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Combination Immunotherapy for Type 1 Diabetes

  • Immunology, Transplantation, and Regenerative Medicine (L Piemonti and V Sordi, Section Editors)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Type 1 diabetes (T1D) is an autoimmune disease marked by β-cell destruction. Immunotherapies for T1D have been investigated since the 1980s and have focused on restoration of tolerance, T cell or B cell inhibition, regulatory T cell (Treg) induction, suppression of innate immunity and inflammation, immune system reset, and islet transplantation. The purpose of this review is to provide an overview and lessons learned from single immunotherapy trials, describe recent and ongoing combination immunotherapy trials, and provide perspectives on strategies for future combination clinical interventions aimed at preserving insulin secretion in T1D.

Recent Findings

Combination immunotherapies have had mixed results in improving short-term glycemic control and insulin secretion in recent-onset T1D.

Summary

A handful of studies have successfully reached their primary end-point of improved insulin secretion in recent-onset T1D. However, long-term improvements glycemic control and the restoration of insulin independence remain elusive. Future interventions should focus on strategies that combine immunomodulation with efforts to alleviate β-cell stress and address the formation of antigens that activate autoimmunity.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69–82.

    Article  PubMed  Google Scholar 

  2. Bottazzo G, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;304(7892):1279–83.

    Article  Google Scholar 

  3. Gepts W, Lecompte PM. The pancreatic islets in diabetes. Am J Med. 1981;70(1):105–15.

    Article  CAS  PubMed  Google Scholar 

  4. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diab. 2008;26(2):77–82.

    Article  Google Scholar 

  6. Feutren G, Papoz L, Assan R, Vialettes B, Karsenty G, Vexiau P, 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. 1986;2(8499):119–24.

    Article  CAS  PubMed  Google Scholar 

  7. Sigal NH, Dumont FJ, Cyclosporin A. FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519–60.

    Article  CAS  PubMed  Google Scholar 

  8. The Canadian-European Randomized Control Trial Group. Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. The Canadian-European Randomized Control Trial Group. Diabetes. 1988;37(11):1574–82.

    Article  Google Scholar 

  9. Fuchtenbusch M, Kredel K, Bonifacio E, Schnell O, Ziegler AG. Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens. Diabetes. 2000;49(6):918–25.

    Article  CAS  PubMed  Google Scholar 

  10. Wallberg M, Cooke A. Immune mechanisms in type 1 diabetes. Trends Immunol. 2013;34(12):583–91.

    Article  CAS  PubMed  Google Scholar 

  11. Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10(7):501–13.

    Article  CAS  PubMed  Google Scholar 

  12. Csorba TR, Lyon AW, Hollenberg MD. Autoimmunity and the pathogenesis of type 1 diabetes. Crit Rev Clin Lab Sci. 2010;47(2):51–71.

    Article  CAS  PubMed  Google Scholar 

  13. Atkinson MA. The pathogenesis and natural history of type 1 diabetes. Cold Spring Harbor perspectives in medicine. 2012;2(11).

  14. McLaughlin RJ, Spindler MP, van Lummel M, Roep BO. Where, how, and when: positioning posttranslational modification within type 1 diabetes pathogenesis. Curr Diab Rep. 2016;16(7):63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hoglund P, Mintern J, Waltzinger C, Heath W, Benoist C, Mathis D. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med. 1999;189(2):331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009;155(2):173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jun HS, Yoon CS, Zbytnuik L, van Rooijen N, Yoon JW. The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Exp Med. 1999;189(2):347–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tarbell KV, Yamazaki S, Steinman RM. The interactions of dendritic cells with antigen-specific, regulatory T cells that suppress autoimmunity. Semin Immunol. 2006;18(2):93–102.

    Article  CAS  PubMed  Google Scholar 

  19. Takahashi K, Honeyman MC, Harrison LC. Impaired yield, phenotype, and function of monocyte-derived dendritic cells in humans at risk for insulin-dependent diabetes. J Immunol (Baltimore, Md : 1950). 1998;161(5):2629–35.

