Skip to main content
SpringerLink
Log in

Customized Cell-Based Treatment Options to Combat Autoimmunity and Restore β-Cell Function in Type 1 Diabetes Mellitus: Current Protocols and Future Perspectives

  • Chapter
  • First Online:
Book cover The Islets of Langerhans

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 654))

Abstract

Type 1 diabetes mellitus (T1D) is considered a classical autoimmune disease which commonly starts during childhood but may appear later in adulthood in a proportion of 30–40% of affected individuals. Its development is based on a combination of a genetic predisposition and autoimmune processes that result in gradual destruction of the β-cells of the pancreas and cause absolute insulin deficiency. Evidence for an autoimmune origin of T1D results from measurable islet β-cell autoantibody directed against various autoantigens such as proinsulin or insulin itself, glutamic acid decarboxylase 65, the islet tyrosine phosphatase IA-2, and the islet-specific glucose-6-phosphatase catalytic subunit-related protein. In addition, T-cell lines with specificity for insulin or glutamic acid decarboxylase have been identified within peripheral blood lymphocytes. Importantly, in most instances the pathogenesis of T1D comprises a slowly progressive destruction of β-cell tissue in the pancreas preceded by several years of a prediabetic phase where autoimmunity has already developed but with no clinically apparent insulin dependency. Unless immunological tolerance to pancreatic autoantigens is re-established, diabetes treated by islet cell transplantation or stimulation/regeneration of endogenous β-cells would remain a chronic disease secondary to immune suppression related morbidity. Hence, if islet cell tolerance could be re-induced, a major clinical hurdle to curing diabetes by islet cell neogenesis may be overcome. Targeted immunotherapies are currently explored in a variety of clinical studies and hold great promise for causative treatment to readjust the underlying immunologic imbalance with the goal to cure the disease. This chapter will outline possible treatment options to stop or reverse the β-cell–specific autoimmune and inflammatory process within pancreatic islets. Special emphasis is given to stem cells of embryonic, mesenchymal, and haematopoietic origin, which, besides their use for regenerative purposes, possess potent immunomodulatory functions and thus have the potential to suppress the autoimmune response. At the end of this chapter we will introduce a novel type of in vitro modified monocytes with immunosuppressive and anti-inflammatory properties. These tolerogenic monocytes provide a feasible option to be used as autologous cellular transplants to halt autoimmunity and to protect still viable β-cells within Langerhans islets.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AHST:

adult haematopoietic stem cell transplantation

AICD:

activation-induced cell death

AIRE:

autoimmune regulator

APC:

antigen-presenting cell

AUC:

mean total area under the curve

BM:

bone marrow

CTL:

cytotoxic T lymphocyte

DA:

Dark-Agouti rat strain

DC:

dendritic cell

DM:

diabetes mellitus

DSS:

dextran sodium sulphate

EBV:

Epstein–Barr virus

ESC:

embryonic stem cell

GAD:

glutamic acid decarboxylase

GVA:

graft-versus-host autoimmunity

GVHD:

graft-versus-host disease

γIFN:

gamma-interferon

HSC:

haematopoietic stem cell

IAA:

insulin autoantigen

IA-2:

insulin antigen 2 specific antibody

IDDM:

insulin-dependent diabetes mellitus

IDO:

indoleamine 2, 3-dioxygenase

IGRP:

islet-specific glucose-6-phosphatase catalytic subunit- related protein

IL-10:

interleukin-10

iNOS:

inducible nitric oxide synthase

LEW:

Lewis rat strain

mAb:

monoclonal antibody

M-CSF:

macrophage colony-stimulating factor

MSC:

mesenchymal stem cell/multipotent stromal cell

mTOR:

mammalian target of rapamycin

NIDDM:

non-insulin-dependentdiabetes mellitus

NK:

natural killer

NOD:

nonobese diabetes (an inbred mouse strain)

PC:

phosphatidylcholine

PCMO:

programmable cell of monocytic origin

RESC:

rat embryonic stem cell

scid:

severe combined immunodeficiency disease

STIC:

self-tolerance inducing cell

TAIC:

transplant acceptance inducing cell

T1D:

type 1 diabetes mellitus

Treg:

regulatory T cells

References

  1. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 2008;57:1759–67.

