Skip to main content
SpringerLink
Log in

Islet Transplantation in Patients with Diabetes Mellitus

Choice of Immunosuppression

  • Therapy Review
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Islet transplantation offers patients with type 1 diabetes mellitus freedom from long-term insulin therapy and a degree of metabolic control that is far superior to injected insulin. The hope is that near-perfect glucose control sustained over time will prevent progression of secondary diabetic complications. The selection of optimal immunosuppressive agents for islet transplantation has been a formidable challenge, given the need to overcome both autoimmune and alloimmune barriers, as well as the potential toxicity of immunosuppressive agents on transplanted islets. Early strategies relied on protocols that had proven success in solid organ transplantation and consisted of azathioprine, cyclosporine and corticosteroids. Under these protocols, fewer than 10% of patients were able to achieve insulin independence. The development of the “Edmonton Protocol’ dramatically transformed clinical outcomes in islet transplantation in recent years through the introduction of a more potent, less diabetogenic, and corticosteroid-free immunosuppressive regimen consisting of sirolimus, low-dose tacrolimus, and induction anti-interleukin-2 receptor antibody. While insulin independence rates under this protocol have been highly successful, patients must be maintained on lifelong immunosuppression. While the risk of malignancy, post-transplant lymphoma and sepsis have been low and diminishing in transplanted patients to date, fears of these complications and a host of drug-related adverse effects have precluded broader application. Patients undergoing islet transplantation today must exchange insulin for chronic immunosuppressive therapy, and therefore the procedure can only be justified in patients with very unstable forms of diabetes, or in those with another solid organ allograft who already endure the risks of immunosuppression. Advances in more specific and less toxic immunosuppressive agents together with progress in better understanding the biology of diabetes will lead to more suitable strategies to control both alloimmune and recurrent autoimmune reactions. These protocols, ultimately aimed at establishing tolerance, are an essential pre-requisite to move towards providing islet transplantation earlier in the course of the disease, including transplantation in children. This review addresses the evolution of immunosuppressive strategies in islet transplantation, and highlights some novel agents in pre-clinical development or in early clinical trials that may offer considerable promise in facilitating the induction of tolerance.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Williams P. Notes on diabetes treated with extract and by grafts of sheep’s pancreas. BMJ 1894; 2: 1303–4

    Google Scholar 

  2. Banting F. Extract from Banting’s notebook 2am October 31st. Canada: Academy of Medicine notebook, Archives of Toronto University, 1920

    Google Scholar 

  3. Bliss M. The discovery of insulin. Toronto: McClelland and Stewart Limited, 1982

    Google Scholar 

  4. Lacy P, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 1967; 16: 35–9

    PubMed  CAS  Google Scholar 

  5. Najarian JS, Sutherland DE, Matas AJ, et al. Human islet transplantation: a preliminary report. Transplant Proc 1977; 9(1): 233–6

    PubMed  CAS  Google Scholar 

  6. Ricordi C, Lacy PE, Finke EH, et al. Automated method for isolation of human pancreatic islets. Diabetes 1988; 37(4): 413–20

    Article  PubMed  CAS  Google Scholar 

  7. Robertson GS, Chadwick DR, Contractor H, et al. The optimization of large-scale density gradient isolation of human islets. Acta Diabetol 1993; 30(2): 93–8

    Article  PubMed  CAS  Google Scholar 

  8. Linetsky E, Bottino R, Lehmann R, et al. Improved human islet isolation using a new enzyme blend, liberase. Diabetes 1997; 46(7): 1120–3

    Article  PubMed  CAS  Google Scholar 

  9. Brendel M, Hering B, Schulz A, et al. International islet transplant registry report. University of Giessen, Germany; 1999. Newsletter No. 8

  10. Boker A, Rothenberg L, Hernandez C, et al. Human islet transplantation: update. World J Surg 2001; 25(4): 481–6

    Article  PubMed  CAS  Google Scholar 

  11. Hering B, Ricordi C. Islet transplantation for patients with type 1 diabetes: results, research priorities, and reasons for optimism. Graft 1999; 2(1): 12–27

    Google Scholar 

  12. Kaufman DB, Morel P, Condie R, et al. Beneficial and detrimental effects of RBC-adsorbed antilymphocyte globulin and prednisone on purified canine islet autograft and allograft function. Transplantation 1991; 51(1): 37–42

    Article  PubMed  CAS  Google Scholar 

  13. Rilo HL, Carroll PB, Zeng YJ, et al. Acceleration of chronic failure of intrahepatic canine islet autografts by a short course of prednisone. Transplantation 1994; 57(2): 181–7

    Article  PubMed  CAS  Google Scholar 

  14. Zeng Y, Ricordi C, Lendoire J, et al. The effect of prednisone on pancreatic islet autografts in dogs. Surgery 1993; 113(1): 98–102

