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Current Status on Immunological Therapies for Type 1 Diabetes Mellitus

  • Therapies and New Technologies in the Treatment of Diabetes (M Pietropaolo, Section Editor)
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Abstract

Purpose of Review

Type 1 diabetes (T1D) occurs when there is destruction of beta cells within the islets of Langerhans in the pancreas due to autoimmunity. It is considered a complex disease, and different complications can surface and worsen the condition if T1D is not managed well. Since it is an incurable disease, numerous treatments and therapies have been postulated in order to control T1D by balancing hyperglycemia control while minimizing hypoglycemic episodes. The purpose of this review is to primarily look into the current state of the available immunological therapies and their advantages for the treatment of T1D.

Recent Findings

Over the years, immunological therapy has become the center of attraction to treat T1D. Immunomodulatory approaches on non-antigens involving agents such as cyclosporine A, mycophenolate mofetil, anti-CD20, cytotoxic T cells, anti-TNF, anti-CD3, and anti-thymocyte globulin as well as immunomodulative approaches on antigens such as insulin, glutamic acid decarboxylase, and heat shock protein 60 have been studied. Aside from these two approaches, studies and trials have also been conducted on regulatory T cells, dendritic cells, interleukin 2, interleukin 4, M2 macrophages, and rapamycin/interleukin 2 combination therapy to test their effects on patients with T1D. Many of these agents have successfully suppressed T1D in non-obese diabetic (NOD) mice and in human trials. However, some have shown negative results.

Summary

To date, the insights into the management of the immune system have been increasing rapidly to search for potential therapies and treatments for T1D. Nevertheless, some of the challenges are still inevitable. A lot of work and effort need to be put into the investigation on T1D through immunological therapy, particularly to reduce complications to improve and enhance clinical outcomes.

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References

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

  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 Suppl 1:S62–9. https://doi.org/10.2337/dc10-S062.

    Article  Google Scholar 

  2. Gupta G, de Jesus Andreoli Pinto T, Chellappan DK, Mishra A, Malipeddi H, Dua K. A clinical update on metformin and lung cancer in diabetic patients. Panminerva Med. 2018;60(2):70–5. https://doi.org/10.23736/s0031-0808.18.03394-3.

    Article  PubMed  Google Scholar 

  3. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl 1):S62–S9. https://doi.org/10.2337/dc10-S062.

    Article  Google Scholar 

  4. Atkinson MA. The pathogenesis and natural history of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(11). doi:https://doi.org/10.1101/cshperspect.a007641.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Eisenbarth GS. Update in type 1 diabetes. J Clin Endocrinol Metab. 2007;92(7):2403–7. https://doi.org/10.1210/jc.2007-0339.

    Article  CAS  PubMed  Google Scholar 

  6. Morales J, Schneider D. Hypoglycemia. Am J Med. 2014;127(10 Suppl):S17–24. https://doi.org/10.1016/j.amjmed.2014.07.004.

    Article  CAS  PubMed  Google Scholar 

  7. Michels A, Zhang L, Khadra A, Kushner JA, Redondo MJ, Pietropaolo M. Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention. Pediatr Diabetes. 2015;16(7):465–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rigby MR, Ehlers MR. Targeted immune interventions for type 1 diabetes: not as easy as it looks! Curr Opin Endocrinol Diabetes Obes. 2014;21(4):271–8. https://doi.org/10.1097/med.0000000000000075.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Weigmann B, Franke RK, Daniel C. Immunotherapy in autoimmune type 1 diabetes. Rev Diabet Stud. 2012;9(2–3):68–81. https://doi.org/10.1900/rds.2012.9.68.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Durnian JM, Stewart RM, Tatham R, Batterbury M, Kaye SB. Cyclosporin-A associated malignancy. Clin Ophthalmol. 2007;1(4):421–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Chatenoud L, Warncke K, Ziegler AG. Clinical immunologic interventions for the treatment of type 1 diabetes. Cold Spring Harbor Perspectives in Medicine. 2012;2(8). doi:https://doi.org/10.1101/cshperspect.a007716.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47(2):85–118. https://doi.org/10.1016/S0162-3109(00)00188-0.