    Article  PubMed  CAS  Google Scholar 

  2. Abrams JR, Lebwohl MG, Guzzo CA, Jegasothy BV, Goldfarb MT, Goffe BS, Menter A, Lowe NJ, Krueger G, Brown MJ, Weiner RS, Birkhofer MJ, Warner GL, Berry KK, Linsley PS, Krueger JG, Ochs HD, Kelley SL, Kang S. CTLA4Ig-mediated blockade of T cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999;103:1243–52.

    Article  PubMed  CAS  Google Scholar 

  3. Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, Lebwohl MG, Guzzo CA, Jegasothy BV, Linsley PS, Krueger JG. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med 2000;192:681–94.

    Article  PubMed  CAS  Google Scholar 

  4. Al Sabbagh A, Nelson PA, Akselband Y, Sobel R, Weiner HL. Antigen-driven peripheral immune tolerance: suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis by aerosol administration of myelin basic protein or type II collagen. Cell Immunol 1996;171:111–9.

    Article  PubMed  CAS  Google Scholar 

  5. Anderson M. Autoimmune endocrine disease. Curr Opin Immunol 2002;14:760–4.

    Article  PubMed  CAS  Google Scholar 

  6. Apostolou I, von Boehmer H. In vivo instruction of suppressor commitment in naïve T cells. J Exp Med 2004;199:1401–8.

    Article  PubMed  CAS  Google Scholar 

  7. Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, Roep BO, Peakman M. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 2004;113:451–63.

    PubMed  CAS  Google Scholar 

  8. Atkinson MA, Leiter EH. The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med 1999;5:601–4.

    Article  PubMed  CAS  Google Scholar 

  9. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002;347:911–20.

    Article  PubMed  Google Scholar 

  10. Bingley P, Bonifacio E, Mueller P. Diabetes Antibody Standardization Program: first assay proficiency evaluation. Diabetes 2003;52:1128–36.

    Article  PubMed  CAS  Google Scholar 

  11. Bluestone JA, St. Clair EW, Turka LA. CTLA4Ig: Bridging the basic immunology with clinical application. Immunity 2006;24:233–38.

    Article  PubMed  Google Scholar 

  12. Bonde S, Chan KM, Zavazava N. ES-cell derived hematopoietic cells induce transplantation tolerance. PLoS ONE 2008;3:e3212.

    Article  PubMed  Google Scholar 

  13. Bougnères PF, Landais P, Boisson C, Carel JC, Frament N, Boitard C, Chaussain JL, Bach JF. Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin. Diabetes 1990;39:1264–72.

    Article  PubMed  Google Scholar 

  14. Boumaza I, Srinivasan S, Witt WT, Feghali-Bostwick C, Dai Y, Garcia-Ocana A, Feili-Hariri M. Autologous bone marrow-derived rat mesenchymal stem cells promote PDX-1 and insulin expression in the islets, alter T cell cytokine pattern and preserve regulatory T cells in the periphery and induce sustained normoglycemia. J Autoimmun 2009;32:33–42.

    Article  PubMed  CAS  Google Scholar 

  15. Brem-Exner BG, Sattler C, Hutchinson JA, Koehl GE, Kronenberg K, Farkas S, Inoue S, Blank C, Knechtle SJ, Schlitt HJ, Fändrich F, Geissler EK. Macrophages driven to a novel state of activation have anti-inflammatory properties in mice. J Immunol 2008;180:530–49.

    Google Scholar 

  16. Bresson D, Togher L, Rodrigo E, Chen Y, Bluestone JA, Herold KC, von Herrath M. AntiCD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs. J Clin Invest 2006;116:1371–81.

    Article  PubMed  CAS  Google Scholar 

  17. Burt RK, Oyama Y, Traynor A, Kenyon NS. Hematopoietic stem cell therapy for type 1 diabetes: induction of tolerance and islet cell neogenesis. Autoimmun Rev 2002;1:133–8.

    Article  PubMed  CAS  Google Scholar 

  18. Calderon B, Suri A, Miller MJ, Unanue ER. Dendritic cells in islets of Langerhans constitutively present beta cell derived peptides bound to their class II MHC molecules. Proc Natl Acad Sci USA 2008;105:6121–6.

    Article  PubMed  CAS  Google Scholar 

  19. Chaillous L, Lefèvre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gepner C, Bouhanick B, Mogenet A, Nicolino M, Carel JC, Lecomte P, Maréchaud R, Bougnères P, Charbonnel B, Saï P. Oral insulin administration and residual β cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Lancet 2000;356:545–9.

