Skip to main content
SpringerLink
Log in

Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes

  • Transplantation (A Pileggi, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Type 1 diabetes mellitus is a chronic disease that results from the autoimmune response against pancreatic insulin producing β cells. Apart of several insulin regimens, since the decade of 80s various immunomodulatory regimens were tested aiming at blocking some steps of the autoimmune process against β cell mass and at promoting β cell preservation. In the last years, some independent research groups tried to cure type 1 diabetes with an “immunologic reset” provided by autologous hematopoietic stem cell transplantation in newly diagnosed patients, and the majority of patients became free form insulin with increasing levels of C-peptide along the time. In this review, we discuss the biology of hematopoietic stem cells and the possible advantages and disadvantages related to the high dose immunosuppression followed by autologous hematopoietic stem cell transplantation.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

  1. Notkins AL, Lernmark A. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest. 2001;108:1247–52.

    PubMed  CAS  Google Scholar 

  2. The Diabetes Control and Complications Trial Research Group. The effect of intensive insulin therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563–9.

    Article  Google Scholar 

  3. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. Ann Intern Med. 1998;128:517–23.

    Google Scholar 

  4. Couri CE, Foss MC, Voltarelli JC. Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting beta-cell regeneration. Braz J Med Biol Res. 2006;39:1271–80.

    Article  PubMed  CAS  Google Scholar 

  5. Lee S, Krause DS. Adult Stem Cell Plasticity. In: Burt RK, Marmont A, editors. Stem cell therapy for autoimmune disease, Chapter 11. Austin: Landes Biosciences; 2004. p. 59–76.

    Google Scholar 

  6. Nagano K, Yoshida Y, Isobe T. Cell surface biomarkers of embryonic stem cells. Proteomics. 2008;8:4025–35.

    Article  PubMed  CAS  Google Scholar 

  7. Witkowska-Zimny M, Wrobel E. Perinatal sources of mesenchymal stem cells: Wharton's Jelly, amnion and chorion. Cell Mol Biol Lett. 2011;16:493–514.

    Article  PubMed  Google Scholar 

  8. Volarevic V, Ljujic B, Stojkovic P, Lukic A, Arsenijevic N, Stojkovic M. Human stem cell research and regenerative medicine-present and future. Br Med Bull. 2011;99:155–68.

    Article  PubMed  Google Scholar 

  9. Hipp J, Atala A. Sources of stem cells for regenerative medicine. Stem Cell Rev. 2008;4:3–11.

    Article  PubMed  Google Scholar 

  10. Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells. 2009;27:2624–6.

    Article  PubMed  CAS  Google Scholar 

  11. Gluckman E. Milestones in umbilical cord blood transplantation. Blood Rev. 2011;25:255–9.

    Article  PubMed  CAS  Google Scholar 

  12. Carvalho MM, Teixeira FG, Reis RL, Sousa N, Salgado AJ. Mesenchymal stem cells in the umbilical cord: phenotypic characterization, secretome and applications in central nervous system regenerative medicine. Curr Stem Cell Res Ther. 2011;6:221–8.

    Article  PubMed  CAS  Google Scholar 

  13. Pozzilli P, Di Mario U. Autoimune diabetes not requiring insulin at diagnosis (latent autoimune diabetes of the adult). Diabetes Care. 2001;24:1460–7.

    Article  PubMed  CAS  Google Scholar 

  14. American Diabetes Association. Diagnosis and classification of diabetes. Diabetes Care. 2012;35:S4–10.

    Article  Google Scholar 

  15. Bennett ST, Todd JA. Human type 1A diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet. 1996;30:343–70.

    Article  PubMed  CAS  Google Scholar 

  16. Fairweather DL, Rose NR. Type 1 diabetes: virus infection or autoimmune disease? Nat Immunol. 2002;3:338–40.

    Article  PubMed  CAS  Google Scholar 

  17. Devendra D, Liu E, Eisenbarth GS. Type 1 diabetes: recent developments. BMJ. 2004;328:750–4.

    Article  PubMed  Google Scholar 

  18. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010;464:1293–300.

    Article  PubMed  CAS  Google Scholar 

  19. Eizirik DL, Mandrup-Poulsen T. A choice of death: the signal transduction of immune-mediated β-cell apoptosis. Diabetologia. 2001;44:2115–33.

    Article  PubMed  CAS  Google Scholar 

  20. Eizirik DL, Kutlu B, Rasschaert J, Darville M, Cardozo AK. Use of microarray analysis to unveil transcription factor and gene networks contributing to β-cell dysfunction and apoptosis. Am N Y Acad Sci. 2003;1005:55–74.

