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Islet Transplantation

  • Bernhard J. Hering
  • Martin Wijkstrom
  • Peter M. Eckman

Abstract

Type 1 diabetes continues to represent a therapeutic challenge and consequently remains a substantial burden for patients and their families. Secondary diabetes complications, observed in 30% to 50% of patients affected by type 1 diabetes, result in poor quality of life, premature death, and considerable healthcare costs.1 The principal determinant of the risk of devastating diabetes complications is the total lifetime exposure to elevated blood glucose levels.2 Therefore, establishing safe and effective methods of achieving and maintaining normoglycemia will have substantial implications for the health and quality of life of individuals with diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that, given a qualified diabetes care team and intensive insulin treatment control, near-normalization of glycemia could be achieved and sustained for several years. However, such a near-perfect level of treatment would increase a patients burden of day-to-day diabetes management, be difficult to implement for many patients, require more attention and medical services than are routinely available in clinical practice,3 and be accompanied by an increased frequency of severe hypoglycemia2 (chapter 3).

Keywords

Human Islet Islet Transplant Islet Graft Islet Isolation Mixed Chimerism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Nathan D. Long-term complications of diabetes mellitus. N Engl J Med 1993; 328: 1676–1684.PubMedGoogle Scholar
  2. 2.
    Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–986.Google Scholar
  3. 3.
    Bloomgarden ZT. American Diabetes Association postgraduate course, 1996: Treatment and prevention of diabetes. Diabetes Care 1996; 19: 784–786.Google Scholar
  4. 4.
    Sutherland DE, Gruessner AC, Gruessner RW. Pancreas transplantation: A review. Transplant Proc 1998; 30: 1940–1943.PubMedGoogle Scholar
  5. 5.
    Fioretto P, Steffes MW, Sutherland DR, Goetz F, Mauer M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339 (2): 69–75.PubMedGoogle Scholar
  6. 6.
    Tyden G, Bolinder J, Solders G, Brattstrom C, Tibell A, Groth CG. Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 1999; 67: 645–648.PubMedGoogle Scholar
  7. 7.
    Zehrer CL, Gross CR. Quality of life of pancreas transplant recipients. Diabetologia 1991; 34 (suppl 1): S145–S149.PubMedGoogle Scholar
  8. 8.
    Douzdjian V, Ferrara D, Silvestri G. Treatment strategies for insulin-dependent diabetics with ESRD: A cost-effectiveness decision analysis model. Am J Kidney Dis 1998; 31: 794–802.PubMedGoogle Scholar
  9. 9.
    Stratta RJ. The economics of pancreas transplantation. Graft 2000; 3: 19–24.Google Scholar
  10. 10.
    Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230–238.PubMedGoogle Scholar
  11. 11.
    Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes S, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001; 50: 710–719.PubMedGoogle Scholar
  12. 12.
    Hering BJ, Ricordi C. Islet transplantation for patients with type 1 diabetes: Results, research priorities and reasons for optimism. Graft 1999; 2: 12–27.Google Scholar
  13. 13.
    Soria B, Roche E, Berna G, Leon-Quinto T, Reig JA, Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozocin-induced diabetic mice. Diabetes 2000; 49: 157–162.PubMedGoogle Scholar
  14. 14.
    Bonner-Weir S, Sharma A. Pancreatic stem cells. J Pathol 2002; 197: 519–526.PubMedGoogle Scholar
  15. 15.
    Meyer C, Hering BJ, Grossmann R, Brandhorst H, Brandhorst D, Gerich J, et al. Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type 1 diabetes mellitus. Transplantation 1998; 66: 233–240.PubMedGoogle Scholar
  16. 16.
    Alejandro R, Lehmann R, Ricordi C, Kenyon NS, et al. Longterm function (6 years) of islet allografts in type 1 diabetes. Diabetes 1997; 46: 1983–1989.PubMedGoogle Scholar
  17. 17.
    Largiader F, Kolb E, Binswanger U. A long-term functioning human pancreatic islet allotransplant. Transplantation 1980; 29: 76–77.PubMedGoogle Scholar
  18. 18.
    Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Falqui L, et al. Insulin independence after islet transplantation into type I diabetic patient. Diabetes 1990; 39: 515–518.PubMedGoogle Scholar
  19. 19.
    Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW. Automated method for isolation of human pancreatic islets. Diabetes 1988; 37: 413–420.PubMedGoogle Scholar
  20. 20.
    Tzakis AG, Ricordi C, Alejandro R, Zeng Y, Fung JJ, Todo S, et al. Pancreatic islet transplantation after upper abdominal exenteration and liver replacement [see comments]. Lancet 1990; 336 (8712): 402–405.PubMedGoogle Scholar
  21. 21.
    Warnock GL, Kneteman NM, Ryan E, Seelis RE, Rabinovitch A, Rajotte, RV et al. Normoglycaemia after transplantation of freshly isolated and cryopreserved pancreatic islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1991; 34: 55–58.PubMedGoogle Scholar
  22. 22.