    PubMed  CAS  Google Scholar 

  15. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343(4): 230–8

    Article  PubMed  CAS  Google Scholar 

  16. Shapiro AM, Ricordi C, Hering B. Edmonton’s islet success has indeed been replicated elsewhere. Lancet 2003; 362(9391): 1242

    Article  PubMed  Google Scholar 

  17. Borel JF, Feurer C, Magnee C, et al. Effects of the new anti-lymphocytic peptide cyclosporin A in animals. Immunology 1977; 32(6): 1017–25

    PubMed  CAS  Google Scholar 

  18. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979; II(8151): 1033–6

    Article  Google Scholar 

  19. Halloran PF, Madrenas J. The mechanism of action of cyclosporine: a perspective for the 90’s. Clin Biochem 1991; 24(1): 3–7

    Article  PubMed  CAS  Google Scholar 

  20. Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 1992; 357(6380): 695–7

    Article  PubMed  CAS  Google Scholar 

  21. Northrop JP, Ho SN, Chen L, et al. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 1994; 369(6480): 497–502

    Article  PubMed  CAS  Google Scholar 

  22. Gunnarsson R, Klintmalm G, Lundgren G, et al. Deterioration in glucose metabolism in pancreatic transplant recipients after conversion from azathioprine to cyclosporine. Transplant Proc 1984; 16(3): 709–12

    PubMed  CAS  Google Scholar 

  23. Andersson A, Borg H, Hallberg A, et al. Long-term effects of cyclosporin A on cultured mouse pancreatic islets. Diabetologia 1984; 27Suppl. 1: 66–9

    Article  PubMed  CAS  Google Scholar 

  24. Robertson RP. Cyclosporin-induced inhibition of insulin secretion in isolated rat islets and HIT cells. Diabetes 1986; 35(9): 1016–9

    Article  PubMed  CAS  Google Scholar 

  25. Nielsen JH, Mandrup-Poulsen T, Nerup J. Direct effects of cyclosporin A on human pancreatic β-cells. Diabetes 1986; 35(9): 1049–52

    Article  PubMed  CAS  Google Scholar 

  26. Hahn HJ, Dunger A, Laube F, et al. Reversibility of the acute toxic effect of cyclosporin A on pancreatic B cells of Wistar rats. Diabetologia 1986; 29(8): 489–94

    Article  PubMed  CAS  Google Scholar 

  27. Helmchen U, Schmidt WE, Siegel EG, et al. Morphological and functional changes of pancreatic B cells in cyclosporin A-treated rats. Diabetologia 1984; 27(3): 416–8

    Article  PubMed  CAS  Google Scholar 

  28. Eun HM, Pak CY, Kim CJ, et al. Role of cyclosporin A in macromolecular synthesis of beta-cells. Diabetes 1987; 36(8): 952–8

    Article  PubMed  CAS  Google Scholar 

  29. Garvin PJ, Niehoff M, Staggenborg J. Cyclosporine’s effect on canine pancreatic endocrine function. Transplantation 1988; 45(6): 1027–31

    Article  PubMed  CAS  Google Scholar 

  30. Kneteman NM, Marchetti P, Tordjman K, et al. Effects of cyclosporine on insulin secretion and insulin sensitivity in dogs with intrasplenic islet autotransplants. Surgery 1992; 111(4): 430–7

    PubMed  CAS  Google Scholar 

  31. Alejandro R, Feldman EC, Bloom AD, et al. Effects of cyclosporin on insulin and C-peptide secretion in healthy beagles. Diabetes 1989; 38(6): 698–703

    Article  PubMed  CAS  Google Scholar 

  32. Jindal RM. Posttransplant diabetes mellitus: a review. Transplantation 1994; 58(12): 1289–98

    PubMed  CAS  Google Scholar 

  33. Jindal RM, Hjelmesaeth J. Impact and management of posttransplant diabetes mellitus. Transplantation 2000; 70(11 Suppl.): SS58–63

    PubMed  CAS  Google Scholar 

  34. Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. Transplantation 1987; 44(3): 376–81

    Article  PubMed  CAS  Google Scholar 

  35. Teuscher AU, Seaquist ER, Robertson RP. Diminished insulin secretory reserve in diabetic pancreas transplant and nondiabetic kidney transplant recipients. Diabetes 1994; 43(4): 593–8

    Article  PubMed  CAS  Google Scholar 

  36. Ziel FH, Venkatesan N, Davidson MB. Glucose transport is rate limiting for skeletal muscle glucose metabolism in normal and STZ-induced diabetic rats. Diabetes 1988; 37(7): 885–90

    Article  PubMed  CAS  Google Scholar 

  37. Venkatesan N, Davidson MB, Hutchinson A. Possible role for the glucose-fatty acid cycle in dexamethasone-induced insulin antagonism in rats. Metabolism 1987; 36(9): 883–91