    Article  PubMed  CAS  Google Scholar 

  20. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 2007;7:622–2.

    Article  PubMed  CAS  Google Scholar 

  21. Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 1994;91:123–7.

    Article  PubMed  CAS  Google Scholar 

  22. Chatenoud L, Primo J, Bach JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 1997;158:2947–54.

    PubMed  CAS  Google Scholar 

  23. Chong AS, Shen J, Tao J, Yin D, Kuznetsov A, Hara M, Philipson LH. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006;311:1774–5.

    Article  PubMed  CAS  Google Scholar 

  24. Diabetes Prevention Trial – Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685–91.

    Article  Google Scholar 

  25. Domenick MA, Ildstad ST. Impact of bone marrow transplantation on type I diabetes. World J Surg 2001;25:474–80.

    Article  PubMed  CAS  Google Scholar 

  26. Ergun-Longmire B, Marker J, Zeidler A, Rapaport R, Raskin P, Bode B, Schatz D, Vargas A, Rogers D, Schwartz S, Malone J, Krischer J, Maclaren NK. Oral insulin therapy to prevent progression of immune-mediated (type 1) diabetes. Ann NY Acad Sci 2004;1029: 260–77.

    Article  PubMed  CAS  Google Scholar 

  27. Fändrich F, Lin X, Chai GX, Schulze M, Ganten D, Bader M, Holle J, Huang DS, Parwaresch R, Zavazava N, Binas B. Preimplantation-stage stem cells induce allogeneic graft tolerance without supplementary host conditioning. Nat Med 2002;8:171–8.

    Article  PubMed  Google Scholar 

  28. Fändrich F, Zhou X, Schlemminger M, Glass B, Lin X, Dreßke B. Future strategies for tolerance induction: a comparative study between hematopoietic stem cells and macrophages. Hum Immunol 2002;63:805–12.

    Article  PubMed  Google Scholar 

  29. Gagnerault MC, Luan JJ, Lotton C, Lepault F. Pancreatic lymph nodes are required for priming of β cell reactive T cells in NOD mice. J Exp Med 196: 2002;369–77.

    Article  PubMed  CAS  Google Scholar 

  30. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N Engl J Med 2005;353:1114–23.

    Article  PubMed  CAS  Google Scholar 

  31. Gottlieb PA and Eisenbarth GS. Diagnosis and treatment of preinsulin dependent diabetes. Annu Rev Med 1998;49:391–405.

    Article  PubMed  CAS  Google Scholar 

  32. Greening JE, Tree TI, Kotowicz KT, van Halteren AG, Roep BO, Klein NJ, Peakman M. Processing and presentation of the islet autoantigen GAD by vascular endothelial cells promotes transmigration of autoreactive T cells. Diabetes 2003;52:717–25.

    Article  PubMed  CAS  Google Scholar 

  33. Haskins K, Portas M, Bradley B, Wegmann D, Lafferty K. T-lymphocyte clone specific for pancreatic islet antigen. Diabetes 1988;37:1444–8.

    Google Scholar 

  34. Haskins K. Pathogenic T cell clones in autoimmune diabetes: more lessons from the NOD mouse. Adv Immunol 2005;87:123–62.

    Google Scholar 

  35. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;364:1692–8.

    Article  Google Scholar 

  36. Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005;54:1763–9.

    Article  PubMed  CAS  Google Scholar 

  37. Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007;27:786–800.

    Article  PubMed  CAS  Google Scholar 

  38. Hutchinson JA, Brem-Exner BG, Riquelme P, Roelen D, Schulze M, Ivens K, Grabensee B, Witzke O, Philipp T, Renders L, Humpe A, Sotnikova A, Matthäi M, Heumann A, Gövert F, Schulte T, Kabelitz D, Claas FH, Geissler EK, Kunzendorf U, Fändrich F. A cell-based approach to the minimization of immunosuppression in renal transplantation. Transpl Int 2008;21:742–54.

    Article  PubMed  Google Scholar 

  39. Hutchinson JA, Riquelme P, Brem-Exner BG, Schulze M, Matthäi M, Renders L, Kunzendorf U, Geissler EK, Fändrich F. Transplant acceptance-inducing cells as an immune-conditioning therapy in renal transplantation. Transpl Int 2008;21:828–41.