    Socci C, Falqui L, Davalli AM, Ricordi C, Braghi S, Bertuzzi F, et al. Fresh human islet transplantation to replace pancreatic endocrine function in type 1 diabetic patients. Report of six cases. Acta Diabetol 1991; 28: 151–157.PubMedGoogle Scholar
  23. 23.
    Gores PF, Najarian JS, Stephanian E, Lloveras JJ, Kelley SL, Sutherland DE. Insulin independence in type I diabetes after transplantation of unpurified islets from single donor with 15deoxyspergualin. Lancet 1993; 341 (8836): 19–21.PubMedGoogle Scholar
  24. 24.
    Hering BJ, Bretzel RG, Hopt UT, Brandhorst H, Brandhorst D, Bollen CC, et al. New protocol toward prevention of early human islet allograft failure. Transplant Proc 1994; 26 (2): 570–571.PubMedGoogle Scholar
  25. 25.
    Hering BJ, Ernst W, Eckhard M, Brandhorst H, Brandhorst D, Jahr H, et al. Improved survival of single donor islet allografts in IDDM recipients by refined peritransplant management. Diabetes 1997; 46 (suppl 1): 64.Google Scholar
  26. 26.
    Oberholzer J, Triponez F, Mage R, Andereggen E, Buhler L, Cretin N, et al. Human islet transplantation: Lessons from 13 autologous and 13 allogeneic transplantations. Transplantation 2000; 69 (6): 1115–1123.PubMedGoogle Scholar
  27. 27.
    Benhamou PY, Oberholzer J, Toso C, Kessler L, Penfornis A, Bayle F, et al. Human islet transplantation network for the treatment of type I diabetes: First data from the Swiss-French GRAGIL consortium (1999–2000). Groupe de Recherche Rhin Rhjne Alpes Geneve pour la transplantation dilots de Langerhans. Diabetologia 2001; 44: 859–864.PubMedGoogle Scholar
  28. 28.
    Secchi A, Socci C, Maffi P, Taglietti MV, Falqui L, Bertuzzi F, et al. Islet transplantation in IDDM patients. Diabetologia 1997; 40 (2): 225–231.PubMedGoogle Scholar
  29. 29.
    Bertuzzi F, Grohovaz F, Maffi P, Caumo A, Aldrighetti L, Nano R, et al. Successful [correction of Succesful] transplantation of human islets in recipients bearing a kidney graft. Diabetologia 2002; 45: 77–84.PubMedGoogle Scholar
  30. 30.
    Brendel MD, Hering BJ, Schultz AO, Bretzel RG. International Islet Transplant Registry Newsletter 9. Giessen, Germany: Department of Medicine, Justus-Liebig-University of Giessen; 2001: 1–20.Google Scholar
  31. 31.
    McAlister VC, Gao Z, Peltekian K, Dominguas J, Mahalati K, MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. Lancet 2000; 355: 376–377.PubMedGoogle Scholar
  32. 32.
    Shapiro AMJ, Ryan EA, Paty B, Korbutt GS, OKelley K, Kneteman NM, et al. Human islet transplantation can correct diabetes. Transplantation 2002; 74 (suppl 4): 119.Google Scholar
  33. 33.
    Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, et al. Successful islet transplantation: Continued insulin reserve provides long-term glycemic control. Diabetes 2002; 51: 2148–2157.PubMedGoogle Scholar
  34. 34.
    Kaufman DB, Baker MS, Chen X, Leventhal JR, Stuart FP. Sequential kidney/islet transplantation using prednisone-free immunosuppression. Am J Transplant 2002; 2: 674–677.PubMedGoogle Scholar
  35. 35.
    Markmann JF, Deng S, Huang X, Desai NM, Velidedeoglu E, Liu C, et al. Evaluation of islets from non-heart beating donors for human transplantation. Transplantation 2002; 74 (suppl 4): 142.Google Scholar
  36. 36.
    Johnson JA, Nanji SA, Supina A, Ryan EA, Shapiro AMJ. Islet transplantation and health related quality of life in type 1 diabetes: Results of an initial pilot study. Am J Transplant 2002; 2 (suppl 3): 229.Google Scholar
  37. 37.
    Fiorina P, Maffi P, Folli F, Bertuzzi F, Davalli A, Socci C, et al. Long term beneficial effects of islet transplantation on diabetic complications in type 1 diabetic kidney transplanted patients. A study of 34 consecutive cases. Transplantation 2002; 74 (suppl 4): 81.Google Scholar
  38. 38.
    Shapiro AM, Lakey JR, Rajotte RV, Warnock GL, Friedlich MS, Jewell, LD et al. Portal vein thrombosis after transplantation of partially purified pancreatic islets in a combined human liver/islet allograft. Transplantation 1995; 59: 1060–1063.PubMedGoogle Scholar
  39. 39.
    Froberg MK, Leone JP, Jessurun J, Sutherland DE. Fatal disseminated intravascular coagulation after autologous islet transplantation. Hum Pathol 1997; 28: 1295–1298.PubMedGoogle Scholar
  40. 40.
    Mehigan DG, Bell WR, Zuidema GD, Eggleston JC, Cameron JL. Disseminated intravascular coagulation and portal hypertension following pancreatic islet autotransplantation. Ann Surg 1980; 191: 287–293.PubMedGoogle Scholar
  41. 41.