    Article  CAS  PubMed  Google Scholar 

  13. Heatwole C, Ciafaloni E. Mycophenolate mofetil for myasthenia gravis: a clear and present controversy. Neuropsychiatr Dis Treat. 2008;4(6):1203–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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. https://doi.org/10.2337/dc09-1349.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Emer JJ, Claire W. Rituximab: a review of dermatological applications. J Clin Aesthet Dermatol. 2009;2(5):29–37.

    PubMed Central  PubMed  Google Scholar 

  16. Randall KL. Rituximab in autoimmune diseases. Aust Prescr. 2016;39(4):131–4. https://doi.org/10.18773/austprescr.2016.053.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, et al. B-lymphocyte depletion with rituximab and β-cell function: two-year results. Diabetes Care. 2014;37(2):453–9. https://doi.org/10.2337/dc13-0626.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Mayer E, Holzl M, Ahmadi S, Dillinger B, Pilat N, Fuchs D, et al. CTLA4-Ig immunosuppressive activity at the level of dendritic cell/T cell crosstalk. Int Immunopharmacol. 2013;15(3):638–45. https://doi.org/10.1016/j.intimp.2013.02.007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Vital EM, Emery P. Abatacept in the treatment of rheumatoid arthritis. Ther Clin Risk Manag. 2006;2(4):365–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Melvin G, Sandhiya S, Subraja K. Belatacept: a worthy alternative to cyclosporine? J Pharmacol Pharmacother. 2012;3(1):90–2. https://doi.org/10.4103/0976-500x.92499.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Tooley JE, Waldron-Lynch F, Herold KC. New and future immunomodulatory therapy in type 1 diabetes. Trends Mol Med. 2012;18(3):173–81. https://doi.org/10.1016/j.molmed.2012.01.001.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. 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. https://doi.org/10.1016/s0140-6736(11)60886-6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol. 2015;27(1):55–62. https://doi.org/10.1093/intimm/dxu102.

    Article  CAS  PubMed  Google Scholar 

  24. Tack CJ, Kleijwegt FS, Van Riel PL, Roep BO. Development of type 1 diabetes in a patient treated with anti-TNF-alpha therapy for active rheumatoid arthritis. Diabetologia. 2009;52(7):1442–4. https://doi.org/10.1007/s00125-009-1381-0.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. 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. https://doi.org/10.2337/dc09-0054.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Penaranda C, Tang Q, Bluestone JA. Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol (Baltimore, Md : 1950). 2011;187(4):2015–22. https://doi.org/10.4049/jimmunol.1100713.

    Article  CAS  Google Scholar 

  27. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692–8. https://doi.org/10.1056/NEJMoa012864.

    Article  CAS  PubMed  Google Scholar 

  28. 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. https://doi.org/10.1056/NEJMoa043980.

    Article  CAS  PubMed  Google Scholar 

  29. Herold KC, Gitelman S, Greenbaum C, Puck J, Hagopian W, Gottlieb P, 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. 2009;132(2):166–73. https://doi.org/10.1016/j.clim.2009.04.007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. 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. https://doi.org/10.2337/db13-0236.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007;21(7):1387–94. https://doi.org/10.1038/sj.leu.2404683.

    Article  CAS  PubMed  Google Scholar 

  32. Luo X, Herold KC, Miller SD. Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity. 2010;32(4):488–99. https://doi.org/10.1016/j.immuni.2010.04.002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. • Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, et al. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia. 2016;59(6):1153–61. https://doi.org/10.1007/s00125-016-3917-4. This study discusses the findings observed from a 2-year randomised trial on antithymocyte globulin in new-onset type 1 diabetes.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Coppieters KT, Harrison LC, von Herrath MG. Trials in type 1 diabetes: antigen-specific therapies. Clin Immunol. 2013;149(3):345–55. https://doi.org/10.1016/j.clim.2013.02.002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Clemente-Casares X, Tsai S, Huang C, Santamaria P. Antigen-specific therapeutic approaches in type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(2):a007773. https://doi.org/10.1101/cshperspect.a007773.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. 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(22):10252–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K. Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med. 1996;184(6):2167–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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 

