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Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience

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Abstract

This report summarizes a 5-year phase 1/2 allogeneic islet transplantation clinical trial conducted at the University of Illinois at Chicago (UIC). Ten patients were enrolled in this single center, open label, and prospective trial in which patients received 1–3 transplants. The first four subjects underwent islet transplantation with the Edmonton immunosuppressive regimen and the remaining six subjects received the UIC immunosuppressive protocol (Edmonton plus etanercept and exenatide). All 10 patients achieved insulin independence after 1–3 transplants. At 5 years of follow-up, 6 of the initial 10 patients were free of exogenous insulin. During the follow-up period, 7 of the 10 patients maintained positive C-peptide levels and a composite hypoglycemic score of 0. Most patients maintained HbA1c levels <6.0 % (42.1 mmol/mol) and a significantly improved β-score. In conclusion, this study demonstrated long-term islet graft function without using T cell depleting induction, with an encouraging outcome that includes 60 % of patients remaining insulin independent after 5 years of initial transplantation.

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Abbreviations

UIC:

University of Illinios at Chicago

MMF:

Mycophenolate mofetil

IEq:

Islet equivalents

CITR:

Collaborate islet transplant registry

TNF:

Tumor necrosis factor

GLP-1:

Glucagon-like peptide-1

MMT:

Mixed meal test

OGTT:

Oral glucose tolerance test

IVGTT:

Intravenous glucose tolerance test

GST:

Glucagon stimulation test

UACR:

Urine albumin and creatinine ratio

References

  1. Ricordi C (2003) Islet transplantation: a brave new world. Diabetes 52(7):1595–1603

    Article  PubMed  CAS  Google Scholar 

  2. Bertuzzi F, Ricordi C (2007) Beta-cell replacement in immunosuppressed recipients: old and new clinical indications. Acta Diabetol 44(4):171–176

    Article  PubMed  CAS  Google Scholar 

  3. Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, Pattou F, Berney T, Secchi A, Messinger S, Senior PA, Maffi P, Posselt A, Stock PG, Kaufman DB, Luo X, Kandeel F, Cagliero E, Turgeon NA, Witkowski P, Naji A, O’Connell PJ, Greenbaum C, Kudva YC, Brayman KL, Aull MJ, Larsen C, Kay TW, Fernandez LA, Vantyghem MC, Bellin M, Shapiro AM (2012) Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care 35(7):1436–1445

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343(4):230–238

    Article  PubMed  CAS  Google Scholar 

  5. Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JRT, Shapiro AMJ (2005) Five-year follow-up after clinical islet transplantation. Diabetes 54(7):2060–2069

    Article  PubMed  CAS  Google Scholar 

  6. Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, Sutherland DE, Alejandro R, Hering BJ (2012) Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 12(6):1576–1583

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Shapiro AM, Hao EG, Lakey JR, Yakimets WJ, Churchill TA, Mitlianga PG, Papadopoulos GK, Elliott JF, Rajotte RV, Kneteman NM (2001) Novel approaches toward early diagnosis of islet allograft rejection. Transplantation 71(12):1709–1718

    Article  PubMed  CAS  Google Scholar 

  8. Vergani A, Fotino C, D’Addio F, Tezza S, Podetta M, Gatti F, Chin M, Bassi R, Molano RD, Corradi D, Gatti R, Ferrero ME, Secchi A, Grassi F, Ricordi C, Sayegh MH, Maffi P, Pileggi A, Fiorina P (2013) Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. Diabetes 62(5):1665–1675

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Jalili RB, Forouzandeh F, Rezakhanlou AM, Hartwell R, Medina A, Warnock GL, Larijani B, Ghahary A (2010) Local expression of indoleamine 2,3 dioxygenase in syngeneic fibroblasts significantly prolongs survival of an engineered three-dimensional islet allograft. Diabetes 59(9):2219–2227

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Monti P, Scirpoli M, Maffi P, Ghidoli N, De Taddeo F, Bertuzzi F, Piemonti L, Falcone M, Secchi A, Bonifacio E (2008) Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells. J Clin Invest 118(5):1806–1814

    PubMed  CAS  PubMed Central  Google Scholar 

  11. Huang G, Wang X, Li Z, Li H, Li X, Zhou Z (2012) Insulin autoantibody could help to screen latent autoimmune diabetes in adults in phenotypic type 2 diabetes mellitus in Chinese. Acta Diabetol 49(5):327–331

    Article  PubMed  CAS  Google Scholar 

  12. Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117(9):2553–2561

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Gillard P, Ling Z, Mathieu C, Crenier L, Lannoo M, Maes B, Roep B, Gorus F, Pipeleers D, Keymeulen B (2008) Comparison of sirolimus alone with sirolimus plus tacrolimus in type 1 diabetic recipients of cultured islet cell grafts. Transplantation 85(2):256–263

    Article  PubMed  CAS  Google Scholar 

  14. Laugharne M, Cross S, Richards S, Dawson C, Ilchyshyn L, Saleem M, Mathieson P, Smith R (2007) Sirolimus toxicity and vascular endothelial growth factor release from islet and renal cell lines. Transplantation 83(12):1635–1638