    Article  PubMed  CAS  Google Scholar 

  38. Rizza RA, Mandarino LJ, Gerich JE. Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. J Clin Endocrinol Metab 1982; 54(1): 131–8

    Article  PubMed  CAS  Google Scholar 

  39. Munck A. Glucocorticoid inhibition of glucose uptake by peripheral tissues: old and new evidence, molecular mechanisms, and physiological significance. Perspect Biol Med 1971; 14(2): 265–9

    PubMed  CAS  Google Scholar 

  40. Ochiai T, Nagata M, Nakajima K, et al. Studies of the effects of FK506 on renal allografting in the beagle dog. Transplantation 1987; 44(6): 729–33

    Article  PubMed  CAS  Google Scholar 

  41. Ost L. Impairment of prednisolone metabolism by cyclosporine treatment in renal graft recipients. Transplantation 1987; 44(4): 533–5

    Article  PubMed  CAS  Google Scholar 

  42. Ricordi C, Tzakis AG, Carroll PB, et al. Human islet isolation and allotransplantation in 22 consecutive cases. Transplantation 1992; 53(2): 407–14

    Article  PubMed  CAS  Google Scholar 

  43. Maffi P, Bertuzzi F, Guiducci D, et al. Per and peri-operative management influences the clinical outcome of islet transplantation. Am J Transplant 2001; 1(1 Suppl. 1): 181

    Google Scholar 

  44. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998; 31(5): 335–40

    Article  PubMed  CAS  Google Scholar 

  45. Sehgal SN. Rapamune (sirolimus, rapamycin): an overview and mechanism of action. Ther Drug Monit 1995; 17(6): 660–5

    Article  PubMed  CAS  Google Scholar 

  46. Ochiai T, Nakajima K, Nagata M, et al. Effect of a new immunosuppressive agent, FK 506, on heterotopic cardiac allotransplantation in the rat. Transplant Proc 1987; 19 (1 Pt 2): 1284–6

    PubMed  CAS  Google Scholar 

  47. Yoshimura N, Matsui S, Hamashima T, et al. Effect of a new immunosuppressive agent, FK506, on human lymphocyte responses in vitro: I. Inhibition of expression of alloantigen-activated suppressor cells, as well as induction of alloreactivity. Transplantation 1989; 47(2): 351–6

    Article  PubMed  CAS  Google Scholar 

  48. Starzl TE, Todo S, Fung J, et al. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989; II(8670): 1000–4

    Article  Google Scholar 

  49. Fung J, Todo S, Abu-Elmagd K, et al. Randomized trial in primary liver transplantation under immunosuppression with FK 506 or cyclosporine. Transplant Proc 1993; 25(1 Pt 2): 1130

    PubMed  CAS  Google Scholar 

  50. European FK506 Multicentre Liver Study Group. Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. Lancet 1994; 344(8920): 423–8

    Article  Google Scholar 

  51. Wiesner RH. A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation 1998; 66(4): 493–9

    Article  PubMed  CAS  Google Scholar 

  52. Rilo HL, Carroll PB, Tzakis A, et al. Insulin independence for 58 months following pancreatic islet cell transplantation in a patient undergoing upper abdominal exenteration. Transplant Proc 1995; 27(6): 3164–5

    PubMed  CAS  Google Scholar 

  53. Carroll PB, Rilo HL, Alejandro R, et al. Long-term (> 3-year) insulin independence in a patient with pancreatic islet cell transplantation following upper abdominal exenteration and liver replacement for fibrolamellar hepatocellular carcinoma. Transplantation 1995; 59(6): 875–9

    PubMed  CAS  Google Scholar 

  54. Scharp DW, Lacy PE, Santiago JV, et al. Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients. Transplantation 1991; 51(1): 76–85

    Article  PubMed  CAS  Google Scholar 

  55. Yakimets WJ, Lakey JR, Yatscoff RW, et al. Prolongation of canine pancreatic islet allograft survival with combined rapamycin and cyclosporine therapy at low doses: rapamycin efficacy is blood level related. Transplantation 1993; 56(6): 1293–8

    Article  PubMed  CAS  Google Scholar 

  56. Shibata S, Matsumoto S, Sageshima J, et al. Temporary treatment with sirolimus and low-trough cyclosporine prevents acute islet allograft rejection, and combination with starch-conjugated deferoxamine promotes islet engraftment in the preclinical pig model. Transplant Proc 2001; 33(1-2): 509

    Article  PubMed  CAS  Google Scholar 

  57. Kahan BD. Concentration-controlled immunosuppressive regimens using cyclosporine with sirolimus or brequinar in human renal transplantation. Transplant Proc 1995; 27(1): 33–6