  39. Fourlanos S, Perry C, Gellert SA, Martinuzzi E, Mallone R, Butler J, et al. Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes. 2011;60(4):1237–45. https://doi.org/10.2337/db10-1360.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Writing committee for the type 1 diabetes TrialNet Oral insulin study group, effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA. 2017;318(19):1891–902.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tian J, Atkinson MA, Clare-Salzler M, Herschenfeld A, Forsthuber T, Lehmann PV, et al. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J Exp Med. 1996;183(4):1561–7.

    Article  CAS  PubMed  Google Scholar 

  42. Ludvigsson J, Cheramy M, Axelsson S, Pihl M, Akerman L, Casas R. GAD-treatment of children and adolescents with recent-onset type 1 diabetes preserves residual insulin secretion after 30 months. Diabetes Metab Res Rev. 2014;30(5):405–14. https://doi.org/10.1002/dmrr.2503.

    Article  CAS  PubMed  Google Scholar 

  43. 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. https://doi.org/10.1016/s0140-6736(11)60895-7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Ludvigsson J, Hjorth M, Cheramy M, Axelsson S, Pihl M, Forsander G, et al. Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial. Diabetologia. 2011;54(3):634–40. https://doi.org/10.1007/s00125-010-1988-1.

    Article  CAS  PubMed  Google Scholar 

  45. Pellegrino MW, Nargund AM, Haynes CM. Signaling the mitochondrial unfolded protein response. Biochim Biophys Acta. 2013;1833(2):410–6. https://doi.org/10.1016/j.bbamcr.2012.02.019.

    Article  CAS  PubMed  Google Scholar 

  46. • Juwono J, Martinus RD. Does Hsp60 provide a link between mitochondrial stress and inflammation in diabetes mellitus. J Diabetes Res. 2016;2016:8017571. https://doi.org/10.1155/2016/8017571. This review summarises the known relationships between the expression of heat shock protein 60 and type 1 diabetes.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Elias D, Markovits D, Reshef T, van der Zee R, Cohen IR. Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1990;87(4):1576–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Raz I, Avron A, Tamir M, Metzger M, Symer L, Eldor R, 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(4):292–8. https://doi.org/10.1002/dmrr.712.

    Article  CAS  PubMed  Google Scholar 

  49. Lazar L, Ofan R, Weintrob N, Avron A, Tamir M, Elias D, 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(4):286–91. https://doi.org/10.1002/dmrr.711.

    Article  CAS  PubMed  Google Scholar 

  50. Corthay A. How do regulatory T cells work? Scand J Immunol. 2009;70(4):326–36. https://doi.org/10.1111/j.1365-3083.2009.02308.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Curotto de Lafaille MA, Muriglan S, Sunshine MJ, Lei Y, Kutchukhidze N, Furtado GC, et al. Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J Exp Med. 2001;194(9):1349–59.

    Article  CAS  PubMed  Google Scholar 

  52. Karlsson MR, Rugtveit J, Brandtzaeg P. Allergen-responsive CD4+CD25+ regulatory T cells in children who have outgrown cow's milk allergy. J Exp Med. 2004;199(12):1679–88. https://doi.org/10.1084/jem.20032121.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Li Z, Li D, Tsun A, Li B. FOXP3+ regulatory T cells and their functional regulation. Cell Mol Immunol. 2015;12(5):558–65. https://doi.org/10.1038/cmi.2015.10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Tonkin DR, He J, Barbour G, Haskins K. Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo. J Immunol (Baltimore, Md : 1950). 2008;181(7):4516–22.