    Article  PubMed  CAS  Google Scholar 

  15. Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, Sutherland DE, Alejandro R, Hering BJ (2012) Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 12(6):1576–1583

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Ngo A, Sutherland DE, Beilman GJ, Bellin MD (2014) Deterioration of glycemic control after corticosteroid administration in islet autotransplant recipients: a cautionary tale. Acta Diabetol 51(1):141–145

    Article  PubMed  CAS  Google Scholar 

  17. Gangemi A, Salehi P, Hatipoglu B, Martellotto J, Barbaro B, Kuechle JB, Qi M, Wang Y, Pallan P, Owens C, Bui J, West D, Kaplan B, Benedetti E, Oberholzer J (2008) Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant 8(6):1250–1261

    Article  PubMed  CAS  Google Scholar 

  18. Qi M, Barbaro B, Wang S, Wang Y, Hansen M, Oberholzer J (2009) Human pancreatic islet isolation: Part I: digestion and collection of pancreatic tissue. J Vis Exp (27). doi:10.3791/1125

  19. Qi M, Barbaro B, Wang S, Wang Y, Hansen M, Oberholzer J (2009) Human pancreatic islet isolation: Part II: purification and culture of human islets. J Vis Exp (27). doi:10.3791/1343

  20. Soltani SM, O’Brien TD, Loganathan G, Bellin MD, Anazawa T, Tiwari M, Papas KK, Vickers SM, Kumaravel V, Hering BJ, Sutherland DE, Balamurugan AN (2013) Severely fibrotic pancreases from young patients with chronic pancreatitis: evidence for a ductal origin of islet neogenesis. Acta Diabetol 50(5):807–814

    Article  PubMed  CAS  Google Scholar 

  21. Koh A, Imes S, Kin T, Dinyari P, Malcolm A, Toso C, Shapiro AM, Senior P (2010) Supplemental islet infusions restore insulin independence after graft dysfunction in islet transplant recipients. Transplantation 89(3):361–365

    Article  PubMed  CAS  Google Scholar 

  22. Lehmann R, Spinas GA, Moritz W, Weber M (2008) Has time come for new goals in human islet transplantation? Am J Transplant 8(6):1096–1100

    Article  PubMed  CAS  Google Scholar 

  23. Teuscher AU, Kendall DM, Smets YF, Leone JP, Sutherland DE, Robertson RP (1998) Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes 47(3):324–330

    Article  PubMed  CAS  Google Scholar 

  24. Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, Shapiro AM, Vantyghem MC (2004) Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 53(4):955–962

    Article  PubMed  CAS  Google Scholar 

  25. Ryan EA, Paty BW, Senior PA, Lakey JR, Bigam D, Shapiro AM (2005) Beta-score: an assessment of beta-cell function after islet transplantation. Diabetes Care 28(2):343–347

    Article  PubMed  Google Scholar 

  26. Justesen TI, Petersen JL, Ekbom P, Damm P, Mathiesen ER (2006) Albumin-to-creatinine ratio in random urine samples might replace 24-h urine collections in screening for micro- and macroalbuminuria in pregnant woman with type 1 diabetes. Diabetes Care 29(4):924–925

    Article  PubMed  Google Scholar 

  27. Salehi P, Stull MA, Martellotto J, Gangemi A, Hatipoglu B, Benedetti E, Oberholzer J (2009) Case report: diabetic myonecrosis of the neck complicated by infection in an islet transplanted patient. J Diabetes Complications 23(2):140–142

    Article  PubMed  Google Scholar 

  28. Froud T, Faradji RN, Pileggi A, Messinger S, Baidal DA, Ponte GM, Cure PE, Monroy K, Mendez A, Selvaggi G, Ricordi C, Alejandro R (2008) The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects. Transplantation 86(1):36–45

    Article  PubMed  PubMed Central  Google Scholar 

  29. Faradji RN, Tharavanij T, Messinger S, Froud T, Pileggi A, Monroy K, Mineo D, Baidal DA, Cure P, Ponte G, Mendez AJ, Selvaggi G, Ricordi C, Alejandro R (2008) Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept. Transplantation 86(12):1658–1665

    Article  PubMed  PubMed Central  Google Scholar 

  30. Johnson JA, Kotovych M, Ryan EA, Shapiro AM (2004) Reduced fear of hypoglycemia in successful islet transplantation. Diabetes Care 27(2):624–625

    Article  PubMed  Google Scholar 

  31. Huurman VA, van der Torren CR, Gillard P, Hilbrands R, van der Meer-Prins EP, Duinkerken G, Gorus FK, Claas FH, Keymeulen B, Roelen DL, Pipeleers DG, Roep BO (2012) Immune responses against islet allografts during tapering of immunosuppression—a pilot study in 5 subjects. Clin Exp Immunol. doi:10.1111/j.1365-2249.2011.04605