    PubMed  CAS  Google Scholar 

  58. Vu MD, Qi S, Xu D, et al. Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat. Transplantation 1997; 64(12): 1853–6

    Article  PubMed  CAS  Google Scholar 

  59. Chen H, Qi S, Xu D, et al. Combined effect of rapamycin and FK 506 in prolongation of small bowel graft survival in the mouse. Transplant Proc 1998; 30(6): 2579–81

    Article  PubMed  CAS  Google Scholar 

  60. McAlister VC, Gao Z, Peltekian K, et al. Sirolimus-tacrolimus combination immunosuppression. Lancet 2000; 355(9201): 376–7

    Article  PubMed  CAS  Google Scholar 

  61. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimuseluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346(23): 1773–80

    Article  PubMed  CAS  Google Scholar 

  62. Tkaczuk J, Milford E, Yu C, et al. Intracellular signaling consequences of anti-IL-2Ralpha blockade by daclizumab. Transplant Proc 2001; 33(1-2): 212–3

    Article  PubMed  CAS  Google Scholar 

  63. Soulillou JP, Cantarovich D, Le Mauff B, et al. Randomized controlled trial of a monoclonal antibody against the interleukin-2 receptor (33B3.1) as compared with rabbit antithymocyte globulin for prophylaxis against rejection of renal allografts. N Engl J Med 1990; 322(17): 1175–82

    Article  PubMed  CAS  Google Scholar 

  64. Kirkman RL, Shapiro ME, Carpenter CB, et al. A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation. Transplant Proc 1991; 23(1 Pt 2): 1066–7

    PubMed  CAS  Google Scholar 

  65. Nashan B, Light S, Hardie IR, et al. Reduction of acute renal allograft rejection by daclizumab: Daclizumab Double Therapy Study Group. Transplantation 1999; 67(1): 110–5

    Article  PubMed  CAS  Google Scholar 

  66. Vincenti F, Nashan B, Light S. Daclizumab: outcome of phase III trials and mechanism of action: double therapy and the Triple Therapy Study Groups. Transplant Proc 1998; 30(5): 2155–8

    Article  PubMed  CAS  Google Scholar 

  67. Ekberg H, Backman L, Tufveson G, et al. Daclizumab prevents acute rejection and improves patient survival post transplantation: 1 year pooled analysis. Transpl Int 2000; 13(2): 151–9

    Article  PubMed  CAS  Google Scholar 

  68. Stratta RJ, Taylor RJ, Castaldo P, et al. Preliminary experience with FK 506 in pancreas transplant recipients. Transplant Proc 1995; 27(6): 3024

    PubMed  CAS  Google Scholar 

  69. Sutherland DE, Gruessner RW, Dunn DL, et al. Lessons learned from more than 1000 pancreas transplants at a single institution. Ann Surg 2001; 233(4): 463–501

    Article  PubMed  CAS  Google Scholar 

  70. Wohlrab J, Fischer M, Taube KM, et al. Treatment of recalcitrant psoriasis with daclizumab. Br J Dermatol 2001; 144(1): 209–10

    Article  PubMed  CAS  Google Scholar 

  71. Ryan EA, Lakey JR, Paty BW, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002; 51(7): 2148–57

    Article  PubMed  CAS  Google Scholar 

  72. Knechtle SJ, Vargo D, Fechner J, et al. FN18-CRM9 immunotoxin promotes tolerance in primate renal allografts. Transplantation 1997; 63(1): 1–6

    Article  PubMed  CAS  Google Scholar 

  73. Contreras JL, Wang PX, Eckhoff DE, et al. Peritransplant tolerance induction with anti-CD3-immunotoxin: a matter of proinflammatory cytokine control. Transplantation 1998; 65(9): 1159–69

    Article  PubMed  CAS  Google Scholar 

  74. Thomas JM, Contreras JL, Jiang XL, et al. Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotoxin and deoxyspergualin. Transplantation 1999; 68(11): 1660–73

    Article  PubMed  CAS  Google Scholar 

  75. Contreras JL, Eckhoff DE, Cartner S, et al. Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. Transplantation 2000; 69(2): 195–201

    Article  PubMed  CAS  Google Scholar 

  76. Thomas FT, Ricordi C, Contreras JL, et al. Reversal of naturally occuring diabetes in primates by unmodified islet xenografts without chronic immunosuppression. Transplantation 1999; 67(6): 846–54

    Article  PubMed  CAS  Google Scholar 

  77. Thomas JM, Contreras JL, Smyth CA, et al. Successful reversal of streptozotocin-induced diabetes with stable allogeneic islet function in a preclinical model of type 1 diabetes. Diabetes 2001; 50(6): 1227–36