    CAS  Google Scholar 

  20. Serreze DV, Fleming SA, Chapman HD, Richard SD, Leiter EH, Tisch RM. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol (Baltimore, Md: 1950). 1998;161(8):3912–8.

    CAS  Google Scholar 

  21. Hussain S, Delovitch TL. Dysregulated B7-1 and B7-2 expression on nonobese diabetic mouse B cells is associated with increased T cell costimulation and the development of insulitis. J Immunol (Baltimore, Md: 1950). 2005;174(2):680–7.

    Article  CAS  Google Scholar 

  22. Faustman DL, Davis M. The primacy of CD8 T lymphocytes in type 1 diabetes and implications for therapies. J Mol Med (Berlin, Germany). 2009;87(12):1173–8.

    Article  CAS  Google Scholar 

  23. Dudek NL, Thomas HE, Mariana L, Sutherland RM, Allison J, Estella E, et al. Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways. Diabetes. 2006;55(9):2412–8.

    Article  CAS  PubMed  Google Scholar 

  24. Kreuwel HT, Morgan DJ, Krahl T, Ko A, Sarvetnick N, Sherman LA. Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus. J Immunol (Baltimore, Md: 1950). 1999;163(8):4335–41.

    CAS  Google Scholar 

  25. Lieberman J. The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol. 2003;3(5):361–70.

    Article  CAS  PubMed  Google Scholar 

  26. Mandrup-Poulsen T. Beta-cell apoptosis: stimuli and signaling. Diabetes. 2001;50(Suppl 1):S58–63.

    Article  CAS  PubMed  Google Scholar 

  27. Eizirik DL, Mandrup-Poulsen T. A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia. 2001;44(12):2115–33.

    Article  CAS  PubMed  Google Scholar 

  28. 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(22):1685–91.

    Article  Google Scholar 

  29. Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial—type 1. Diabetes Care. 2005;28(5):1068–76.

    Article  CAS  PubMed  Google Scholar 

  30. •• Raab J, Haupt F, Scholz M, Matzke C, Warncke K, Lange K, et al. Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study. BMJ Open. 2016;6(5):e011144. This study provides an overview of the Fr1da study, a large population-based T1D prevention study, and the screening methods for inclusion.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nanto-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, 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(9651):1746–55.

    Article  PubMed  CAS  Google Scholar 

  32. Harrison LC, Honeyman MC, Steele CE, Stone NL, Sarugeri E, Bonifacio E, et al. Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care. 2004;27(10):2348–55.

    Article  CAS  PubMed  Google Scholar 

  33. Knip M, Virtanen SM, Seppa K, Ilonen J, Savilahti E, Vaarala O, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med. 2010;363(20):1900–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hummel S, Beyerlein A, Tamura R, Uusitalo U, Aronsson CA, Yang J, et al. First infant formula type and risk of islet autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Diabetes Care. 2017.

  35. Vaarala O, Ilonen J, Ruohtula T, Pesola J, Virtanen SM, Harkonen T, et al. Removal of bovine insulin from cow’s milk formula and early initiation of beta-cell autoimmunity in the FINDIA Pilot Study. Arch Pediatr Adolesc Med. 2012;166(7):608–14.

    Article  PubMed  Google Scholar 

  36. Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care. 2011;34(6):1301–5.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA. 2007;298(12):1420–8.

    Article  CAS  PubMed  Google Scholar 

  38. Gale EA, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004;363(9413):925–31.

    Article  CAS  PubMed  Google Scholar 

  39. Masharani UB, Becker J. Teplizumab therapy for type 1 diabetes. Expert Opin Biol Ther. 2010;10(3):459–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ Jr, et al. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet. 2011;378(9790):487–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hagopian W, Ferry RJ Jr, Sherry N, Carlin D, Bonvini E, Johnson S, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protege trial. Diabetes. 2013;62(11):3901–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. • Tooley JE, Vudattu N, Choi J, Cotsapas C, Devine L, Raddassi K, et al. Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol. 2016;46(1):230–41. This study shows the importance of identifying populations of responders through mechanistic studies.

