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Targeting Innate Immunity for Type 1 Diabetes Prevention

  • Therapies and New Technologies in the Treatment of Type 1 Diabetes (M Pietropaolo, Section Editor)
  • Published:
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Abstract

Purpose of Review

Despite immense research efforts, type 1 diabetes (T1D) remains an autoimmune disease without a known trigger or approved intervention. Over the last three decades, studies have primarily focused on delineating the role of the adaptive immune system in the mechanism of T1D. The discovery of Toll-like receptors in the 1990s has advanced the knowledge on the role of the innate immune system in host defense as well as mechanisms that regulate adaptive immunity including the function of autoreactive T cells.

Recent Findings

Recent investigations suggest that inflammation plays a key role in promoting a large number of autoimmune disorders including T1D. Data from the LEW1.WR1 rat model of virus-induced disease and the RIP-B7.1 mouse model of diabetes suggest that innate immune signaling plays a key role in triggering disease progression. There is also evidence that innate immunity may be involved in the course of T1D in humans; however, a small number of clinical trials have shown that interfering with the function of the innate immune system following disease onset exerts only a modest effect on β-cell function.

Summary

The data implying that innate immune pathways are linked with mechanisms of islet autoimmunity hold great promise for the identification of novel disease pathways that may be harnessed for clinical intervention. Nevertheless, more work needs to be done to better understand mechanisms by which innate immunity triggers β-cell destruction and assess the therapeutic value in blocking innate immunity for diabetes prevention.

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References

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

  1. Schranz DB, Lernmark A. Immunology in diabetes: an update. Diabetes Metab Rev. 1998;14(1):3–29. doi:https://doi.org/10.1002/(SICI)1099-0895(199803)14:1<3::AID-DMR206>3.0.CO;2-T [pii].

  2. Seissler J, de Sonnaville JJ, Morgenthaler NG, Steinbrenner H, Glawe D, Khoo-Morgenthaler UY, et al. Immunological heterogeneity in type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease. Diabetologia. 1998;41(8):891–7.

    Article  CAS  PubMed  Google Scholar 

  3. Srikanta S, Ganda OP, Jackson RA, Gleason RE, Kaldany A, Garovoy MR, et al. Type I diabetes mellitus in monozygotic twins: chronic progressive beta cell dysfunction. Ann Intern Med. 1983;99(3):320–6.

    Article  CAS  PubMed  Google Scholar 

  4. Jun HS, Yoon JW. The role of viruses in type I diabetes: two distinct cellular and molecular pathogenic mechanisms of virus-induced diabetes in animals. Diabetologia. 2001;44(3):271–85.

    Article  CAS  PubMed  Google Scholar 

  5. Jun HS, Yoon JW. A new took at viruses in type 1 diabetes. Diabetes-Metab Res. 2003;19(1):8–31.

    Article  CAS  Google Scholar 

  6. Soltesz G, Patterson CC, Dahlquist G. Worldwide childhood type 1 diabetes incidence—what can we learn from epidemiology? Pediatr Diabetes. 2007;8(Suppl 6):6–14.

    Article  PubMed  Google Scholar 

  7. Redondo MJ, Jeffrey J, Fain PR, Eisenbarth GS, Orban T. Concordance for islet autoimmunity among monozygotic twins. N Engl J Med. 2008;359(26):2849–50. https://doi.org/10.1056/NEJMc0805398.

    Article  CAS  PubMed  Google Scholar 

  8. Tuomilehto J. The emerging global epidemic of type 1 diabetes. Curr Diab Rep. 2013;13(6):795–804. https://doi.org/10.1007/s11892-013-0433-5.

    Article  CAS  PubMed  Google Scholar 

  9. The DPG. Incidence and trends of childhood type 1 diabetes worldwide 1990–1999. Diabet Med. 2006;23(8):857–66. https://doi.org/10.1111/j.1464-5491.2006.01925.x.

    Article  Google Scholar 

  10. CfDCa P. National Diabetes Statistics Report: estimates of diabetes and its burden in the United States. Atlanta: US Department of Health and Human Services; 2014.