    Article  PubMed  CAS  Google Scholar 

  78. Chatenoud L, Primo J, Bach JF. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 1997; 158(6): 2947–54

    PubMed  CAS  Google Scholar 

  79. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002; 346(22): 1692–8

    Article  PubMed  CAS  Google Scholar 

  80. Herold KC, Burton JB, Francois F, et al. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gammal(Ala-Ala). J Clin Invest 2003; 111(3): 409–18

    PubMed  CAS  Google Scholar 

  81. Hering BJ, Matsumoto I, Sawada T, et al. Impact of two-layer pancreas preservation on islet isolation and transplantation. Transplantation 2002; 74(12): 1813–6

    Article  PubMed  Google Scholar 

  82. Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol 2003; 30(4): 424–33

    Article  PubMed  CAS  Google Scholar 

  83. Lockwood CM, Thiru S, Isaacs JD, et al. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 1993; 341(8861): 1620–2

    Article  PubMed  CAS  Google Scholar 

  84. Coles AJ, Wing MG, Compston DA. Disease activity and the immune set in multiple sclerosis: blood markers for immunotherapy. Mult Scler 1998; 4(3): 232–8

    PubMed  CAS  Google Scholar 

  85. Killick SB, Marsh JC, Hale G, et al. Sustained remission of severe resistant autoimmune neutropenia with Campath-1H. Br J Haematol 1997; 97(2): 306–8

    Article  PubMed  CAS  Google Scholar 

  86. Lim SH, Hale G, Marcus RE, et al. CAMPATH-1 monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic purpura. Br J Haematol 1993; 84(3): 542–4

    Article  PubMed  CAS  Google Scholar 

  87. Calne R, Moffatt SD, Friend PJ, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 1999; 68(10): 1613–6

    Article  PubMed  CAS  Google Scholar 

  88. Calne R, Moffatt SD, Friend PJ, et al. Prope tolerance with induction using Campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients. Nippon Geka Gakkai Zasshi 2000; 101(3): 301–6

    PubMed  CAS  Google Scholar 

  89. Knechtle SJ, Pirsch JD, Fechner JJH, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3(6): 722–30

    Article  PubMed  CAS  Google Scholar 

  90. Harding FA, McArthur JG, Gross JA, et al. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 1992; 356(6370): 607–9

    Article  PubMed  CAS  Google Scholar 

  91. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996; 14: 233–58

    Article  PubMed  CAS  Google Scholar 

  92. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990; 248(4961): 1349–56

    Article  PubMed  CAS  Google Scholar 

  93. Levisetti MG, Padrid PA, Szot GL, et al. Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation. J Immunol 1997; 159(11): 5187–91

    PubMed  CAS  Google Scholar 

  94. Kenyon NS, Chatzipetrou M, Masetti M, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci U S A 1999; 96(14): 8132–7

    Article  PubMed  CAS  Google Scholar 

  95. Kenyon NS, Fernandez LA, Lehmann R, et al. Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD 154. Diabetes 1999; 48(7): 1473–81

    Article  PubMed  CAS  Google Scholar 

  96. Zheng XX, Markees TG, Hancock WW, et al. CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment. J Immunol 1999; 162(8): 4983–90

    PubMed  CAS  Google Scholar 

  97. Knosalla C, Gollackner B, Cooper DK. Anti-CD154 monoclonal antibody and thromboembolism revisted. Transplantation 2002; 74(3): 416–7

    Article  PubMed  Google Scholar 

  98. Buhler L, Alwayn IP, Appel JZ, et al. Anti-CD 154 monoclonal antibody and thromboembolism. Transplantation 2001; 71(3): 491

    Article  PubMed  CAS  Google Scholar 

  99. Garlichs CD, Geis T, Goppelt-Struebe M, et al. Induction of cyclooxygenase-2 and enhanced release of prostaglandin E(2) and I(2) in human endothelial cells by engagement of CD40. Atherosclerosis 2002; 163(1): 9–16

    Article  PubMed  CAS  Google Scholar 

  100. Szabolcs MJ, Cannon PJ, Thienel U, et al. Analysis of CD154 and CD40 expression in native coronary atherosclerosis and transplant associated coronary artery disease. Virchows Arch 2000; 437(2): 149–59

    Article  PubMed  CAS  Google Scholar 

  101. Larsen CP, Pearson TC. The CD40 pathway in allograft rejection, acceptance, and tolerance. Curr Opin Immunol 1997; 9(5): 641–7

    Article  PubMed  CAS  Google Scholar 

  102. Pearson TC, Trambley J, Odom K, et al. Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation 2002; 74(7): 933–40

    Article  PubMed  CAS  Google Scholar 

  103. Adams AB, Shirasugi N, Durham MM, et al. Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates. Diabetes 2002; 51(2): 265–70

    Article  PubMed  CAS  Google Scholar 

  104. Coyle AJ, Gutierrez-Ramos JC. The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function. Nat Immunol 2001; 2(3): 203–9