    Article  CAS  PubMed  Google Scholar 

  43. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352(25):2598–608.

    Article  CAS  PubMed  Google Scholar 

  44. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):412–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol (Baltimore, Md: 1950). 2003;171(7):3348–52.

    Article  CAS  Google Scholar 

  46. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juscinska J, et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets—results of one year follow-up. Clin Immunol (Orlando, Fla). 2014;153(1):23–30.

    Article  CAS  Google Scholar 

  47. Axelsson S, Cheramy M, Akerman L, Pihl M, Ludvigsson J, Casas R. Cellular and humoral immune responses in type 1 diabetic patients participating in a phase III GAD-alum intervention trial. Diabetes Care. 2013;36(11):3418–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143–52.

    Article  CAS  PubMed  Google Scholar 

  49. Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, et al. B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care. 2014;37(2):453–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Traxler P, Bold G, Buchdunger E, Caravatti G, Furet P, Manley P, et al. Tyrosine kinase inhibitors: from rational design to clinical trials. Med Res Rev. 2001;21(6):499–512.

    Article  CAS  PubMed  Google Scholar 

  51. Hagerkvist R, Sandler S, Mokhtari D, Welsh N. Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning. FASEB J. 2007;21(2):618–28.

    Article  PubMed  CAS  Google Scholar 

  52. Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2008;105(48):18895–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mastrandrea L, Yu J, Behrens T, Buchlis J, Albini C, Fourtner S, et al. Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care. 2009;32(7):1244–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mertens M, Singh JA. Anakinra for rheumatoid arthritis. The Cochrane database of systematic reviews. 2009(1):Cd005121.

  55. Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381(9881):1905–15.

    Article  CAS  PubMed  Google Scholar 

  56. Faustman DL, Wang L, Okubo Y, Burger D, Ban L, Man G, et al. Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes. PLoS One. 2012;7(8):e41756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shehadeh N, Calcinaro F, Bradley BJ, Bruchim I, Vardi P, Lafferty KJ. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet. 1994;343(8899):706–7.

    Article  CAS  PubMed  Google Scholar 

  58. van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91(1):79–118.

    Article  PubMed  CAS  Google Scholar 

  59. Shoda LKM, Young DL, Ramanujan S, Whiting CC, Atkinson MA, Bluestone JA, et al. A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity. 23(2):115–26.

  60. Reed JC, Herold KC. Thinking bedside at the bench: the NOD mouse model of T1DM. Nat Rev Endocrinol. 2015;11(5):308–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230–8.

    Article  CAS  PubMed  Google Scholar 

  62. Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318–30.

    Article  CAS  PubMed  Google Scholar 

  63. Shapiro AM, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nature Reviews Endocrinology. 2016.

  64. Bellin MD, Kandaswamy R, Parkey J, Zhang HJ, Liu B, Ihm SH, et al. Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2008;8(11):2463–70.

    Article  CAS  Google Scholar 

  65. Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2012;12(6):1576–83.

    Article  CAS  Google Scholar 

  66. Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T, et al. Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA. 2005;293(7):830–5.

    Article  CAS  PubMed  Google Scholar 

  67. Hering BJ. Achieving and maintaining insulin independence in human islet transplant recipients. Transplantation. 2005;79(10):1296–7.

    Article  PubMed  Google Scholar 

  68. Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit. 1995;17(6):681–4.

    Article  CAS  PubMed  Google Scholar 

  69. Wiendl H, Gross CC. Modulation of IL-2R[alpha] with daclizumab for treatment of multiple sclerosis. Nat Rev Neurol. 2013;9(7):394–404.

    Article  CAS  PubMed  Google Scholar 

  70. Ugrasbul F, Moore WV, Tong PY, Kover KL. Prevention of diabetes: effect of mycophenolate mofetil and anti-CD25 on onset of diabetes in the DRBB rat. Pediatr Diabetes. 2008;9(6):596–601.