    Google Scholar 

  40. Hutchinson JA, Gövert F, Riquelme P, Brösen JH, Brem-Exner BG, Matthäi M, Schulze M, Renders L, Kunzendorf U, Geissler EK, Fändrich F. Administration of donor-derived transplant acceptance-inducing cells to the recipients of renal transplants from deceased donors is technically feasible. Clin Transplant 2009;23:140–5.

    Google Scholar 

  41. Itakura S, Asari S, Rawson J, Ito T, Todorov I, Liu CP, Sasaki N, Kandeel F, Mullen Y. Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat. Am J Transplant 2007;7:336–46.

    Article  PubMed  CAS  Google Scholar 

  42. Iyer SS, Rojas M. Anti-inflammatory effects of mesenchymal stem cells: novel concept for future therapies. Expert Opin Biol Ther 2008;8:569–81.

    Article  PubMed  CAS  Google Scholar 

  43. Jaeckel E, Lipes MA, von Boehmer H. Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol 2004;5:1028–35.

    Google Scholar 

  44. Kabelitz D, Geissler EK, Soria B, Schroeder IS, Fändrich F, Chatenoud L. Toward cell-based therapy of type I diabetes. Trends Immunol 2008;29:68–74.

    PubMed  CAS  Google Scholar 

  45. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell 1987;49:273–80.

    Article  PubMed  CAS  Google Scholar 

  46. Karounos DG, Bryson JS, Cohen DA. Metabolically inactive insulin analog prevents type I diabetes in prediabetic NOD mice. J Clin Invest 1997;100:1344–8.

    Article  PubMed  CAS  Google Scholar 

  47. Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV. Spontaneous loss of T cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993;366:69–72.

    Article  PubMed  CAS  Google Scholar 

  48. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;352:2598–608.

    Article  PubMed  CAS  Google Scholar 

  49. Khadra A, Santamaria P, Edelstein-Keshet L. The role of low avidity T cells in the protection against type 1 diabetes: a modeling investigation. J Theor Biol 2009;256:126–41.

    Article  PubMed  CAS  Google Scholar 

  50. Khare SD, Krco CJ, Griffiths MM, Luthra HS, David CS. Oral administration of an immunodominant human collagen peptide modulates collagen-induced arthritis. J Immunol 1995;155:3653–9.

    PubMed  CAS  Google Scholar 

  51. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4:337–32.

    Article  PubMed  CAS  Google Scholar 

  52. Knip M, Veijola R, Virtanen SM, Hyöty H, Vaarala O, Akerblom HK. Environmental triggers and determinants of type 1 diabetes. Diabetes 2005;54 (Suppl 2), S125–36.

    Article  PubMed  CAS  Google Scholar 

  53. Koch CA, Geraldes P, Platt JL. Immunosuppression by embryonic stem cells. Stem Cells 2008;26:89–98.

    Article  PubMed  CAS  Google Scholar 

  54. Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 2003;302:1223–7.

    Article  PubMed  CAS  Google Scholar 

  55. Koeleman BP, Lie BA, Undlien DE, Dudbridge F, Thorsby E, de Vries RR, Cucca F, Roep BO, Giphart MJ, Todd JA. Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimmer associations with disease. Genes Immun 2004;5:381–8.

    Article  PubMed  CAS  Google Scholar 

  56. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, Russell A, Dougados M, Emery P, Nuamah IF, Williams GR, Becker JC, Hagerty DT, Moreland LW. Treatment of rheumatoid arthritis by selective inhibition of T cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907–15.

    Article  PubMed  CAS  Google Scholar 

  57. Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, Steinfeld S, Tindall E, Becker JC, Li T, Nuamah IF, Aranda R, Moreland LW. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263–71.

    Article  PubMed  CAS  Google Scholar 

  58. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 2004;6:1219–27.

    Article  Google Scholar 

  59. Kulmala P, Savola K, Reijonen H, Veijola R, Vähäsalo P, Karjalainen J, Tuomilehto-Wolf E, Ilonen J, Tuomilehto J, Akerblom HK, Knip M. Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group. Diabetes 2000;49:48–58.

    Article  PubMed  CAS  Google Scholar 

  60. Lampeter EF, Homberg M, Quabeck K, Schaefer UW, Wernet P, Bertrams J, Grosse-Wilde H, Gries FA, Kolb H. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation. Lancet 1993;341:1243–4.