    Mittal VK, Toledo-Pereyra LH, Sharma M, Ramaswamy K, Puri VK, Cortez, JA et al. Acute portal hypertension and disseminated intravascular coagulation following pancreatic islet autotransplantation after subtotal pancreatectomy. Transplantation 1981; 31: 302–304.PubMedGoogle Scholar
  42. 42.
    Taylor GD, Kirkland T, Lakey J, Rajotte R, Warnock GL. Bacteremia due to transplantation of contaminated cryopreserved pancreatic islets. Cell Transplant 1994; 3: 103–106.PubMedGoogle Scholar
  43. 43.
    Roep BO, Stobbe I, Duinkerken G, van Rood J, Lernmark A, Keymeulen B, et al. Auto-and alloimmune reactivity to human islet allografts transplanted into type I diabetic patients. Diabetes 1999; 48: 484–490.PubMedGoogle Scholar
  44. 44.
    Olack BJ, Swanson CJ, Flavin KS, Phelan D, Brennan DC, White NH, et al. Sensitization to HLA antigens in islet recipients with failing transplants. Transplant Proc 1997;29(4):22682269.Google Scholar
  45. 45.
    Alejandro R, Angelico MC, Esquenazi V, Kenyon NS, Garcia-Morales R, Ciancio G, et al. Development of cytotoxic antibodies against donor HLA antigens in islet allograft recipients. Presented at the 23rd Scientific Meeting of the American Society of Transplant Surgeons. 1997.Google Scholar
  46. 46.
    Sutherland DE, Gores PF, Farney AC, Wahoff DC, Matas AJ, Dunn DL, et al. Evolution of kidney, pancreas, and islet transplantation for patients with diabetes at the University of Minnesota. Am J Surg 1993; 166: 456–491.PubMedGoogle Scholar
  47. 47.
    Clayton HA, Swift SM, Turner JM, James RF, Bell PR. Nonheart-beating organ donors: A potential source of islets for transplantation? Transplantation 2000; 69: 2094–2098.PubMedGoogle Scholar
  48. 48.
    Zeng Y, Torre MA, Karrison T, Thistlethwaite JR. The correlation between donor characteristics and the success of human islet isolation. Transplantation 1994; 57: 954–958.PubMedGoogle Scholar
  49. 49.
    Benhamou PY, Watt PC, Mullen Y, et al. Human islet isolation in 104 consecutive cases. Transplantation 1994; 57: 1804–1808.PubMedGoogle Scholar
  50. 50.
    Brandhorst H, Brandhorst D, Hering BJ, Federlin K, Bretzel RG. Body mass index of pancreatic donors: A decisive factor for human islet isolation. Exp Clin Endocrinol Diabetes 1995; 103 (suppl 2): 23–26.PubMedGoogle Scholar
  51. 51.
    Lakey JR, Warnock GL, Rajotte RV, Suarez-Alamazor ME, Ao Z, Shapiro AMJ, et al. Variables in organ donors that affect the recovery of human islets of Langerhans. Transplantation 1996; 61: 1047–1053.PubMedGoogle Scholar
  52. 52.
    Korbutt G, Ao Z, Rajotte RV. Effect of human islet donor age on correcting diabetes in SCID mice. International Pancreas and Islet Transplant Association; August 1999. Sidney.Google Scholar
  53. 53.
    Marsh CL, Perkins JD, Sutherland DER, Cony RJ, Sterioff S. Combined hepatic and pancreaticoduodenal procurement for transplantation. Surg Gynecol Obstet 1989; 168: 254–258.PubMedGoogle Scholar
  54. 54.
    Sollinger HW, Vernon WB, DAlessandro AM, Kalayoglu M, Stratta RJ, Belzer FO. Combined liver and pancreas procurement with Belzer-UW solution. Surgery 1989; 106: 685–691.PubMedGoogle Scholar
  55. 55.
    Lakey JR, Kneteman NM, Rajotte RV, Wu DC, Bigam D, Shapiro AM. Effect of core pancreas temperature during cadaveric procurement on human islet isolation and functional viability. Transplantation 2002; 73: 1106–1110.PubMedGoogle Scholar
  56. 56.
    Wahlberg JA, Love R, Landegaard L, Southard JH, Belzer FO. Successful 72 hours preservation of the canine pancreas. Transplant Proc 1987; 19 (1, pt 2): 1337–1338.PubMedGoogle Scholar
  57. 57.
    Ploeg RJ, Goossens D, Sollinger HW, Southard JH, Belzer FO. The Belzer-UW solution for effective long-term preservation in canine pancreas transplantation. Transplant Proc 1989; 21 (1, pt 2): 1378–1380.PubMedGoogle Scholar
  58. 58.
    Belzer FO, Ploeg RJ, Knechtle SJ, DAlessandro AM, Pirsch JD, Kalayoglu M, et al. Clinical pancreas preservation and transplantation. Transplant Proc 1994; 26: 550–551.PubMedGoogle Scholar
  59. 59.