    Google Scholar 

  11. Clark AL, Urano F. Endoplasmic reticulum stress in beta cells and autoimmune diabetes. Curr Opin Immunol. 2016;43:60–6. https://doi.org/10.1016/j.coi.2016.09.006.

  12. Kamada N, Seo SU, Chen GY, Nunez G. Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol. 2013;13(5):321–35.

    Article  CAS  PubMed  Google Scholar 

  13. Alkanani AK, Hara N, Gottlieb PA, Ir D, Robertson CE, Wagner BD, et al. Alterations in intestinal microbiota correlate with susceptibility to type 1 diabetes. Diabetes. 2015; https://doi.org/10.2337/db14-1847.

  14. Hara N, Alkanani AK, Ir D, Robertson CE, Wagner BD, Frank DN, et al. Prevention of virus-induced type 1 diabetes with antibiotic therapy. J Immunol. 2012;189(8):3805–14.

    Article  CAS  PubMed  Google Scholar 

  15. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature. 2008;455(7216):1109–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987;28(10):1221–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Layden BT, Angueira AR, Brodsky M, Durai V, Lowe WL Jr. Short chain fatty acids and their receptors: new metabolic targets. Transl Res. 2013;161(3):131–40. https://doi.org/10.1016/j.trsl.2012.10.007.

    Article  CAS  PubMed  Google Scholar 

  18. Schwiertz A, Taras D, Schaffer K, Beijer S, Bos NA, Donus C, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity. 2010;18(1):190–5.

    Article  PubMed  Google Scholar 

  19. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858–876. doi:https://doi.org/10.3390/nu3100858 [doi];nutrients-03-00858 [pii].

  20. Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008;57(10):2555–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhao G, Vatanen T, Droit L, Park A, Kostic AD, Poon TW, et al. Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proc Natl Acad Sci. 2017; https://doi.org/10.1073/pnas.1706359114.

  22. Frank DN, Zhu W, Sartor RB, Li E. Investigating the biological and clinical significance of human dysbioses. Trends Microbiol. 2011;19(9):427–434. doi:S0966-842X(11)00126-0 [pii];https://doi.org/10.1016/j.tim.2011.06.005 [doi].

  23. Control TD, Group CTR. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86. https://doi.org/10.1056/nejm199309303291401.

    Article  Google Scholar 

  24. Garyu JW, Meffre E, Cotsapas C, Herold KC. Progress and challenges for treating type 1 diabetes. J Autoimmun. 2016;71:1–9. https://doi.org/10.1016/j.jaut.2016.04.004.

  25. Keymeulen B, Walter M, Mathieu C, Kaufman L, Gorus F, Hilbrands R, 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 beta cell mass. Diabetologia. 2010;53(4):614–23. https://doi.org/10.1007/s00125-009-1644-9.

    Article  CAS  PubMed  Google Scholar 

  26. Bougneres PF, Landais P, Boisson C, Carel JC, Frament N, Boitard C, et al. Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin. Diabetes. 1990;39(10):1264–72.

    Article  CAS  PubMed  Google Scholar 

  27. Martin S, Schernthaner G, Nerup J, Gries FA, Koivisto VA, Dupré J, et al. Follow-up of cyclosporin a treatment in type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects. Diabetologia. 1991;34(6):429–34. https://doi.org/10.1007/bf00403182.

    Article  CAS  PubMed  Google Scholar 

  28. Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 2009;52(6):1143–51.

    Article  CAS  PubMed  Google Scholar 

  29. Roep BO, Kleijwegt FS, Van Halteren AGS, Bonato V, Boggi U, Vendrame F, et al. Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin Exp Immunol. 2010;159(3):338–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tanaka S, Nishida Y, Aida K, Maruyama T, Shimada A, Suzuki M, et al. Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes. Diabetes. 2009;58(10):2285–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zipris D. Toll-like receptors and type 1 diabetes. Adv Exp Med Biol. 2010;654:585–610.