    Article  CAS  PubMed  Google Scholar 

  71. Gottlieb PA, Quinlan S, Krause-Steinrauf H, Greenbaum CJ, Wilson DM, Rodriguez H, et al. Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new-onset type 1 diabetes. Diabetes Care. 2010;33(4):826–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.

    Article  CAS  PubMed  Google Scholar 

  73. Manirarora JN, Wei CH. Combination therapy using IL-2/IL-2 monoclonal antibody complexes, rapamycin, and islet autoantigen peptides increases regulatory T cell frequency and protects against spontaneous and induced type 1 diabetes in nonobese diabetic mice. J Immunol (Baltimore, Md: 1950). 2015;195(11):5203–14.

    Article  CAS  Google Scholar 

  74. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, Rajotte RV, Power R. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes. 2002;51(3):638–45.

    Article  CAS  PubMed  Google Scholar 

  75. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009;9(5):324–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010;33(3):301–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Monti P, Scirpoli M, Maffi P, Piemonti L, Secchi A, Bonifacio E, et al. Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells. Diabetes. 2008;57(9):2341–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med. 2010;207(9):1871–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008;28(5):687–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes. 2012;61(9):2340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Barlow AD, Nicholson ML, Herbert TP. Evidence for rapamycin toxicity in pancreatic β-cells and a review of the underlying molecular mechanisms. Diabetes. 2013;62(8):2674–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. •• Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Rosenthal SM, Shuster JJ, et al. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J Clin Invest. 2015;125(1):448–55. This study shows that combined ATG/GCSF intervention in patients with established T1D can be effective in prolonging glycemic control and suggests this therapy may also be beneficial prior to clinical onset.

    Article  PubMed  Google Scholar 

  84. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21(7):1387–94.

    Article  CAS  PubMed  Google Scholar 

  85. Martins A, Han J, Kim SO. The multifaceted effects of granulocyte colony-stimulating factor in immunomodulation and potential roles in intestinal immune homeostasis. IUBMB Life. 2010;62(8):611–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. • Haller MJ, Gitelman SE, Gottlieb PA, Michels AW, Perry DJ, Schultz AR, et al. Antithymocyte globulin plus G-CSF combination therapy leads to sustained immunomodulatory and metabolic effects in a subset of responders with established type 1 diabetes. Diabetes. 2016;65(12):3765–75. This study shows the importance of mechanistic outcomes in intervention responders.

    Article  CAS  PubMed  Google Scholar 

  87. Ludvigsson J, Wahlberg J, Casas R. Intralymphatic injection of autoantigen in type 1 diabetes. N Engl J Med. 2017;376(7):697–9.

    Article  PubMed  Google Scholar 

  88. Arvan P, Pietropaolo M, Ostrov D, Rhodes CJ. Islet autoantigens: structure, function, localization, and regulation. Cold Spring Harbor perspectives in medicine. 2012;2(8).

  89. Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18):1909–20.

    Article  CAS  PubMed  Google Scholar 

  90. Pihl M, Akerman L, Axelsson S, Cheramy M, Hjorth M, Mallone R, et al. Regulatory T cell phenotype and function 4 years after GAD-alum treatment in children with type 1 diabetes. Clin Exp Immunol. 2013;172(3):394–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hjorth M, Axelsson S, Ryden A, Faresjo M, Ludvigsson J, Casas R. GAD-alum treatment induces GAD65-specific CD4+CD25highFOXP3+ cells in type 1 diabetic patients. Clin Immunol (Orlando, Fla). 2011;138(1):117–26.

    Article  CAS  Google Scholar 

  92. Ludvigsson J, Krisky D, Casas R, Battelino T, Castano L, Greening J, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012;366(5):433–42.