    Article  PubMed  CAS  Google Scholar 

  105. Nanji S, Hancock WW, Anderson CC, et al. Multiple combination therapies involving blockade of ICOS/B7R-1 costimulation facilitate long-term islet allograft survival. Am J Transplant 2004; 4(4): 526–36

    Article  PubMed  CAS  Google Scholar 

  106. Nakamura Y, Yasunami Y, Satoh M, et al. Acceptance of islet allografts in the liver of mice by blockade of an inducible costimulator. Transplantation 2003; 75(8): 1115–8

    Article  PubMed  CAS  Google Scholar 

  107. Gao W, Demirci G, Li XC. Negative T cell costimulation and islet tolerance. Diabetes Metab Res Rev 2003; 19(3): 179–85

    Article  PubMed  CAS  Google Scholar 

  108. Gao W, Demirci G, Strom TB, et al. Stimulating PD-1-negative signals concurrent with blocking CD154 co-stimulation induces long-term islet allograft survival. Transplantation 2003; 76(6): 994–9

    Article  PubMed  CAS  Google Scholar 

  109. Rothstein DM, Livak MF, Kishimoto K, et al. Targeting signal 1 through CD45RB synergizes with CD40 ligand blockade and promotes long term engraftment and tolerance in stringent transplant models. J Immunol 2001; 166(1): 322–9

    PubMed  CAS  Google Scholar 

  110. Basadonna GP, Auersvald L, Khuong CQ, et al. Antibody-mediated targeting of CD45 isoforms: a novel immunotherapeutic strategy. Proc Natl Acad Sci U S A 1998; 95(7): 3821–6

    Article  PubMed  CAS  Google Scholar 

  111. Auersvald LA, Rothstein DM, Oliveira SC, et al. Indefinite islet allograft survival in mice after a short course of treatment with anti-CD45 monoclonal antibodies. Transplantation 1997; 63(9): 1355–8

    Article  PubMed  CAS  Google Scholar 

  112. Auersvald LA, Rothstein DM, Oliveira SC, et al. Anti-CD45RB treatment prolongs islet allograft survival in mice. Transplant Proc 1997; 29(1-2): 771

    Article  PubMed  CAS  Google Scholar 

  113. Shapiro ME, Liu M. Prolongation of islet allograft survival by anti-CD45 antibody pretreatment. Transplant Proc 1995; 27(1): 613–4

    PubMed  CAS  Google Scholar 

  114. Molano RD, Berney T, Pileggi A, et al. Prolonged survival of allogeneic islet grafts in NOD mice treated with a combination of anti-CD45RB and anti-CD154 antibodies. Transplant Proc 2001; 33(1-2): 248–9

    Article  PubMed  CAS  Google Scholar 

  115. Molano RD, Pileggi A, Berney T, et al. Prolonged islet allograft survival in diabetic NOD mice by targeting CD45RB and CD154. Diabetes 2003; 52(4): 957–64

    Article  PubMed  CAS  Google Scholar 

  116. Kirk AD, Burkly LC, Batty DS, et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999; 5(6): 686–93

    Article  PubMed  CAS  Google Scholar 

  117. Li Y, Li XC, Zheng XX, et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999; 5(11): 1298–302

    Article  PubMed  CAS  Google Scholar 

  118. Wells AD, Li XC, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999; 5(11): 1303–7

    Article  PubMed  CAS  Google Scholar 

  119. Nelson PJ, Krensky AM. Chemokines and allograft rejection: narrowing the list of suspects. Transplantation 2001; 72(7): 1195–7

    Article  PubMed  CAS  Google Scholar 

  120. Hancock WW, Gao W, Faia KL, et al. Chemokines and their receptors in allograft rejection. Curr Opin Immunol 2000; 12(5): 511–6

    Article  PubMed  CAS  Google Scholar 

  121. Abdi R, Means TK, Luster AD. Chemokines in islet allograft rejection. Diabetes Metab Res Rev 2003; 19(3): 186–90

    Article  PubMed  CAS  Google Scholar 

  122. Lee I, Wang L, Wells AD, et al. Blocking the monocyte chemoattractant protein-1/ CCR2 chemokine pathway induces permanent survival of islet allografts through a programmed death-1 ligand-1-dependent mechanism. J Immunol 2003; 171(12): 6929–35

    PubMed  CAS  Google Scholar 

  123. Abdi R, Smith RN, Makhlouf L, et al. The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection. Diabetes 2002; 51(8): 2489–95

    Article  PubMed  CAS  Google Scholar 

  124. Baker MS, Chen X, Rotramel AR, et al. Genetic deletion of chemokine receptor CXCR3 or antibody blockade of its ligand IP-10 modulates posttransplantation graft-site lymphocytic infiltrates and prolongs functional graft survival in pancreatic islet allograft recipients. Surgery 2003; 134(2): 126–33