    Article  CAS  PubMed  Google Scholar 

  32. Zipris D. Innate immunity in type 1 diabetes. Diabetes Metab Res Rev. 2011;27(8):824–9.

    Article  CAS  PubMed  Google Scholar 

  33. Herold KC, Vignali DAA, Cooke A, Bluestone JA. Type 1 diabetes: translating mechanistic observations into effective clinical outcomes. Nature Rev Immunol. 2013;13(4):243–56.

    Article  CAS  Google Scholar 

  34. Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–35.

    Article  CAS  PubMed  Google Scholar 

  35. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5(10):987–95.

    Article  CAS  PubMed  Google Scholar 

  36. • Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16(4):343–53. https://doi.org/10.1038/ni.3123. This review article discusses recent advances in the study of innate control of adaptive immunity and highlights new concepts that expand the pattern-recognition paradigm. It also discusses some of the major knowledge gaps and unknowns

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216.

    Article  CAS  PubMed  Google Scholar 

  38. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1(2):135–45.

    Article  CAS  PubMed  Google Scholar 

  39. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007;449(7164):819–26.

    Article  CAS  PubMed  Google Scholar 

  40. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med. 2000;343(5):338–44.

    Article  CAS  PubMed  Google Scholar 

  41. Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev. 2000;173:89–97.

    Article  CAS  PubMed  Google Scholar 

  42. Medzhitov R, Janeway C Jr. The toll receptor family and microbial recognition. Trends Microbiol. 2000;8(10):452–6.

    Article  CAS  PubMed  Google Scholar 

  43. Joosten LAB, Abdollahi-Roodsaz S, Dinarello CA, O’Neill L, Netea MG. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol. 2016;12(6):344–57. https://doi.org/10.1038/nrrheum.2016.61.

    Article  CAS  PubMed  Google Scholar 

  44. Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10(12):826–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009;22(2):240–73. https://doi.org/10.1128/cmr.00046-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ma H, Matsuzaki K, Yang YD, Tokunaga E, Nakane D, Ozawa T, et al. Enantioselective monofluoromethylation of aldehydes with 2-fluoro-1,3-benzodithiole-1,1,3,3-tetraoxide catalyzed by a bifunctional cinchona alkaloid-derived thiourea-titanium complex. Chem Commun (Camb). 2013;49(95):11206–8. https://doi.org/10.1039/c3cc46544f.

    Article  CAS  Google Scholar 

  47. Brodsky I, Medzhitov R. Two modes of ligand recognition by TLRs. Cell. 2007;130(6):979–81.

    Article  CAS  PubMed  Google Scholar 

  48. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7(2):131–7.

    Article  CAS  PubMed  Google Scholar 

  49. Kawai T, Akira S. Signaling to NF-[kappa]B by toll-like receptors. Trends Mol Med. 2007;13(11):460–9.

    Article  CAS  PubMed  Google Scholar 

  50. Walker LSK, von Herrath M. CD4 T cell differentiation in type 1 diabetes. Clin Exp Immunol. 2016;183(1):16–29. https://doi.org/10.1111/cei.12672.

    Article  CAS  PubMed  Google Scholar 

  51. Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and [beta]-cell loss in type 1 diabetes. Nat Rev Endocrinol. 2009;5(4):219–26.

    Article  CAS  PubMed  Google Scholar 

  52. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation. Clin Exp Immunol. 2007;147(2):227–35. https://doi.org/10.1111/j.1365-2249.2006.03261.x.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. In’t Veld P, Lievens D, De Grijse J, Ling Z, Van der Auwera B, Pipeleers-Marichal M, et al. Screening for insulitis in adult autoantibody-positive organ donors. Diabetes. 2007;56(9):2400–4. https://doi.org/10.2337/db07-0416.

    Article  PubMed  CAS  Google Scholar 

  54. Campbell-Thompson ML, Atkinson MA, Butler AE, Chapman NM, Frisk G, Gianani R, et al. The diagnosis of insulitis in human type 1 diabetes. Diabetologia. 2013;56(11):2541–3. https://doi.org/10.1007/s00125-013-3043-5.