    PubMed Central  Google Scholar 

  32. Smith RN, Kent SC, Nagle J, Selig M, Iafrate AJ, Najafian N, Hafler DA, Auchincloss H, Orban T, Cagliero E (2008) Pathology of an islet transplant 2 years after transplantation: evidence for a nonimmunological loss. Transplantation 86(1):54–62

    Article  PubMed  Google Scholar 

  33. Westermark GT, Westermark P, Berne C, Korsgren O (2008) Widespread amyloid deposition in transplanted human pancreatic islets. N Engl J Med 359(9):977–979

    Article  PubMed  CAS  Google Scholar 

  34. Ponte GM, Baidal DA, Romanelli P, Faradji RN, Poggioli R, Cure P, Froud T, Selvaggi G, Pileggi A, Ricordi C, Alejandro R (2007) Resolution of severe atopic dermatitis after tacrolimus withdrawal. Cell Transplant 16(1):23–30

    Article  PubMed  Google Scholar 

  35. Bumbea V, Kamar N, Ribes D, Esposito L, Modesto A, Guitard J, Nasou G, Durand D, Rostaing L (2005) Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 20(11):2517–2523

    Article  PubMed  CAS  Google Scholar 

  36. Liew A, Chiang GS, Vathsala A (2009) Factors associated with proteinuria in renal transplant recipients treated with sirolimus. Transpl Int 22(3):313–322

    Article  PubMed  CAS  Google Scholar 

  37. Senior PA, Zeman M, Paty BW, Ryan EA, Shapiro AM (2007) Changes in renal function after clinical islet transplantation: four-year observational study. Am J Transplant 7(1):91–98

    Article  PubMed  CAS  Google Scholar 

  38. Kaplan B, Schold J, Srinivas T, Womer K, Foley DP, Patton P, Howard R, Meier-Kriesche HU (2004) Effect of sirolimus withdrawal in patients with deteriorating renal function. Am J Transplant 4(10):1709–1712

    Article  PubMed  CAS  Google Scholar 

  39. Senior PA, Paty BW, Cockfield SM, Ryan EA, Shapiro AM (2005) Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant 5(9):2318–2323

    Article  PubMed  Google Scholar 

  40. Olack BJ, Swanson CJ, Flavin KS, Phelan D, Brennan DC, White NH, Lacy PE, Scharp DW, Poindexter N, Mohanakumar T (1997) Sensitization to HLA antigens in islet recipients with failing transplants. Transplant Proc 29(4):2268–2269

    Article  PubMed  CAS  Google Scholar 

  41. Campbell PM, Senior PA, Salam A, Labranche K, Bigam DL, Kneteman NM, Imes S, Halpin A, Ryan EA, Shapiro AM (2007) High risk of sensitization after failed islet transplantation. Am J Transplant 7(10):2311–2317

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by funding from the College of Medicine, University of Illinois at Chicago. J.O. and J. M. were supported by the Islet Cell Resources Center NIH grant (5 U42 RR023245-02), the Christopher Family Foundation, and the Efroymson Foundation. The subjects are evaluated at the UIC Clinical Research Center, which is supported by the University of Illinois at Chicago Center for Clinical and Translational Science (Award Number UL1RR029879) from the National Center for Research Resources. Data acquisition aided by the CITR, Emmes corporation. The islet program was supported by the Chicago Diabetes Project, and the Washington Square Health Foundation.

Conflict of interest

Meirigeng Qi, Katie Kinzer, Kirstie K. Danielson, Joan Martellotto, Barbara Barbaro, Yong Wang, James T. Bui, Ron C. Gaba, Grace Knuttinen, Raquel Garcia-Roca, Ivo Tzvetanov, Andrew Heitman, Maureen Davis, James J. McGarrigle, Enrico Benedetti, and Jose Oberholzer declare that they have no conflict of interest.

Ethical disclosure

All human studies have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

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Authors and Affiliations

  1. Division of Transplantation, Department of Surgery, University of Illinois at Chicago, 840 South Wood Street CSB (Rm 402), Chicago, IL, 60612, USA

    Meirigeng Qi, Katie Kinzer, Kirstie K. Danielson, Joan Martellotto, Barbara Barbaro, Yong Wang, Raquel Garcia-Roca, Ivo Tzvetanov, Maureen Davis, James J. McGarrigle, Enrico Benedetti & Jose Oberholzer

  2. Department of Radiology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    James T. Bui, Ron C. Gaba & Grace Knuttinen

  3. The Emmes Corporation Rockville, Rockville, MD, 20850, USA

    Andrew Heitman

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  1. Meirigeng Qi
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Corresponding author

Correspondence to Jose Oberholzer.

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Managed by Antonio Secchi.

Meirigeng Qi and Katie Kinzer have contributed equally to this article.

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Qi, M., Kinzer, K., Danielson, K.K. et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol 51, 833–843 (2014). https://doi.org/10.1007/s00592-014-0627-6

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  • DOI: https://doi.org/10.1007/s00592-014-0627-6

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