    Google Scholar 

  61. Lampeter EF, McCann SR, Kolb H. Transfer of diabetes type 1 by bone-marrow transplantation. Lancet 1998;351:568–9.

    Article  PubMed  CAS  Google Scholar 

  62. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 2006;103:17438–43.

    Article  PubMed  CAS  Google Scholar 

  63. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4+CD25+ T cells from patients with type 1 diabetes. Diabetes 2005;54:92–99.

    Article  PubMed  CAS  Google Scholar 

  64. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Front Biosci 2008;13:453–61.

    Article  PubMed  CAS  Google Scholar 

  65. Mellor AL, Baban B, Chandler P, Marshall B, Jhaver K, Hansen A, Koni PA, Iwashima M, Munn DH. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 2006;171:1652–5.

    Google Scholar 

  66. Melzer B, Wraith DC. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int Immunol 1993;5:1159–65.

    Article  Google Scholar 

  67. Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 2007;7:610–21.

    Article  PubMed  CAS  Google Scholar 

  68. Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 2006;311:1775–78.

    Article  PubMed  CAS  Google Scholar 

  69. Oehler JR, Herberman RB, Campbell DA Jr, Djeu JY. Inhibition of rat mixed lymphocyte cultures by suppressor macrophages. Cell Immunol 1977;29:238–50.

    Article  PubMed  CAS  Google Scholar 

  70. Ohashi PS. T cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol 2002;2:427–38.

    PubMed  CAS  Google Scholar 

  71. Oresic M, Simell S, Sysi-Aho M, Näntö-Salonen K, Seppänen-Laakso T, Parikka V, Katajamaa M, Hekkala A, Mattila I, Keskinen P, Yetukuri L, Reinikainen A, Lähde J, Suortti T, Hakalax J, Simell T, Hyöty H, Veijola R, Ilonen J, Lahesmaa R, Knip M, Simell O. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med 2008;205:2975–84.

    Article  PubMed  CAS  Google Scholar 

  72. Peakman M, Stevens EJ, Lohmann T, Narendran P, Dromey J, Alexander A, Tomlinson AJ, Trucco M, Gorga JC, Chicz RM. Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. J Clin Invest 1999;104:1449–57.

    Article  PubMed  CAS  Google Scholar 

  73. Pihoker C, Gilliam LK, Hampe CS, Lernmark A. Autoantibodies in Diabetes. Diabetes 54 Suppl 2005;2:S52–61.

    Article  Google Scholar 

  74. Pociaot F, McDermott MF. Genetics of type 1 diabetes mellitus. Genes Immun 2002;3: 235–49.

    Article  Google Scholar 

  75. Redondo MJ, Rewers M, Yu L, Garg S, Pilcher CC. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ 1999;318:689–702.

    Google Scholar 

  76. Redondo MJ, Fain PR, Eisenbarth GS. Genetics of type 1A diabetes. Recent Prog Horm Res 2001;56:69–89.

    Article  PubMed  CAS  Google Scholar 

  77. Schulze M, Fändrich F, Ungefroren H, Kremer B. Adult stem cells – perspectives in treatment of metabolic diseases. Acta Gastro-Enterologica Belgica 2005;68:461–65.

    PubMed  CAS  Google Scholar 

  78. Shoda LK, Young DL, Ramanujan S, Whiting CC, Atkinson MA, Bluestone JA, Eisenbarth GS, Mathis D, Rossini AA, Campbell SE, Kahn R, Kreuwel HT Shoda L. A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity 2005;23:115–26.

    Article  PubMed  CAS  Google Scholar 

  79. Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-Mervis LE, Chase HP, Leschek E. Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial – type 1. Diabetes Care 2005;28:1068–76.

    Article  PubMed  CAS  Google Scholar 

  80. Sospedra M, Martin R. Antigen-specific therapies in multiple sclerosis. Int Rev Immunol 2005;24:393–413.

    Article  PubMed  CAS  Google Scholar 

  81. Steinmann RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003;21:685–711.

    Article  Google Scholar 

  82. Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006;311:1778–80.

    Article  PubMed  CAS  Google Scholar 

  83. Suri A, Levisetti MG, Unanue ER. Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity? Curr Opin Immunol 2008;20:105–10.