    Article  CAS  PubMed  Google Scholar 

  55. • Donath MY, Hess C, Palmer E. What is the role of autoimmunity in type 1 diabetes? A clinical perspective. Diabetologia. 2014;57(4):653–5. https://doi.org/10.1007/s00125-013-3153-0. This article raises questions about the role of autoimmunity in the pathogenesis of type 1 diabetes. It reviews human data in an attempt to reconsider the importance and relevance of the immunological alterations in patients with type 1 diabetes

    Article  CAS  PubMed  Google Scholar 

  56. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TWH, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med. 2012;209(1):51–60. https://doi.org/10.1084/jem.20111187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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):173–181. doi: CEI3860 [pii];https://doi.org/10.1111/j.1365-2249.2008.03860.x [doi].

  58. Skog O, Korsgren S, Melhus Å, Korsgren O. Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease. Curr Opin Endocrinol Diabetes Obes. 2013;20(2):118–23. https://doi.org/10.1097/MED.0b013e32835edb89.

    Article  CAS  PubMed  Google Scholar 

  59. 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. 2009;32(7):1244–1249. doi:https://doi.org/10.2337/dc09-0054.

  60. Gabbay ML, Sato MN, Finazzo C, Duarte AS, Dib SA. Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual β-cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med. 2012;166(7):601–7. https://doi.org/10.1001/archpediatrics.2012.164.

    Article  PubMed  Google Scholar 

  61. Zipris D, Lien E, Xie JX, Greiner DL, Mordes JP, Rossini AA. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol. 2005;174(1):131–42.

    Article  CAS  PubMed  Google Scholar 

  62. Serreze DV, Ottendorfer EW, Ellis TM, Gauntt CJ, Atkinson MA. Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets. Diabetes. 2000;49(5):708–11.

    Article  CAS  PubMed  Google Scholar 

  63. Jacoby RO, Ball-Goodrich LJ, Besselsen DG, McKisic MD, Riley LK, Smith AL. Rodent parvovirus infections. Lab Anim Sci. 1996;46(4):370–80.

    CAS  PubMed  Google Scholar 

  64. Takasawa N, Munakata Y, Ishii KK, Takahashi Y, Takahashi M, Fu Y, et al. Human parvovirus B19 transgenic mice become susceptible to polyarthritis. J Immunol. 2004;173(7):4675–83.

    Article  CAS  PubMed  Google Scholar 

  65. Mordes JP, Bortell R, Blankenhorn EP, Rossini AA, Greiner DL. Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J. 2004;45(3):278–91.

    Article  CAS  PubMed  Google Scholar 

  66. Burrows MP, Volchkov P, Kobayashi KS, Chervonsky AV. Microbiota regulates type 1 diabetes through toll-like receptors. Proc Natl Acad Sci U S A. 2015;112(32):9973–7. https://doi.org/10.1073/pnas.1508740112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Londono P, Komura A, Hara N, Zipris D. Brief dexamethasone treatment during acute infection prevents virus-induced autoimmune diabetes. Clin Immunol. 2010;135(3):401–11.

    Article  CAS  PubMed  Google Scholar 

  68. Sai P, Rivereau AS. Prevention of diabetes in the nonobese diabetic mouse by oral immunological treatments. Comparative efficiency of human insulin and two bacterial antigens, lipopolysacharide from Escherichia coli and glycoprotein extract from Klebsiella pneumoniae. Diabetes Metab. 1996;22(5):341–8.

    CAS  PubMed  Google Scholar 

  69. Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL. Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol. 2001;167(2):1081–9.

    Article  CAS  PubMed  Google Scholar 

  70. Quintana FJ, Rotem A, Carmi P, Cohen IR. Vaccination with empty plasmid DNA or CpG oligonucleotide inhibits diabetes in nonobese diabetic mice: modulation of spontaneous 60-kDa heat shock protein autoimmunity. J Immunol. 2000;165(11):6148–55.