    Kuroda Y, Kawamura T, Suzuki Y, Fujiwara H, Yamamoto K, Saitoh Y. A new, simple method for cold storage of the pancreas using perfluorochemical. Transplantation 1988;46:457460. Comments.Google Scholar
  60. 60.
    Matsumoto S, Kandaswamy R, Sutherland DE, Hassoun A, Hiraoka K, Sageshima J, et al. Clinical application of the two-layer [University of Wisconsin solution (UW)/perfluorochem-ical (PFC) plus 02] method of pancreas preservation before transplantation. Transplantation 2000; 70 (5): 771–774.PubMedGoogle Scholar
  61. 61.
    Hering BJ, Kandaswamy R, Harmon JV, Ansite JD, Clemmings S, Sakai T, et al. Insulin independence after single-donor islet transplantation in type 1 diabetes with hOKT3gammal (Ala-Ala), sirolimus, and tacrolimus therapy. Am J Transplant 2001; 1 (suppl 1): 180.Google Scholar
  62. 62.
    Ricordi C, Fraker C, Szust J, al-Abdullah I, Poggioli R, Kirelew T, et al. Towards making every pancreas count: Significant improvement in human islet isolation from marginal (older) donors following addition of oxygenated perflourocarbon to the cold storage solution. Am J Transplant 2002; 2 (suppl 3): 229.Google Scholar
  63. 63.
    Lakey JRT, Warnock GL, Shapiro AM, Korbutt GS, Ao Z, Kneteman NM, et al. Intraductal collagenase delivery into the human pancreas using syringe loading or controlled perfusion. Cell Transplant 1999; 8: 285–292.PubMedGoogle Scholar
  64. 64.
    Linetsky E, Bottino R, Lehmann R, Alejandro R, Inverardi L, Ricordi C. Improved human islet isolation using a new enzyme blend, Liberase. Diabetes 1997; 46: 1120–1123.PubMedGoogle Scholar
  65. 65.
    Lakey JR, Helms LM, Kin T, Korbutt GS, Rajotte RV, Shapiro AM, et al. Serine-protease inhibition during islet isolation increases islet yield from human pancreases with prolonged ischemia. Transplantation 2001; 72: 565–570.PubMedGoogle Scholar
  66. 66.
    Lakey JR, Warnock GL, Shapiro AM, Korbutt GS, Ao Z, Kneteman NM, et al. Intraductal collagenase delivery into the human pancreas using syringe loading or controlled perfusion. Cell Transplant 1999; 8: 285–292.PubMedGoogle Scholar
  67. 67.
    Brandhorst H, Brandhorst D, Brendel M, Hering BJ, Bretzel RG. Assessment of intracellular insulin contents during all steps of human islet isolation procedure. Cell Transplant 1998; 7: 489–495.PubMedGoogle Scholar
  68. 68.
    Lake SP, Bassett PD, Larkins A, Revell J, Walczak K, Chamberlain J, et al. Large-scale purification of human islets utilizing discontinuous albumin gradient on IBM 2991 cell separator. Diabetes 1989; 38 (suppl 1): 143–145.PubMedGoogle Scholar
  69. 69.
    Meyer C, Hering BJ, Grossmann R, Brandhorst H, Brandhorst D, Gerich J, et al. Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type 1 diabetes mellitus. Transplantation 1998; 66: 233–240.PubMedGoogle Scholar
  70. 70.
    Cryer PE, Fisher JN, Shamoon H. Hypoglycemia. Diabetes Care 1994; 17: 734–755.PubMedGoogle Scholar
  71. 71.
    Cryer PE. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes 1994; 43: 1378–1389.PubMedGoogle Scholar
  72. 72.
    Cryer PE. Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: A vicious cycle. Diabetes 1992; 41: 255–260.Google Scholar
  73. 73.
    Gerich JE, Langlois M, Noacco C, Karam JH, Forsham PH. Lack of glucagon response to hypoglycemia in diabetes: Evidence for an intrinsic pancreatic alpha cell defect. Science 1973; 182: 171–173.PubMedGoogle Scholar
  74. 74.
    White NH, Skor D, Cryer PE, Bier DM, Levandoski L, Santiago JV. Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive therapy. N Engl J Med 1983; 308: 485–491.PubMedGoogle Scholar
  75. 75.
    Bolli GB, De Feo P, De Cosmo S, Perriello G, Ventura MM, Masssi-Benedetti M, et al. A reliable and reproducible test for adequate glucose counterregulation in type 1 diabetes. Diabetes 1984; 33: 732–737.PubMedGoogle Scholar
  76. 76.
    Diabetes Control and Complications Trial Research Group. Epi-demiology of severe hypoglycemia in the Diabetic Control and Complications Trial. Am J Med 1991; 90: 450–459.Google Scholar
  77. 77.
    Muhlhauser I, Berger M, Sonnenberg G, Koch J, Jorgens V, Schernthaner G, et al. Incidence and management of severe hypoglycemia in 434 adults with insulin-dependent diabetes mellitus. Diabetes Care 1985; 8: 268–273.PubMedGoogle Scholar
  78. 78.