    Article  CAS  Google Scholar 

  21. Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes. 2005;54(Suppl):S97–107.

    Article  PubMed  CAS  Google Scholar 

  22. Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci USA. 1992;89:2804–8.

    Article  PubMed  CAS  Google Scholar 

  23. Morton JL, et al. Transplantation of autoimmune potential: development of antinuclear antibodies in H-2 histocompatible recipients of bone marrow from New Zealand black mice. Proc Natl Acad Sci USA. 1974;71:2162–6.

    Article  PubMed  CAS  Google Scholar 

  24. Van Gelder M, van Bekkum DW. Effective treatment of relapsing experimental autoimmune encephalomyelitis with pseudoautologous bone marrow transplantation. Bone Marrow Transplant. 1996;18:1029–34.

    PubMed  Google Scholar 

  25. Breban M, Hammer RE, Richardson JA, Taurog JD. Transfer of the inflammatory disease of HLA-B27 transgenic rats by bone marrow engraftment. J Exp Med. 1993;178:1607–16.

    Article  PubMed  CAS  Google Scholar 

  26. Van Bekkum DW. New opportunities for the treatment of severe autoimmune diseases: bone marrow transplantation. Clin Immunol Immunopathol. 1998;89:1–10.

    Article  PubMed  Google Scholar 

  27. Knaan-Shanzer S, Houben P, Kinwel-Bohré EP, van Bekkum DW. Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation. Bone Marrow Transplant. 1991;8:333–8.

    PubMed  CAS  Google Scholar 

  28. Nelson JL, Torrez R, Louie FM, Choe OS, Storb R, Sullivan KM. Pre-existing autoimmune disease in patients with long-term survival after allogeneic bone marrow transplantation. J Rheumatol. 1997;24(Suppl):S23–9.

    Google Scholar 

  29. Marmont AM. Coincidental autoimmune disease in patients transplanted for coincidental indications. Best Pract Res Clin Haematol. 2004;17:223–32.

    Article  PubMed  Google Scholar 

  30. Tamm M, Gratwohl A, Tichelli A, Perruchoud AP, Tyndall A. Autologous haematopoietic stem cell transplantation in a patient with severe pulmonary hypertension complicating connective tissue disease. Ann Rheum Dis. 1996;55:779–80.

    Article  PubMed  CAS  Google Scholar 

  31. Snowden JA, Brooks PM, Biggs JC. Haematopoietic stem cell transplantation for autoimmune disease. Br J Haematol. 1997;99:9–22.

    Article  PubMed  CAS  Google Scholar 

  32. Atkins HL, Muraro PA, van Laar JM, Pavletic SZ. Autologous hematopoietic stem cell transplantation for autoimmune disease–is it now ready for prime time? Biol Blood Marrow Transplant. 2012;18(Suppl):S177–83.

    Article  PubMed  Google Scholar 

  33. McFarland RD, Douek DC, Koup RA, Picker LJ. Identification of a human recent thymic emigrant phenotype. Proc Natl Acad Sci USA. 2000;97:4215–20.

    Article  PubMed  CAS  Google Scholar 

  34. Burt RK, Verda L, Oyama Y, Statkute L, Slavin S. Non-myeloablative stem cell transplantation for autoimmune diseases. Springer Semin Immunopathol. 2004;26:57–69.

    Article  PubMed  Google Scholar 

  35. de Oliveira GL, Malmegrim KC, Ferreira AF, Tognon R, Kashima S, Couri CE, et al. Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation. Clin Exp Immunol. 2012;168:291–302.

    Google Scholar 

  36. Kang EM, Zickler MM, Burns S, Langemeijer SM, Brenner S, Phang AO, et al. Hematopoietic stem cell transplantation prevents diabetes in NOD mice but does not contribute to significant islet cell regeneration once disease is established. Exp Hematol. 2005;33:699–705.

    Article  PubMed  CAS  Google Scholar 

  37. Yelin EH. The economic and functional impact of rheumatic disease in the US. In: Klippel JH, Dieppe PA. editors. Rheumatology. London: Mosby International. 1998. p. 1.5.1–1.5.4.

  38. Burt RK, Loh Y, Cohen B, Stefoski D, Balabanov R, Katsamakis G, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8:244–53.

    Article  PubMed  CAS  Google Scholar 

  39. Couri CE, Voltarelli JC. Stem cell-based therapies and immunomodulatory approaches in newly diagnosed type 1 diabetes. Curr Stem Cell Res Ther. 2011;6:10–5.

    Article  PubMed  CAS  Google Scholar 

  40. Fiorina P, Voltarelli J, Zavazava N. Immunological applications of stem cells in type 1 diabetes. Endocr Rev. 2011;32:725–54.