    Article  CAS  PubMed  Google Scholar 

  71. Aumeunier A, Grela F, Ramadan A, Pham Van L, Bardel E, Gomez Alcala A, et al. Systemic toll-like receptor stimulation suppresses experimental allergic asthma and autoimmune diabetes in NOD mice. PLoS One. 2010;5(7):e11484. https://doi.org/10.1371/journal.pone.0011484.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Zipris D, Lien E, Nair A, Xie JX, Greiner DL, Mordes JP, et al. TLR9-Signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol. 2007;178(2):693–701.

    Article  CAS  PubMed  Google Scholar 

  73. Ellerman KE, Like AA. Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia. 2000;43(7):890–8.

    Article  CAS  PubMed  Google Scholar 

  74. Ellerman KE, Richards CA, Guberski DL, Shek WR, Like AA. Kilham rat triggers T-cell-dependent autoimmune diabetes in multiple strains of rat. Diabetes. 1996;45(5):557–62.

    Article  CAS  PubMed  Google Scholar 

  75. Alkanani AK, Hara N, Gianani R, Zipris D. Kilham rat virus-induced type 1 diabetes involves beta cell infection and intra-islet JAK–STAT activation prior to insulitis. Virology. 2014;468–470:19–27. https://doi.org/10.1016/j.virol.2014.07.041.

    Article  PubMed  CAS  Google Scholar 

  76. Guerder S, Picarella DE, Linsley PS, Flavell RA. Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice. Proc Natl Acad Sci U S A. 1994;91(11):5138–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Devendra D, Jasinski J, Melanitou E, Nakayama M, Li M, Hensley B, et al. Interferon-{alpha} as a mediator of polyinosinic:polycytidylic acid-induced type 1 diabetes. Diabetes. 2005;54(9):2549–56.

    Article  CAS  PubMed  Google Scholar 

  78. Wen L, Peng J, Li Z, Wong FS. The effect of innate immunity on autoimmune diabetes and the expression of toll-like receptors on pancreatic islets. J Immunol. 2004;172(5):3173–80.

    Article  CAS  PubMed  Google Scholar 

  79. Alkanani AK, Hara N, Lien E, Ir D, Kotter CV, Robertson CE et al. Induction of diabetes in the RIP-B7.1 mouse model is critically dependent on TLR3 and MyD88 pathways and is associated with alterations in the intestinal microbiome. Diabetes. 2014;63(2):619–631. doi: db13-1007 [pii];https://doi.org/10.2337/db13-1007 [doi].

  80. Zhang Y, Lee AS, Shameli A, Geng X, Finegood D, Santamaria P, et al. TLR9 Blockade inhibits activation of diabetogenic CD8+ T cells and delays autoimmune diabetes. J Immunol. 2010;184(10):5645–53.

    Article  CAS  PubMed  Google Scholar 

  81. Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotech. 2007;25(1):84–90. https://doi.org/10.1038/nbt1272.

    Article  CAS  Google Scholar 

  82. Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, et al. Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol. 2006;176(8):5015–22.

    Article  CAS  PubMed  Google Scholar 

  83. Camelo S, Iglesias AH, Hwang D, Due B, Ryu H, Smith K, et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005;164(1GÇô2):10–21.

    Article  CAS  PubMed  Google Scholar 

  84. Chung YL, Lee MY, Wang AJ, Yao LF. A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther. 2003;8(5):707–17.

    Article  CAS  PubMed  Google Scholar 

  85. Hara N, Alkanani A, Dinarello C, Zipris D. Histone deacetylase inhibitor suppresses virus-induced proinflammatory responses and type 1 diabetes. J Mol Med. 2013:1–10.

  86. Lewis EC, Blaabjerg L, Storling J, Ronn SG, Mascagni P, Dinarello CA et al. The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet beta cells in vivo and in vitro. Mol Med. 2011;17(5–6):369–377. doi: molmed.2010.00152 [pii];https://doi.org/10.2119/molmed.2010.00152 [doi].

  87. Larsen L, Tonnesen M, Ronn SG, Storling J, Jorgensen S, Mascagni P, et al. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells. Diabetologia. 2007;50(4):779–89. https://doi.org/10.1007/s00125-006-0562-3.