    Muhlhauser I, Bruckner I, Berger M, Cheta D, Jorgens V, Ionescu-Tirgoviste C, et al. Evaluation of an intensified insulin treatment and teaching programme as routine management of type 1 (insulin-dependent) diabetes. The Bucharest-Dusseldorf Study. Diabetologia 1987; 30: 681–690.PubMedGoogle Scholar
  79. 79.
    Mecklenburg RS, Benson EA, Benson JW Jr, Fredlund PN, Guinn T, Metz RJ, et al. Acute complications associated with insulin infusion pump therapy. Report of experience with 161 patients. JAMA 1984; 252: 3265–3269.Google Scholar
  80. 80.
    Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier BM. Unawareness of hypoglycemia in insulin-treated diabetic patients: Prevalance and relationship to autonomic neuropathy. Diabetes Med 1990; 7: 711–717.Google Scholar
  81. 81.
    Ryder REJ, Owens DR, Hayes TM, Ghatei M, Bloom SR. Unawareness of hypoglycemia and inadequate glucose counter-regulation: No causal relationship with diabetic autonomic neuropathy. Br Med J 1990; 301: 783–787.Google Scholar
  82. 82.
    Dagogo-Jack S, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. J Clin Invest 1993; 91: 819–828.PubMedGoogle Scholar
  83. 83.
    Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997; 46: 271–286.Google Scholar
  84. 84.
    Macleod KM, Gold AE, Frier BM. Frequency of severe hypoglycemia in insulin-dependent diabetic patients with altered awareness of typoglycemia. Diabetes 1993; 42 (suppl 1): 26A.Google Scholar
  85. 85.
    Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994; 17: 697–703.PubMedGoogle Scholar
  86. 86.
    Gill G. Socioeconomic problems of hypoglycemia. In: Frier BM, Fisher BM, eds. Hypoglycemia and Diabetes. London: Edward Arnold; 1993: 362–370.Google Scholar
  87. 87.
    Hansotia P, Broste SK. The effect of epilepsy or diabetes mellitus on the risk of automobile accidents. N Engl J Med 1991; 324: 22–26.PubMedGoogle Scholar
  88. 88.
    Irvine AA, Cox DJ, Gonder-Frederick LA. Fear of hypoglycemia: Relationship to physical and psychological symptoms in patients with insulin dependent diabetes mellitus. Health Psychol 1992; 11: 135–138.PubMedGoogle Scholar
  89. 89.
    Irvine AA, Cox DJ, Gonder-Frederick LA. Methodological issues in examination of fear of hypoglycemia. Diabetes Care 1991;14:76. Letter.Google Scholar
  90. 90.
    Pramming S, Thorsteinsson B, Bendtson I, Binder C. Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabetes Med 1991; 8 (3): 217–222.Google Scholar
  91. 91.
    Langan SJ, Deary IJ, Hepburn DA, Frier BM. Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus. Diabetologia 1991; 34: 337–344.PubMedGoogle Scholar
  92. 92.
    Perros P, Sellar RJ, Frier BM. Chronic pontine dysfunction following insulin-induced hypoglycemia in an IDDM patient. Diabetes Care 1994; 17: 725–727.PubMedGoogle Scholar
  93. 93.
    Wredling R, Levander S, Adamson U, Lins PE. Permanent neu-ropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia 1990; 33: 152–157.PubMedGoogle Scholar
  94. 94.
    Gold AE, Deary IJ, Frier BM. Recurrent severe hypoglycaemia and cognitive function in type 1 diabetes. Diabetes Med 1993; 10: 503–508.Google Scholar
  95. 95.
    Deary IJ, Crawford J, Hepburn DA, Langan SJ, Blackmore LM, Frier BM. Severe hypoglycemia and intelligence in adult patients with insulin-treated diabetes. Diabetes 1993; 42: 341–344.PubMedGoogle Scholar
  96. 96.
    Lincoln NB, Faleiro RM, Kelly C, Kirk BA, Jeffcoate WJ. Effect of long-term glycemic control on cognitive function. Diabetes Care 1996; 19: 656–658.PubMedGoogle Scholar
  97. 97.
    Bale RN. Brain damage in diabetes mellitus. Br J Psychiatry 1973; 122 (568): 337–341.PubMedGoogle Scholar
  98. 98.
    Tattersall RB, Gale EAM. Mortality. In: Frier BM, Fisher BM, eds. Hypoglycemia and Diabetes. London: Edward Arnold; 1993: 190–198.Google Scholar
  99. 99.
    Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 1994; 43: 1426–1434.PubMedGoogle Scholar
  100. 100.
    Fanelli CG, Epifano L, Rambotti AM, Pampanelli S, DiVincenzo A, Modarelli F, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most neuroendocrine responses to, symptoms of and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 1993; 42: 1683–1689.PubMedGoogle Scholar
  101. 101.
    Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Di Vincenzo A, Modarelli F, et al. Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM. Diabetologia 1994;37:12651276. Published erratum appears in Diabetologia 1995; 38: 254.Google Scholar
  102. 102.
    Cranston I, Lomas J, Maran A, Macdonald I, Amiel S. Restoration of hypoglycemia unawareness in patients with long duration insulin-depenedent diabetes mellitus. Lancet 1994; 344: 283–287.PubMedGoogle Scholar
  103. 103.