    Article  CAS  PubMed  Google Scholar 

  93. Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 2011;378(9788):319–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gysemans CA, Cardozo AK, Callewaert H, Giulietti A, Hulshagen L, Bouillon R, et al. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology. 2005;146(4):1956–64.

    Article  CAS  PubMed  Google Scholar 

  95. Penna G, Amuchastegui S, Giarratana N, Daniel KC, Vulcano M, Sozzani S, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol (Baltimore, Md: 1950). 2007;178(1):145–53.

    Article  CAS  Google Scholar 

  96. Pitocco D, Crino A, Di Stasio E, Manfrini S, Guglielmi C, Spera S, et al. The effects of calcitriol and nicotinamide on residual pancreatic beta-cell function in patients with recent-onset type 1 diabetes (IMDIAB XI). Diabet Med. 2006;23(8):920–3.

    Article  CAS  PubMed  Google Scholar 

  97. Walter M, Kaupper T, Adler K, Foersch J, Bonifacio E, Ziegler AG. No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care. 2010;33(7):1443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Burt RK, Slavin S, Burns WH, Marmont AM. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood. 2002;99(3):768–84.

    Article  CAS  PubMed  Google Scholar 

  99. Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009;301(15):1573–9.

    Article  CAS  PubMed  Google Scholar 

  100. Snarski E, Milczarczyk A, Halaburda K, Torosian T, Paluszewska M, Urbanowska E, et al. Immunoablation and autologous hematopoietic stem cell transplantation in the treatment of new-onset type 1 diabetes mellitus: long-term observations. Bone Marrow Transplant. 2016;51(3):398–402.

    Article  CAS  PubMed  Google Scholar 

  101. Malmegrim KCR, de Azevedo JTC, Arruda LCM, Abreu JRF, Couri CEB, de Oliveira GLV, et al. immunological balance is associated with clinical outcome after autologous hematopoietic stem cell transplantation in type 1 diabetes. Frontiers in Immunology. 2017;8(167).

  102. D’Addio F, Valderrama Vasquez A, Ben Nasr M, Franek E, Zhu D, Li L, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: a multicenter analysis. Diabetes. 2014;63(9):3041–6.

    Article  PubMed  Google Scholar 

  103. Zhang X, Ye L, Hu J, Tang W, Liu R, Yang M, et al. Acute response of peripheral blood cell to autologous hematopoietic stem cell transplantation in type 1 diabetic patient. PLoS One. 2012;7(2):e31887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gu W, Hu J, Wang W, Li L, Tang W, Sun S, et al. Diabetic ketoacidosis at diagnosis influences complete remission after treatment with hematopoietic stem cell transplantation in adolescents with type 1 diabetes. Diabetes Care. 2012;35(7):1413–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kovatchev B, Cheng P, Anderson SM, Pinsker JE, Boscari F, Buckingham BA, et al. Feasibility of long-term closed-loop control: a multicenter 6-month trial of 24/7 automated insulin delivery. Diabetes Technol Ther. 2017;19(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  106. Sharifi A, De Bock MI, Jayawardene D, Loh MM, Horsburgh JC, Berthold CL, et al. Glycemia, treatment satisfaction, cognition, and sleep quality in adults and adolescents with type 1 diabetes when using a closed-loop system overnight versus sensor-augmented pump with low-glucose suspend function: a randomized crossover study. Diabetes Technol Ther. 2016;18(12):772–83.

    Article  CAS  PubMed  Google Scholar 

  107. Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA, et al. IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun. 1996;9(3):415–21.

    Article  CAS  PubMed  Google Scholar 

  108. Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE, et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet. 2008;40(12):1399–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bottini N, Vang T, Cucca F, Mustelin T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol. 2006;18(4):207–13.