    Article  CAS  PubMed  Google Scholar 

  88. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50. https://doi.org/10.1146/annurev.immunol.021908.132612.

    Article  CAS  PubMed  Google Scholar 

  89. Dinarello CA, Simon A, Van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Needell JC, Dinarello CA, Ir D, Robertson CE, Ryan SM, Kroehl ME, et al. Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes. PLoS One. 2017;12(3). doi:ARTN):e0173968. https://doi.org/10.1371/journal.pone.0173968.

  91. Nicoletti F, di Marcou R, Barcelliniu W, Magro G, Schorlemmeru HU, Kurrleu R, et al. Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor. Eur J Immunol. 1994;24(8):1843–7.

    Article  CAS  PubMed  Google Scholar 

  92. Ablamunits V, Henegariu O, Hansen JB, Opare-Addo L, Preston-Hurlburt P, Santamaria P, et al. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation. Diabetes. 2012;61(1):145–54.

    Article  CAS  PubMed  Google Scholar 

  93. Thomas HE, Irawaty W, Darwiche R, Brodnicki TC, Santamaria P, Allison J, et al. IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. Diabetes. 2004;53(1):113–21.

    Article  CAS  PubMed  Google Scholar 

  94. Schott WH, Haskell BD, Tse HM, Milton MJ, Piganelli JD, Choisy-Rossi CM, et al. Caspase-1 is not required for type 1 diabetes in the NOD mouse. Diabetes. 2004;53(1):99–104.

    Article  CAS  PubMed  Google Scholar 

  95. Hara N, Alkanani AK, Dinarello CA, Zipris D. Modulation of virus-induced innate immunity and type 1 diabetes by IL-1 blockade. Innate Immun. 2014;20(6):574–84.

    Article  PubMed  CAS  Google Scholar 

  96. Wolter TR, Wong R, Sarkar SA, Zipris D. DNA microarray analysis for the identification of innate immune pathways implicated in virus-induced autoimmune diabetes. Clin Immunol. 2009;132(1):103–15.

    Article  CAS  PubMed  Google Scholar 

  97. Mandrup-Poulsen T, Pickersgill L, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol. 2010;6(3):158–66.

    Article  CAS  PubMed  Google Scholar 

  98. Sandler S, Andersson A, Hellerstrom C. Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology. 1987;121(4):1424–31.

    Article  CAS  PubMed  Google Scholar 

  99. Spinas GA, Hansen BS, Linde S, Kastern W, Molvig J, Mandrup-Poulsen T, et al. Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans. Diabetologia. 1987;30(7):474–80.

    Article  CAS  PubMed  Google Scholar 

  100. Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110(6):851–60. https://doi.org/10.1172/JCI15318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yamada K, Takane-Gyotoku N, Yuan X, Ichikawa F, Inada C, Nonaka K. Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia. 1996;39(11):1306–12.

    Article  CAS  PubMed  Google Scholar 

  102. Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F, et al. IL-1b mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J Exp Med. 2012;209(9):1595–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Foulis A, Farquharson M, Meager A. Immunoreactive [alpha]-interferon in insulin-secreting [beta] cells in type 1 diabetes mellitus. Lancet. 1987;330(8573):1423–7.

    Article  Google Scholar 

  104. Dotta F, Censini S, van Halteren AGS, Marselli L, Masini M, Dionisi S, et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007;104(12):5115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Somoza N, Vargas F, Roura-Mir C, Vives-Pi M, Fernández-Figueras MT, Ariza A, et al. Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. J Immunol. 1994;153(3):1360–77.

    CAS  PubMed  Google Scholar 

  106. Huang X, Yuang J, Goddard A, Foulis A, James RFL, Lernmark Å, et al. Interferon expression in the pancreases of patients with type I diabetes. Diabetes. 1995;44(6):658–64. https://doi.org/10.2337/diab.44.6.658.

    Article  CAS  PubMed  Google Scholar 

  107. Lundberg M, Krogvold L, Kuric E, Dahl-Jørgensen K, Skog O. Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes. 2016;65(10):3104–10. https://doi.org/10.2337/db16-0616.