    Article  PubMed  CAS  Google Scholar 

  84. Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: A jack of all trades, master of regulation. Nat Immunol 2008;9:239–44.

    Article  PubMed  CAS  Google Scholar 

  85. Tateishi K, He J, Taranova O, Liang G, D’Alessio AC, Zhang Y. Generation of insulin-secreting islet-like clusters from human skin fibroblasts. J Biol Chem 2008 ;283:31601–7.

    Article  PubMed  CAS  Google Scholar 

  86. Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996;85:291–7.

    Article  PubMed  CAS  Google Scholar 

  87. Tree TI, Peakman M. Autoreactive T cells in human type 1 diabetes. Endocrinol Metab Clin North Am 2004;33:113–33.

    Article  PubMed  CAS  Google Scholar 

  88. Tisch R, Wang B. Dysregulation of T cell peripheral tolerance in type 1 diabetes. Adv Immunol 2008;100:125–49.

    Article  PubMed  CAS  Google Scholar 

  89. Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol 1997;158:5091–4.

    PubMed  CAS  Google Scholar 

  90. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, Bailey R, Nejentsev S, Field SF, Payne F, Lowe CE, Szeszko JS, Hafler JP, Zeitels L, Yang JH, Vella A, Nutland S, Stevens HE, Schuilenburg H, Coleman G, Maisuria M, Meadows W, Smink LJ, Healy B, Burren OS, Lam AA, Ovington NR, Allen J, Adlem E, Leung HT, Wallace C, Howson JM, Guja C, Ionescu-Tîrgovişte C. Genetics of Type 1 Diabetes in Finland, Simmonds MJ, Heward JM, Gough SC; Wellcome Trust Case Control Consortium, Dunger DB, Wicker LS, Clayton DG. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007;39:857–64.

    Article  PubMed  CAS  Google Scholar 

  91. Tsai S, Shameli A, Santamaria P. CD8+ T cells in type 1 diabetes. Adv Immunol 2008;100: 79–124.

    Article  PubMed  CAS  Google Scholar 

  92. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Rønningen KS, Guja C, Ionescu-Tîrgovişte C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC. Association of the T cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423:506–11.

    Article  PubMed  CAS  Google Scholar 

  93. Van der Werf N, Kroese FG, Rozing J, Hillebrands JL. Viral infections as potential triggers of type 1 diabetes. Diabetes Metab Res Rev 2007;23:169–83.

    Article  PubMed  Google Scholar 

  94. Verda L, Kim DA, Ikehara S, Statkute L, Bronesky D, Petrenko Y, Oyama Y, He X, Link C, Vahanian NN, Burt RK. Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice. Stem Cells 2008;26:381–6.

    Article  PubMed  CAS  Google Scholar 

  95. Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KC, Foss-Freitas MC, Simões BP, Foss MC, Squiers E, Burt RK. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2007;297:1568–76.

    Article  PubMed  CAS  Google Scholar 

  96. Wegmann DR, Norbury-Glaser M, Daniel D. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol 1994;24:1853–7.

    Article  PubMed  CAS  Google Scholar 

  97. Young DA, Nickerson-Nutter CL. mTOR-beyond transplantation. Curr Opin Pharmacol 2005;5:418–23.

    Article  PubMed  CAS  Google Scholar 

  98. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to β cells. Nature 2008;455:627–33.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinic for Applied Cellular Therapy (CACT), University of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus 18, 24105, Kiel, Germany

    Fred Fändrich

  2. Clinic for Applied Cellular Medicine, UK S-H, Campus Kiel, 24105, Kiel, Germany

    Hendrik Ungefroren

Authors
  1. Fred Fändrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hendrik Ungefroren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fred Fändrich .

Editor information

Editors and Affiliations

  1. Dept. Clinical Research & Education, Karolinska Institutet, Stockholm, 118 83, Sweden

    Md. Shahidul Islam

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Fändrich, F., Ungefroren, H. (2010). Customized Cell-Based Treatment Options to Combat Autoimmunity and Restore β-Cell Function in Type 1 Diabetes Mellitus: Current Protocols and Future Perspectives. In: Islam, M. (eds) The Islets of Langerhans. Advances in Experimental Medicine and Biology, vol 654. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3271-3_28

Download citation

Publish with us

Policies and ethics

Search

Navigation