    Bottini P, Boschetti E, Pampanelli S, Ciofetta M, Del Sindaco P, Scionti L, et al. Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: Evidence for a nonselective defect. Diabetes 1997; 46: 814–823.PubMedGoogle Scholar
  104. 104.
    Fanelli C, Pampanelli S, Lalli C, Del SP, Ciofetta M, Lepore M, et al. Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation. Diabetes 1997;46(7):11721181.Google Scholar
  105. 105.
    Cryer PE. Hypoglycemia begets hypoglycemia in IDDM. Diabetes 1993; 42: 1691–1693.PubMedGoogle Scholar
  106. 106.
    Kendall DM, Rooney DP, Smets YF, Salazar BL, Robertson RP. Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 1997; 46: 249–257.PubMedGoogle Scholar
  107. 107.
    Aiello LP, Gardner TW, King GL, Blankenship G, Cavalierano JD, Ferris FL III, et al. Diabetic retinopathy. Diabetes Care 1998; 21: 143–156.PubMedGoogle Scholar
  108. 108.
    Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the diabetes control and complications trial. Arch Ophthalmol 1998; 116: 874–886.Google Scholar
  109. 109.
    Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1985; 28: 590–596.PubMedGoogle Scholar
  110. 110.
    Krolewski M, Eggers PW, Warram JH. Magnitude of end-stage renal disease in IDDM: A 35 year follow-up study. Kidney Int 1996; 50: 2041–2046.PubMedGoogle Scholar
  111. 111.
    Borch-Johnsen K. The prognosis of insulin-dependent diabetes mellitus. An epidemiological approach. Dan Med Bull 1989; 36: 336–348.PubMedGoogle Scholar
  112. 112.
    Brennan DC, Stratta RI, Lowell JA, Miller SA, Taylor RI. Cyclosporine challenge in the decision of combined kidney-pancreas versus solitary pancreas transplantation. Transplantation 1994; 57: 1606–1611.PubMedGoogle Scholar
  113. 113.
    Rathmann W, Ziegler D, Jahnke M, Haastert B, Goes FA. Mortality in diabetic patients with cardiovascular autonomic neuropathy. Diabetes Med 1993; 10: 820–824.Google Scholar
  114. 114.
    Ewing DJ, Campbell 1W, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med 1980; 92 (2, pt 2): 308–311.PubMedGoogle Scholar
  115. 115.
    Navarro X, Kennedy WR, Loewenson RB, Sutherland DE. Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction, and mortality in diabetes mellitus. Diabetes 1990; 39: 802–806.PubMedGoogle Scholar
  116. 116.
    Sampson MJ, Wilson S, Karagiannis P, Edmonds M, Watkins PJ. Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics. Q J Med 1990;75(278):635646.Google Scholar
  117. 117.
    Dyck PJ, Karnes JL, Daube J, OBrien P, Service FI. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985; 108: 861–880.PubMedGoogle Scholar
  118. 118.
    Dyck PJ. Detection, characterization, and staging of polyneuropathy: Assessed in diabetics. Muscle Nerve 1988; 11: 21–32.Google Scholar
  119. 119.
    Levitt NS, Stansberry KB, Wynchank S, Vinik AI. The natural progression of autonomic neuropathy and autonomic function tests in a cohort of people with IDDM. Diabetes Care 1996; 19: 751–754.PubMedGoogle Scholar
  120. 120.
    Young RJ, Ewing DJ, Clark BF. Chronic and remitting painful diabetic polyneuropathy. Diabetes Care 1988; 11: 34–40.PubMedGoogle Scholar
  121. 121.
    Morley GK, Mooradian AD, Levine AL, Morley JE. Mechanisms of pain in diabetic peripheral neuropathy: Effect of glucose on pain perception in humans. Am J Med 1984; 77: 79–82.PubMedGoogle Scholar
  122. 122.
    Kemp CB, Knight MJ, Scharp DW, Ballinger WF, Lacy PE. Effect of transplantation site on the results of pancreatic islet isografts in diabetic rats. Diabetologia 1973; 9: 486–491.PubMedGoogle Scholar
  123. 123.
    Alejandro R, Mintz DH, Noel J, Latif Z, Koh N, Russell E, et al. Islet cell transplantation in type I diabetes mellitus. Transplant Proc 1987; 19 (1, pt 3): 2359–2361.PubMedGoogle Scholar
  124. 124.
    Weimar B, Rauber K, Brendel MD, Bretzel RG, Rau WS. Per-cutaneous transhepatic catheterization of the portal vein: A combined CT- and fluoroscopy-guided technique. Cardiovasc Intervent Radiol 1999; 22: 342–344.PubMedGoogle Scholar
  125. 125.
    Wahoff DC, Papalois BE, Najarian JS, Kendall DM, Farney AC, Leone JP, et al. Autologous islet transplantation to prevent diabetes after pancreatic resection. Ann Surg 1995; 222: 562–575.PubMedGoogle Scholar
  126. 126.