    Article  CAS  Google Scholar 

  55. Cabrera SM, Rigby MR, Mirmira RG. Targeting regulatory T cells in the treatment of type 1 diabetes mellitus. Curr Mol Med. 2012;12(10):1261–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Okubo Y, Torrey H, Butterworth J, Zheng H, Faustman DL. Treg activation defect in type 1 diabetes: correction with TNFR2 agonism. Clin Transl Immunol. 2016;5(1):e56. https://doi.org/10.1038/cti.2015.43.

    Article  CAS  Google Scholar 

  57. Wu L, Dakic A. Development of dendritic cell system. Cell Mol Immunol. 2004;1(2):112–8.

    PubMed  Google Scholar 

  58. Shang N, Figini M, Shangguan J, Wang B, Sun C, Pan L, et al. Dendritic cells based immunotherapy. Am J Cancer Res. 2017;7(10):2091–102.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Marin-Gallen S, Clemente-Casares X, Planas R, Pujol-Autonell I, Carrascal J, Carrillo J, et al. Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes. Clin Exp Immunol. 2010;160(2):207–14. https://doi.org/10.1111/j.1365-2249.2009.04082.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Creusot RJ, Giannoukakis N, Trucco M, Clare-Salzler MJ, Fathman CG. It's time to bring dendritic cell therapy to type 1 diabetes. Diabetes. 2014;63(1):20–30. https://doi.org/10.2337/db13-0886.

    Article  CAS  PubMed  Google Scholar 

  61. Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011;34(9):2026–32. https://doi.org/10.2337/dc11-0472.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med. 2002;196(6):851–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bachmann MF, Oxenius A. Interleukin 2: from immunostimulation to immunoregulation and back again. EMBO Rep. 2007;8(12):1142–8. https://doi.org/10.1038/sj.embor.7401099.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006;441(7095):890–3. https://doi.org/10.1038/nature04790.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. 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 

  66. Diaz-de-Durana Y, Lau J, Knee D, Filippi C, Londei M, McNamara P, et al. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes. PLoS One. 2013;8(10):e78483. https://doi.org/10.1371/journal.pone.0078483.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Luzina IG, Keegan AD, Heller NM, Rook GA, Shea-Donohue T, Atamas SP. Regulation of inflammation by interleukin-4: a review of "alternatives". J Leukoc Biol. 2012;92(4):753–64. https://doi.org/10.1189/jlb.0412214.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Rapoport MJ, Jaramillo A, Zipris D, Lazarus AH, Serreze DV, Leiter EH, et al. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med. 1993;178(1):87–99.

    Article  CAS  PubMed  Google Scholar 

  69. Cameron MJ, Arreaza GA, Zucker P, Chensue SW, Strieter RM, Chakrabarti S, et al. IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol (Baltimore, Md : 1950). 1997;159(10):4686–92.

    CAS  Google Scholar 

  70. Cameron MJ, Arreaza GA, Waldhauser L, Gauldie J, Delovitch TL. Immunotherapy of spontaneous type 1 diabetes in nonobese diabetic mice by systemic interleukin-4 treatment employing adenovirus vector-mediated gene transfer. Gene Ther. 2000;7(21):1840–6. https://doi.org/10.1038/sj.gt.3301309.

    Article  CAS  PubMed  Google Scholar 

  71. Elhelu MA. The role of macrophages in immunology. J Natl Med Assoc. 1983;75(3):314–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Gensel JC, Kopper TJ, Zhang B, Orr MB, Bailey WM. Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment. Sci Rep. 2017;7:40144. https://doi.org/10.1038/srep40144.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000 Prime Rep. 2014;6:13. https://doi.org/10.12703/p6-13.