    Article  CAS  PubMed  Google Scholar 

  108. Schulte BM, Lanke KHW, Piganelli JD, Kers-Rebel ED, Bottino R, Trucco M, et al. Cytokine and chemokine production by human pancreatic islets upon enterovirus infection. Diabetes. 2012;61(8):2030–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sarkar SA, Lee CE, Victorino F, Nguyen TT, Walters JA, Burrack A, et al. Expression and regulation of chemokines in murine and human type 1 diabetes. Diabetes. 2012;61(2):436–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Hollander GA, et al. Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med. 2002;8(12):1414–20.

    Article  CAS  PubMed  Google Scholar 

  111. Liu D, Cardozo AK, Darville MI, Eizirik DL. Double-stranded RNA cooperates with interferon-{gamma} and IL-1{beta} to induce both chemokine expression and nuclear factor-{kappa}B-dependent apoptosis in pancreatic {beta}-cells: potential mechanisms for viral-induced insulitis and {beta}-cell death in type 1 diabetes mellitus. Endocrinology. 2002;143(4):1225–34.

    Article  CAS  PubMed  Google Scholar 

  112. Dogusan Z, Garcia M, Flamez D, Alexopoulou L, Goldman M, Gysemans C, et al. Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways. Diabetes. 2008;57(5):1236–45.

    Article  CAS  PubMed  Google Scholar 

  113. Flodstrom M, Maday A, Balakrishna D, Cleary MM, Yoshimura A, Sarvetnick N. Target cell defense prevents the development of diabetes after viral infection. Nat Immunol. 2002;3(4):373–82.

    Article  CAS  PubMed  Google Scholar 

  114. Hultcrantz M, Huhn MH, Wolf M, Olsson A, Jacobson S, Williams BR, et al. Interferons induce an antiviral state in human pancreatic islet cells. Virology. 2007;367(1):92–101.

    Article  CAS  PubMed  Google Scholar 

  115. Rasschaert J, Ladriere L, Urbain M, Dogusan Z, Katabua B, Sato S, et al. Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA+ interferon-{gamma}-induced apoptosis in primary pancreatic {beta}-cells. J Biol Chem. 2005;280(40):33984–91.

    Article  CAS  PubMed  Google Scholar 

  116. Cabrera SM, Chen Y-G, Hagopian WA, Hessner MJ. Blood-based signatures in type 1 diabetes. Diabetologia. 2016;59(3):414–25. https://doi.org/10.1007/s00125-015-3843-x.

    Article  CAS  PubMed  Google Scholar 

  117. Alkanani AK, Rewers M, Dong F, Waugh K, Gottlieb PA, Zipris D. Dysregulated toll-like receptor-induced interleukin-1β and interleukin-6 responses in subjects at risk for the development of type 1 diabetes. Diabetes. 2012;61:2525–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kristiansen OP, Mandrup-Poulsen T. Interleukin-6 and diabetes. Diabetes. 2005;54(suppl 2):S114–S24.

    Article  CAS  PubMed  Google Scholar 

  119. Negrin KA, Roth Flach RJ, DiStefano MT, Matevossian A, Friedline RH, Jung D, et al. IL-1 signaling in obesity-induced hepatic lipogenesis and steatosis. PLoS One. 2014;9(9):e107265. https://doi.org/10.1371/journal.pone.0107265.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ballak DB, Stienstra R, Tack CJ, Dinarello CA, van Diepen JA. IL-1 family members in the pathogenesis and treatment of metabolic disease: focus on adipose tissue inflammation and insulin resistance. Cytokine. 2015;75(2):280–90. https://doi.org/10.1016/j.cyto.2015.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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;38(9881):1905–15.

    Article  CAS  Google Scholar 

  122. Breit SN, Wakefield D, Robinson JP, Luckhurst E, Clark P, Penny R. The role of alpha 1-antitrypsin deficiency in the pathogenesis of immune disorders. Clin Immunol Immunopathol. 1985;35(3):363–80.

