grey, S. T. 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. 31, 301–305 (2008).

    Article  CAS  PubMed  Google Scholar 

  211. Zipris, D. Innate immunity and its role in type 1 diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 15, 326–331 (2008).

    Article  CAS  PubMed  Google Scholar 

  212. Morran, M. P., McInerney, M. F. & Pietropaolo, M. Innate and adaptive autoimmunity in type 1 diabetes. Pediatr. Diabetes 9, 152–161 (2008).

    Article  CAS  PubMed  Google Scholar 

  213. Ly, D. et al. An α-galactosylceramide C20:2 N-acyl variant enhances anti-inflammatory and regulatory T cell-independent responses that prevent type 1 diabetes. Clin. Exp. Immunol. 160, 185–198 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. You, S. et al. Immunoregulatory pathways controlling progression of autoimmunity in NOD mice. Ann. NY Acad. Sci. 1150, 300–310 (2008).

    Article  CAS  PubMed  Google Scholar 

  215. Haller, M. J., Atkinson, M. A. & Schatz, D. A. The road not taken: a path to curing type 1 diabetes? Eur. J. Immunol. 39, 2054–2058 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Bresson, D. & von Herrath, M. Immunotherapy for the prevention and treatment of type 1 diabetes: optimizing the path from bench to bedside. Diabetes Care 32, 1753–1768 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. von Herrath, M. G., Dockter, J. & Oldstone, M. B. How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity 1, 231–242 (1994).

    Article  CAS  PubMed  Google Scholar 

  218. Filippi, C. & von Herrath, M. How viral infections affect the autoimmune process leading to type 1 diabetes. Cell. Immunol. 233, 125–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. Bresson, D. & von Herrath, M. G. Anti-thymoglobulin (ATG) treatment does not reverse type 1 diabetes in the acute virally induced rat insulin promoter–lymphocytic choriomeningitis virus (RIP–LCMV) model. Clin. Exp. Immunol. 163, 375–380 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. MacroGenics. The Protégé Study — Clinical Trial of MGA031 in Children and Adults With Recent-Onset Type 1 Diabetes Mellitus. ClinicalTrials.gov[online], (2010).

  221. Tolerx Inc. Trial of Otelixizumab for Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-1. ClinicalTrials.gov[online], (2010).

Download references

Acknowledgements

The authors wish to acknowledge the contribution of patients who participate in clinical trials of immunotherapy in type 1 diabetes.

Author information

Authors and Affiliations

  1. Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, 300 George Street, Suite 353, New Haven, 06511, Connecticut, 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

Corresponding author

Correspondence to Frank Waldron-Lynch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Author's homepages

Author's homepages

TEDDY

ToleRx and GlaxoSmithKline announce Phase 3 DEFEND-1 study of otelixizumab in type 1 diabetes did not meet its primary endpoint

Glossary

Tolerance

The failure of the immune system to respond to an antigen. The immune system is usually tolerant to self-antigens. Central tolerance is the process whereby developing, potentially autoreactive T and B lymphocytes are deleted from the mature repertoire. It occurs in the thymus for T cells and in the bone marrow for B cells.

Type 1 diabetes

Type 1 diabetes is caused by the autoimmune-mediated destruction of pancreatic islet β-cells, which usually leads to absolute insulin deficiency.

C-peptide response

C-peptide is produced when proinsulin is cleaved to form insulin. It is released by pancreatic islet β-cells in a 1:1 ratio with insulin and used to monitor endogenous insulin production.

Regulatory T (TReg) cell

A subset of CD4+CD25+ and CD8 T cells that can inhibit responses of other T cells to antigens. They are an essential component of the immune system for the maintenance of peripheral tolerance.

Bystander suppression

A form of suppression in which responses to a second, unrelated Ag can be inhibited when it is presented together with the Ag to which tolerance is established.

Peripheral tolerance

A mechanism whereby potentially autoreactive T cells are prevented from responding to self-antigens in the peripheral tissues.

Latent autoimmune diabetes

A form of type 1 diabetes that usually presents in adults.

Type 2 diabetes

Type 2 diabetes is caused by a progressive defect in the insulin secretory capacity of pancreatic islet β-cells on the background of insulin resistance.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waldron-Lynch, F., Herold, K. Immunomodulatory therapy to preserve pancreatic β-cell function in type 1 diabetes. Nat Rev Drug Discov 10, 439–452 (2011). https://doi.org/10.1038/nrd3402

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3402

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research