    Article  CAS  PubMed  Google Scholar 

  110. Fisher MM, Watkins RA, Blum J, Evans-Molina C, Chalasani N, DiMeglio LA, et al. Elevations in circulating methylated and unmethylated preproinsulin DNA in new-onset type 1 diabetes. Diabetes. 2015;64(11):3867–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Herold KC, Usmani-Brown S, Ghazi T, Lebastchi J, Beam CA, Bellin MD, et al. Beta cell death and dysfunction during type 1 diabetes development in at-risk individuals. J Clin Invest. 2015;125(3):1163–73.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Truyen I, De Pauw P, Jorgensen PN, Van Schravendijk C, Ubani O, Decochez K, et al. Proinsulin levels and the proinsulin:c-peptide ratio complement autoantibody measurement for predicting type 1 diabetes. Diabetologia. 2005;48(11):2322–9.

    Article  CAS  PubMed  Google Scholar 

  113. Sims EK, Chaudhry Z, Watkins R, Syed F, Blum J, Ouyang F, et al. Elevations in the fasting serum proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes. Diabetes Care. 2016;39(9):1519–26.

    Article  PubMed  Google Scholar 

  114. Syed F, Evans-Molina C. Nucleic acid biomarkers of beta cell stress and death in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2016;23(4):312–7.

    Article  CAS  PubMed  Google Scholar 

  115. • Roep BO, Kracht MJ, van Lummel M, Zaldumbide A. A roadmap of the generation of neoantigens as targets of the immune system in type 1 diabetes. Curr Opin Immunol. 2016;43:67–73. This review provides an overview of antigen formation in developing T1D.

    Article  CAS  PubMed  Google Scholar 

  116. Kracht MJ, Zaldumbide A, Roep BO. Neoantigens and microenvironment in type 1 diabetes: lessons from antitumor immunity. Trends Endocrinol Metab: TEM. 2016;27(6):353–62.

    Article  CAS  PubMed  Google Scholar 

  117. Engin F. ER stress and development of type 1 diabetes. J Investig Med. 2016;64(1):2–6.

    PubMed  Google Scholar 

  118. Marre ML, James EA, Piganelli JD. Beta cell ER stress and the implications for immunogenicity in type 1 diabetes. Front Cell Dev Biol. 2015;3:67.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Tersey SA, Nishiki Y, Templin AT, Cabrera SM, Stull ND, Colvin SC, et al. Islet beta-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes. 2012;61(4):818–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014;158(3):534–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nyalakonda K, Sharma T, Ismail-Beigi F. Preservation of beta-cell function in type 2 diabetes. Endocr Pract. 2010;16(6):1038–55.

    Article  PubMed  Google Scholar 

  122. Page KA, Reisman T. Interventions to preserve beta-cell function in the management and prevention of type 2 diabetes. Curr Diab Rep. 2013;13(2):252–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Indiana School of Medicine, 635 Barnhill Dr, MS 2031A, Indianapolis, IN, 46202, USA

    Robert N. Bone & Carmella Evans-Molina

  2. Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Robert N. Bone & Carmella Evans-Molina

  3. Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Carmella Evans-Molina

  4. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Carmella Evans-Molina

  5. Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Carmella Evans-Molina

  6. Roudebush VA Medical Center, Indianapolis, IN, 46202, USA

    Carmella Evans-Molina

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  1. Robert N. Bone
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Correspondence to Carmella Evans-Molina.

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Conflict of Interest

Robert N. Bone and Carmella Evans-Molina declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Carmella Evans-Molina is a coauthor on three references cited that utilized human or animal subjects; these studies complied with all relevant human and animal subject ethical guidelines.

Funding

The authors wish to acknowledge the following funding sources: NIH/NIDDK R01-DK093954 and UC4-DK104166, JDRF 3-SRA-2014-41-Q-R, VA Merit Award 1I01BX00733 (C.E-M.), and NIH/NIAID T32-AI060519 (R.N.B.).

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This article is part of the Topical Collection on Immunology, Transplantation, and Regenerative Medicine

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Bone, R.N., Evans-Molina, C. Combination Immunotherapy for Type 1 Diabetes. Curr Diab Rep 17, 50 (2017). https://doi.org/10.1007/s11892-017-0878-z

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