    Article  PubMed  Google Scholar 

  125. Brinkmann V, Pinschewer D, Chiba K, et al. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharmacol Sci 2000; 21(2): 49–52

    Article  PubMed  CAS  Google Scholar 

  126. Brinkmann V, Pinschewer DD, Feng L, et al. FTY720: altered lymphocyte traffic results in allograft protection. Transplantation 2001; 72(5): 764–9

    Article  PubMed  CAS  Google Scholar 

  127. Brinkmann V, Chen S, Feng L, et al. FTY720 alters lymphocyte homing and protects allografts without inducing general immunosuppression. Transplant Proc 2001; 33(1-2): 530–1

    Article  PubMed  CAS  Google Scholar 

  128. Chiba K, Hoshino Y, Suzuki C, et al. FTY720, a novel immunosuppressant possessing unique mechanisms: I. prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant Proc 1996; 28(2): 1056–9

    PubMed  CAS  Google Scholar 

  129. Xu M, Pirenne J, Antoniou EA, et al. Effect of peritransplant FTY720 alone or in combination with post-transplant tacrolimus in a rat model of cardiac allotransplantation. Transpl Int 1998; 11(4): 288–94

    Article  PubMed  CAS  Google Scholar 

  130. Stepkowski SM, Wang M, Qu X, et al. Synergistic interaction of FTY720 with cyclosporine or sirolimus to prolong heart allograft survival. Transplant Proc 1998; 30(5): 2214–6

    Article  PubMed  CAS  Google Scholar 

  131. Hoshino Y, Suzuki C, Ohtsuki M, et al. FTY720, a novel immunosuppressant possessing unique mechanisms: II. Long-term graft survival induction in rat heterotopic cardiac allografts and synergistic effect in combination with cyclosporine A. Transplant Proc 1996; 28(2): 1060–1

    PubMed  CAS  Google Scholar 

  132. Schuurman HJ, Menninger K, Audet M, et al. Oral efficacy of the new immunomodulator FTY720 in cynomolgus monkey kidney allotransplantation, given alone or in combination with cyclosporine or RAD. Transplantation 2002; 74(7): 951–60

    Article  PubMed  CAS  Google Scholar 

  133. Fu F, Hu S, Li S, et al. FTY720, a novel immunosuppressive agent with insulinotropic activity, prolongs graft survival in a mouse islet transplantation model. Transplant Proc 2001; 33(1-2): 672–3

    Article  PubMed  CAS  Google Scholar 

  134. Fu F, Hu S, Deleo J, et al. Long-term islet graft survival in streptozotocin- and autoimmune-induced diabetes models by immunosuppressive and potential insulinotropic agent FTY720. Transplantation 2002; 73(9): 1425–30

    Article  PubMed  CAS  Google Scholar 

  135. Wijkstrom M, Kenyon NS, Kirchhof N, et al. Islat allograft survival in nonhuman primates immunosuppressed with basiliximab, RAD, and FTY720. Transplantation 2004; 77(6): 827–35

    Article  PubMed  CAS  Google Scholar 

  136. Maki T, Gottschalk R, Monaco AP. Prevention of autoimmune diabetes by FTY720 in nonobese diabetic mice. Transplantation 2002; 74(12): 1684–6

    Article  PubMed  CAS  Google Scholar 

  137. Bennet W, Groth CG, Larsson R, et al. Isolated human islets trigger an instant blood mediated inflammatory reaction: implications for intraportal islet transplantation as a treatment for patients with type 1 diabetes. Ups J Med Sci 2000; 105(2): 125–33

    PubMed  CAS  Google Scholar 

  138. Moberg L, Johansson H, Lukinius A, et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet 2002; 360 (9350): 2039–45

    Article  Google Scholar 

  139. Ozmen L, Ekdahl KN, Elgue G, et al. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. Diabetes 2002; 51(6): 1779–84

    Article  PubMed  CAS  Google Scholar 

  140. Goto M, Johansson H, Maeda A, et al. Low molecular weight dextran sulfate prevents the instant blood-mediated inflammatory reaction induced by adult porcine islets. Transplantation 2004; 77(5): 741–7

    Article  PubMed  CAS  Google Scholar 

  141. Farney AC, Xenos E, Sutherland DE, et al. Inhibition of pancreatic islet beta cell function by tumor necrosis factor is blocked by a soluble tumor necrosis factor receptor. Transplant Proc 1993; 25(1 Pt 2): 865–6

    PubMed  CAS  Google Scholar 

  142. Brandhorst D, Brandhorst H, Zwolinski A, et al. High-dosed nicotinamide decreases early graft failure after pig to nude rat intraportal islet transplantation. Transplantation 2002; 73(1): 74–9