    Article  Google Scholar 

  74. Parsa R, Andresen P, Gillett A, Mia S, Zhang XM, Mayans S, et al. Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice. Diabetes. 2012;61(11):2881–92. https://doi.org/10.2337/db11-1635.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Culina S, Boitard C, Mallone R. Antigen-based immune therapeutics for type 1 diabetes: magic bullets or ordinary blanks? Clin Dev Immunol. 2011;2011:286248–15. https://doi.org/10.1155/2011/286248.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. 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. https://doi.org/10.2337/db12-0049.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Matthews JB, Staeva TP, Bernstein PL, Peakman M, von Herrath M. Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF type 1 diabetes combination therapy assessment group. Clin Exp Immunol. 2010;160(2):176–84. https://doi.org/10.1111/j.1365-2249.2010.04153.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Lord S, Greenbaum CJ. Disease modifying therapies in type 1 diabetes: where have we been, and where are we going? Pharmacol Res. 2015;98:3–8. https://doi.org/10.1016/j.phrs.2015.02.002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, Farinelli L, et al. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler. 2012;18(12):1721–36. https://doi.org/10.1177/1352458512441381.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Faucard R, Madeira A, Gehin N, Authier FJ, Panaite PA, Lesage C, et al. Human endogenous retrovirus and neuroinflammation in chronic inflammatory demyelinating polyradiculoneuropathy. EBioMedicine. 2016;6:190–8. https://doi.org/10.1016/j.ebiom.2016.03.001.

    Article  PubMed Central  PubMed  Google Scholar 

  81. •• Levet S, Medina J, Joanou J, Demolder A, Queruel N, Reant K et al. An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes. JCI Insight. 2017;2(17). doi:https://doi.org/10.1172/jci.insight.94387. The study reports on the potential of human endogenous retroviruses as therapeutic targets in the potential cure of type 1 diabetes.

  82. Curtin F, Bernard C, Levet S, Perron H, Porchet H, Medina J, et al. A new therapeutic approach for type 1 diabetes: rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody. Diabetes Obes Metab. 2018;20(9):2075–84. https://doi.org/10.1111/dom.13357.

    Article  CAS  PubMed  Google Scholar 

  83. Rewers M, Gottlieb P. Immunotherapy for the prevention and treatment of type 1 diabetes: human trials and a look into the future. Diabetes Care. 2009;32(10):1769–82. https://doi.org/10.2337/dc09-0374.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. von Herrath M, Peakman M, Roep B. Progress in immune-based therapies for type 1 diabetes. Clin Exp Immunol. 2013;172(2):186–202. https://doi.org/10.1111/cei.12085.

    Article  CAS  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. School of Health Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Griselda Lim Loo Xin, Yap Pui Khee & Tan Yoke Ying

  2. Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Jestin Chellian & Dinesh Kumar Chellappan

  3. School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, Jaipur, 302017, India

    Gaurav Gupta

  4. Division of Applied Biomedical Science and Biotechnology, School of Health Sciences, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Anil Philip Kunnath

  5. School of Science and Health, Western Sydney University, Sydney, NSW, 2751, Australia

    Srinivas Nammi

  6. NICM Health Research Institute, Western Sydney University, Sydney, NSW, 2751, Australia

    Srinivas Nammi

  7. Innovative Medicines Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Brisbane, Queensland, 4059, Australia

    Trudi Collet

  8. Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS), Ultimo, NSW, 2007, Australia

    Philip Michael Hansbro & Kamal Dua

  9. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of Biomedical Sciences and Pharmacy, The University of Newcastle (UoN), Callaghan, Newcastle, NSW, 2308, Australia

    Philip Michael Hansbro & Kamal Dua

Authors
  1. Griselda Lim Loo Xin
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  2. Yap Pui Khee
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  3. Tan Yoke Ying
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  4. Jestin Chellian
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  5. Gaurav Gupta
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  6. Anil Philip Kunnath
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  7. Srinivas Nammi
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  8. Trudi Collet
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  9. Philip Michael Hansbro
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  10. Kamal Dua
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  11. Dinesh Kumar Chellappan
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Corresponding author

Correspondence to Dinesh Kumar Chellappan.

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This article is part of the Topical Collection on Therapies and New Technologies in the Treatment of Diabetes

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Xin, G.L.L., Khee, Y.P., Ying, T.Y. et al. Current Status on Immunological Therapies for Type 1 Diabetes Mellitus. Curr Diab Rep 19, 22 (2019). https://doi.org/10.1007/s11892-019-1144-3

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