    Article  PubMed  CAS  Google Scholar 

  41. •• Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2007;297:1568–76. This is the first article analyzing the safety and efficacy of autologous stem cell transplantation in humans with type 1 diabetes mellitus.

  42. •• Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009;301:1573–9. This article is an update of the results previously published by Dr. Voltarelli`s group in Brazil with more patients included for a longer follow-up.

  43. • Li L, Shen S, Ouyang J, Hu Y, Hu L, Cui W, et al. Autologous hematopoietic stem cell transplantation modulates immunocompetent cells and improves β-cell function in Chinese patients with new onset of type 1 diabetes. J Clin Endocrinol Metab. 2012;97:1729–36. This trial shows that a small number of patients who presented diabetic ketoacidosis at the time of diagnosis may stay free from insulin for some periods.

  44. • Snarski E, Milczarczyk A, Torosian T, Paluszewska M, Urbanowska E, Król M, et al. Independence of exogenous insulin following immunoablation and stem cell reconstitution in newly diagnosed diabetes type I. Bone Marrow Transplant. 2011;46:562–6. This article reproduces great part of the results published by Voltarelli et al.

  45. Snarski E, Torosian T, Paluszewska M, Urbanowska E, Milczarczyk A, Jedynasty K, et al. Alleviation of exogenous insulin requirement in type 1 diabetes mellitus after immunoablation and transplantation of autologous hematopoietic stem cells. Pol Arch Med Wewn. 2009;119:422–6.

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. 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;33:826–32.

    Article  PubMed  CAS  Google Scholar 

  48. Mastrandrea L, Yu J, Behrens T, Buchlis J, Albini C, Fourtner S, et al. Etanercept treatment in children with new-onset type 1 diabetes. Diabetes Care. 2009;32:1244–9.

    Article  Google Scholar 

  49. 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 randomized, double-blind, placebo-controlled trial. Lancet. 2011;378:412–9.

    Article  PubMed  CAS  Google Scholar 

  50. 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 β-cell function. Diabetes. 2012. doi:10.2337/db12-0049.

  51. Liu J, Malhotra R, Voltarelli J. Ovarian recovery after stem cell transplantation. Bone Marrow Transplant. 2008;41:275–8.

    Article  PubMed  CAS  Google Scholar 

  52. Sanders JE, Hawley J, Levy W, Gooley T, Buckner CD, Deeg HJ, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. 1996;87:3045–52.

    PubMed  CAS  Google Scholar 

  53. Tauchmanovà L, Selleri C, Rosa GD, Pagano L, Orio F, Lombardi G, et al. High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases. Cancer. 2002;95:1076–84.

    Google Scholar 

  54. Tauchmanovà L, Selleri C, De Rosa G, Esposito M, Orio F Jr, Palomba S, et al. Gonadal status in reproductive age women after hematopoietic stem cell transplantation for hematological malignancies. Hum Reprod. 2003;18:1410–6.

    Google Scholar 

  55. • Leal AM, Oliveira MC, Couri CE, Moraes DA, Stracieri AB, Pieroni F, et al. Testicular function in patients with type 1 diabetes treated with high-dose CY and autologous hematopoietic SCT. Bone Marrow Transplant. 2012;47:467–8. This paper makes an update on side effects of autologous hematopoietic stem cell transplantation in gonadal function of patients included in Brazilian trial.

    Article  PubMed  CAS  Google Scholar 

  56. Au WY, Lie AK, Kung AW, Liang R, Hawkins BR, Kwong YL. Autoimmune thyroid dysfunction after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35:383–8.

    Article  PubMed  CAS  Google Scholar 

  57. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350:2068–79.

    Article  PubMed  CAS  Google Scholar 

  58. A Trial of High Dose Immunosuppression and Autologous Hematopoietic Stem Cell Support Versus Intensive Insulin Therapy in Adults With Early Onset Type I Diabetes Mellitus. Available at: http://www.clinicaltrials.gov. Accessed 15 June 2012.

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto, Av. Bandeirantes, 3900 (6° andar), Ribeirão Preto, SP, Brazil, CEP 14048-900

    Carlos Eduardo Barra Couri, Maria Carolina de Oliveira & Belinda Pinto Simões

Authors
  1. Carlos Eduardo Barra Couri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Carolina de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Belinda Pinto Simões
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlos Eduardo Barra Couri.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Couri, C.E.B., de Oliveira, M.C. & Simões, B.P. Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes. Curr Diab Rep 12, 604–611 (2012). https://doi.org/10.1007/s11892-012-0309-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-012-0309-0

Keywords

Search

Navigation