    Article  PubMed  CAS  Google Scholar 

  143. Knip M, Douek IF, Moore WP, et al. Safety of high-dose nicotinamide: a review. Diabetologia 2000; 43(11): 1337–45

    Article  PubMed  CAS  Google Scholar 

  144. Gysemans C, Van Etten E, Overbergh L, et al. Treatment of autoimmune diabetes recurrence in non-obese diabetic mice by mouse interferon-beta in combination with an analogue of 1alpha, 25-dihydroxyvitamin-D3. Clin Exp Immunol 2002; 128(2): 213–20

    Article  PubMed  CAS  Google Scholar 

  145. Riachy R, Vandewalle B, Belaich S, et al. Beneficial effect of 1,25 dihydroxyvitamin D3 on cytokine-treated human pancreatic islets. J Endocrinol 2001; 169(1): 161–8

    Article  PubMed  CAS  Google Scholar 

  146. Contreras JL, Smyth CA, Bilbao G, et al. Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets. Transplantation 2002; 74(8): 1063–9

    Article  PubMed  CAS  Google Scholar 

  147. Arita S, Nagai T, Ochiai M, et al. Prevention of primary nonfunction of canine islet autografts by treatment with pravastatin. Transplantation 2002; 73(1): 7–12

    Article  PubMed  CAS  Google Scholar 

  148. Auchincloss H. In search of the elusive Holy Grail: the mechanisms and prospects for achieving clinical transplantation tolerance. Am J Transplant 2001; 1(1): 6–12

    Article  PubMed  Google Scholar 

  149. Adams AB, Shirasugi N, Jones TR, et al. Conventional immunosuppression is compatible with costimulation blockade-based, mixed chimerism tolerance induction. Am J Transplant 2003; 3(7): 895–901

    Article  PubMed  Google Scholar 

  150. Buhler LH, Spitzer TR, Sykes M, et al. Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 2002; 74(10): 1405–9

    Article  PubMed  Google Scholar 

  151. Sayegh MH, Fine NA, Smith JL, et al. Immunologic tolerance to renal allografts after bone marrow transplants from the same donors. Ann Intern Med 1991;114(11): 954–5

    PubMed  CAS  Google Scholar 

  152. Spitzer TR, Delmonico F, Tolkoff-Rubin N, et al. Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism. Transplantation 1999; 68(4): 480–4

    Article  PubMed  CAS  Google Scholar 

  153. Sykes M, Spitzer TR. Non-myeloblative induction of mixed hematopoietic chimerism: application to transplantation tolerance and hematologic malignancies in experimental and clinical studies. Cancer Treat Res 2002; 110: 79–99

    Article  PubMed  Google Scholar 

  154. Seung E, Iwakoshi N, Woda BA, et al. Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 2000; 95(6): 2175–82

    PubMed  CAS  Google Scholar 

  155. Li H, Inverardi L, Molano RD, et al. Nonlethal conditioning for the induction of allogeneic chimerism and tolerance to islet allografts. Transplantation 2003; 75(7): 966–70

    Article  PubMed  Google Scholar 

  156. Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic immunosuppression for organ transplantation. Lancet 2003; 361(9368): 1502–10

    Article  PubMed  Google Scholar 

  157. Oike F, Yokoi A, Nishimura E, et al. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc 2002; 34(5): 1521

    Article  PubMed  Google Scholar 

  158. Tanaka K, Kiuchi T. Living-donor liver transplantation in the new decade: perspective from the twentieth to the twenty-first century. J Hepatobiliary Pancreat Surg 2002; 9(2): 218–22

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

SAN receives salary support from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. AMJS is supported by a jointly funded Wyeth-CIHR-University of Alberta Clinical Research Chair in Transplantation, and through a Clinical Center Grant from the Juvenile Diabetes Research Foundation. AMJS is a Scholar with the Alberta Heritage Foundation for Medical Research (AHFMR). Tacrolimus, sirolimus and daclizumab have been generously supplied by Fujisawa Canada, Wyeth Canada, and Roche Canada, respectively, for our clinical islet transplant trials.

Author information

Authors and Affiliations

  1. Department of Surgery, University of Alberta, Edmonton, Alberta, Canada

    Sulaiman A. Nanji & A.M. James Shapiro

  2. Roberts Centre, University of Alberta, 2000 College Plaza, 8215 112 St, Edmonton, AB T6G 2C8, Canada

    A.M. James Shapiro

Authors
  1. Sulaiman A. Nanji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A.M. James Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A.M. James Shapiro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nanji, S.A., Shapiro, A.J. Islet Transplantation in Patients with Diabetes Mellitus. BioDrugs 18, 315–328 (2004). https://doi.org/10.2165/00063030-200418050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200418050-00004

Keywords

Search

Navigation