    Gores PF, Sutherland DER. Immunosuppression for islet transplantation. In: Lanza RP, Chick WL, eds. Pancreatic Islet Transplantation Volume II: Immunomodulation of Pancreatic Islets. Austin, TX: R.G. Landes Co, 1994: 63–74.Google Scholar
  127. 127.
    Ryan EA, Lakey JR, Shapiro AM. Clinical results after islet transplantation. J Investig Med 2001; 49: 559–562.PubMedGoogle Scholar
  128. 128.
    Zeng Y, Ricordi C, Lendoire J, Carroll PB, Alejandro R, Bereiter DR, et al. The effect of prednisone on pancreatic islet autografts in dogs. Surgery 1993; 113: 98–102.PubMedGoogle Scholar
  129. 129.
    Rilo HL, Carroll PB, Zeng YJ, Fontes P, Demetris J, Ricordi C. Acceleration of chronic failure of intrahepatic canine islet autografts by a short course of prednisone. Transplantation 1994; 57: 181–187.PubMedGoogle Scholar
  130. 130.
    Shapiro AM, Hao E, Lakey JR, Finegood D, Rajotte RV, Knete-man NM. Diabetogenic synergism in canine islet autografts from cyclosporine and steroids in combination. Transplant Proc 1998; 30 (2): 527.PubMedGoogle Scholar
  131. 131.
    Bergman RN, Beard JC, Chen M. The minimal modeling method: Assessment of insulin sensitivity and B-cell function in vivo. In: Clarke WL, Larner J, Pohl SL, eds. Methods in Diabetes Research. Clinical Methods. New York: Wiley; 1986: 15–34.Google Scholar
  132. 132.
    Finegood DT, Warnock GL, Kneteman NM, Rajotte RV. Insulin sensitivity and glucose effectiveness in long-term isletautotransplanted dogs. Diabetes 1989; 38 (suppl 1): 189–191.PubMedGoogle Scholar
  133. 133.
    Kneteman NM, Marchetti P, Tordjman K, Bier DM, Santiago JV, Swanson CJ, et al. Effects of cyclosporine on insulin secretion and insulin sensitivity in dogs with intrasplenic islet autotransplants. Surgery 1992; 111: 430–437.PubMedGoogle Scholar
  134. 134.
    Jindal RM, Sidner RA, Milgrom ML. Post-transplant diabetes mellitus. The role of immunosuppression. Drug Safety 1997; 16 (4): 242–257.PubMedGoogle Scholar
  135. 135.
    Christiansen E, et al. Pancreatic 0–cell function and glucose metabolism in human segmental pancreas and kidney transplantation. Am J Physiol 1993; 264: 441–449.Google Scholar
  136. 136.
    Shapiro AM, Gallant H, Hao E, Wong J, Rajotte R, Yatscoff R, et al. Portal vein immunosuppressant levels and islet graft toxicity. Transplant Proc 1998; 30 (2): 641.PubMedGoogle Scholar
  137. 137a.
    Sutherland DE, Gores PF, Hering BJ, Wahoff D, McKeehen DA, Gruessner RW, et al. Islet transplantation: Un update. Diabetes Met Rev 1996; 12: 137–150.Google Scholar
  138. 137b.
    Hering BJ, Wijkstrom M. Sirolimus and islet transplants. Trans Proc 2003; 35 (suppl 3): S187–S190.Google Scholar
  139. 138.
    Groth CG, Backman L, Morales JM, Caine R, Kreis H, Lang P, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation. Similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036–1042.PubMedGoogle Scholar
  140. 139.
    Kahan BD, Podbielski J, Napoli K, Katz SM, Meier-Kriesche HU, Van Buren CT. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040–1046.PubMedGoogle Scholar
  141. 140.
    Shibata S, Matsumoto S, Sageshima J, Hiraoka K, Sutherland DE, Kirchhof N, 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.PubMedGoogle Scholar
  142. 141.
    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: 335–340.PubMedGoogle Scholar
  143. 142.
    Dumont FJ, Melino MR, Staruch MJ, Koprak SL, Fischer PA, Sigal NH. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in mutine T cells. J Immunol 1990; 144: 1418–1424.PubMedGoogle Scholar
  144. 143.
    Vu MD, Qi S, Xu D, Wu J, Fitzsimmons WE, Sehgal SN, 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: 1853–1856.PubMedGoogle Scholar
  145. 144.
    Kneteman NM, Lakey JR, Wagner T, Finegood D. The metabolic impact of rapamycin (sirolimus) in chronic canine islet graft recipients. Transplantation 1996; 61: 1206–1210.PubMedGoogle Scholar
  146. 145.
    Alejandro R, Ferreira JV, Caulfield A, Froud T, Baidal D, Geiger M, et al. Insulin independence in 7 patients following transplantation of cultured human islets. Transplantation 2002; 2 (suppl 3): 227.Google Scholar
  147. 146.
    Rother KI, Hirschberg B, Gaglia JL, Chang R, Wood B, Kirk AD, et al. Islet transplantation in patients with type 1 diabetes. NIH experience in 6 patients. Transplantation 2002; 2 (suppl 3): 228.Google Scholar
  148. 147a.