    Article  CAS  PubMed  Google Scholar 

  123. Breit SN, Penny R. The role of alpha 1 protease inhibitor (alpha 1 anti-trypsin) in the regulation of immunological and inflammatory reactions. Aust NZ J Med. 1980;10(4):449–53. https://doi.org/10.1111/j.1445-5994.1980.tb04101.x.

    Article  CAS  Google Scholar 

  124. Ganrot PO, Gydell K, Ekelund H. Serum concentration of α2-macroglobulin, haptoglobin and α1-antitrypsin in diabetes mellitus. Acta Endocrinol. 1967;55(3):537–44. https://doi.org/10.1530/acta.0.0550537.

    CAS  PubMed  Google Scholar 

  125. Hashemi M, Naderi M, Rashidi H, Ghavami S. Impaired activity of serum alpha-1-antitrypsin in diabetes mellitus. Diabetes Res Clin Pract. 2007;75(2):246–8. https://doi.org/10.1016/j.diabres.2006.06.020.

  126. Lisowska-Myjak B, Pachecka J, Kaczyńska B, Miszkurka G, Kądziela K. Serum protease inhibitor concentrations and total antitrypsin activity in diabetic and non-diabetic children during adolescence. Acta Diabetol. 2006;43(4):88–92. https://doi.org/10.1007/s00592-006-0220-8.

    Article  CAS  PubMed  Google Scholar 

  127. Sandler M, Gemperli BM, Hanekom C, Kuhn SH. Serum Alpha-1-protease inhibitor in diabetes-mellitus—reduced concentration and impaired activity. Diabetes Res Clin Pract. 1988;5(4):249–55. https://doi.org/10.1016/S0168-8227(88)80059-7.

    Article  CAS  PubMed  Google Scholar 

  128. Pott GB, Chan ED, Dinarello CA, Shapiro L. a1-Antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J Leukoc Biol. 2009;85(5):886–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Janciauskiene S, Larsson S, Larsson P, Virtala R, Jansson L, Stevens T. Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha 1-antitrypsin. Biochem Biophys Res Commun. 2004;321(3):592–600.

    Article  CAS  PubMed  Google Scholar 

  130. Shapiro L, Pott GB, Ralston AH. Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J. 2001;15(1):115–22.

    Article  CAS  PubMed  Google Scholar 

  131. Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H, et al. Curative and beta cell regenerative effects of a1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci U S A. 2008;105(42):16242–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ma H, Lu Y, Li H, Campbell-Thompson M, Parker M, Data L, et al. Intradermal a1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease. Diabetologia. 2010;53(10):2198–204.

    Article  CAS  PubMed  Google Scholar 

  133. Grant CW, Moran-Paul CM, Duclos SK, Guberski DL, Arreaza-Rubin G, Spain LM. Testing agents for prevention or reversal of type 1 diabetes in rodents. PLoS One. 2013;8(8):e72989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Gottlieb PA, Alkanani AK, Michels AW, Lewis EC, Shapiro L, Dinarello CA, et al. alpha1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1beta responses in monocytes and myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 diabetes. J Clin Endocrinol Metab. 2014;99(8):E1418–26. https://doi.org/10.1210/jc.2013-3864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Clement LC, Avila-Casado C, Mace C, Soria E, Bakker WW, Kersten S, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. 2011;17(1):117–22. http://www.nature.com/nm/journal/v17/n1/abs/nm.2261.html - supplementary-information

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Our studies were supported by grants from JDRF.

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Authors and Affiliations

  1. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, 80045, USA

    James C. Needell

  2. Innate Biotechnologies LLC, Denver, CO, 80231, USA

    Danny Zipris

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J.C.N. and D.Z. declare that they have no conflict of interest.

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This article is part of the Topical Collection on Therapies and New Technologies in the Treatment of Type 1 Diabetes

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Needell, J.C., Zipris, D. Targeting Innate Immunity for Type 1 Diabetes Prevention. Curr Diab Rep 17, 113 (2017). https://doi.org/10.1007/s11892-017-0930-z

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