    Markmann JF, Deng S, Huang X, Liu C, Velidedeoglu E, Desai NM, et al. Reversal of type 1 diabetes by transplanting isolated pancreatic islets from single donors. Transplantation 2002; 2 (suppl 3): 228.Google Scholar
  149. 147b.
    Shapiro J, Hering B, Ricordi C, Dimercurio B, Lindblad R, Cagliero E, et al. International multicenter trial of islet transplantation using the Edmonton in patients with type 1 diabetes. Am J Transplant 2003; 3 (suppl 5): 152.Google Scholar
  150. 148.
    Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H, et al. Incompatibility between human blood and isolated islets of Langerhans: A finding with implications for clinical intraportal islet transplantation? Diabetes 1999; 48: 1907–1914.PubMedGoogle Scholar
  151. 149.
    Geiger MC, Ferreira JV, Froud T, Caulfield A, Baidal D, Rothenberg L, et al. Evaluation of metabolic control by continuous subcutaneous glucose monitoring system in patients with type 1 diabetes mellitus after islet cell transplantation. Am J Transplant 2002; 74 (suppl 4): 110.Google Scholar
  152. 150.
    Haffner SM, Gonzalez C, Miettinen H, Kennedy E, Stern MP. A prospective analysis of the HOMA model. Diabetes Care 1996; 19: 1138–1141.PubMedGoogle Scholar
  153. 151.
    Levy JC, Matthews DR, Hermans MP. Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 1998; 21: 2191–2192.PubMedGoogle Scholar
  154. 152.
    Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1183–1197.Google Scholar
  155. 153.
    Scharp DW, Lacy PE, Weide LG, Marchetti P, McCullough CS, Flavin K, et al. Intraportal islet allografts: The use of a stimulation index to represent functional results. Transplant Proc 1991;23(1, pt 1):796–798. Published erratum appears in Transplant Proc 1991; 23 (5): 2702.Google Scholar
  156. 154.
    Alejandro R, Lehmann R, Ricordi C, Kenyon NS, Angelico MC, Burke G, et al. Long-term function (6 years) of islet allografts in type 1 diabetes. Diabetes 1997; 46: 1983–1989.PubMedGoogle Scholar
  157. 155.
    Teuscher AU, Kendall DM, Smets YF, Leone JP, Sutherland DE, Robertson RP. Successful islet autotransplantation in humans: Functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes 1998; 47: 324–330.PubMedGoogle Scholar
  158. 156.
    Bingley PJ, Colman P, Eisenbarth GS, Jackson R, McCulloch DK, Riley WJ, et al. Standardization of IVGTT to predict IDDM. Diabetes Care 1992; 15: 1313–1316.PubMedGoogle Scholar
  159. 157.
    Chase HP, Cuthbertson DD, Dolan LM, Kaufman F, Krischer JP, Schatz DA, et al. First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes. J Pediatr 2001; 138: 244–249.PubMedGoogle Scholar
  160. 158.
    Davalli AM, Maffi P, Socci C, Sanvito F, Freschi M, Bertuzzi F, et al. Insights from a successful case of intrahepatic islet transplantation into a type 1 diabetic patient. J Clin Endocrinol Metab 2000; 85: 3847–3852.PubMedGoogle Scholar
  161. 159.
    White SA, Koppiker NP, Burden AC, Davies MJ, Davies JE, Clayton HA, et al. Insulin deficiency and increased intact and 32/33 split proinsulin secretion following human islet auto-transplantation. Transplant Proc 1998; 30 (2): 627–628.PubMedGoogle Scholar
  162. 160.
    Luzi L, Hering BJ, Socci C, Raptis G, Battezzati A, Terruzzi I, et al. Metabolic effects of successful intraportal islet transplantation in insulin-dependent diabetes mellitus. J Clin Invest 1996; 97: 2611–2618.PubMedGoogle Scholar
  163. 161.
    Petruzzo P, Badet L, Lefrancois N, Laville M, Reintera R, Dubernard JM, et al. Insulin sensitivity and resistance in simultaneous pancreas kidney transplantation with portal or systemic venous drainage. Transplantation 2002; 74 (suppl 4): 81.Google Scholar
  164. 162.
    Jaeger C, Brendel M, Hering BJ, Eckhard M, Bretzel RG. Progressive islet graft failure occurs significantly earlier in autoantibody-positive than in autoantibody-negative IDDM recipients of intrahepatic islet allografts. Diabetes 1997; 46: 1907 1910.Google Scholar
  165. 163.
    Bosi E, Braghi S, Maffi P, Scirpoli M, Bertuzzi F, Pozza G, et al. Autoantibody response to islet transplantation in type 1 diabetes. Diabetes 2001; 50: 2464–2471.PubMedGoogle Scholar
  166. 164.
    Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Boyle PJ, et al. Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients. Transplantation 1991; 51: 76–85.PubMedGoogle Scholar
  167. 165.
    Gebauer BS, Hricik DE, Atallah A, Bryan K, Riley J, TaryLehmann M, et al. ELISPOT analysis of donor-reactive immunity posttransplantation as a clinically useful immune monitoring tool. Am J Transplant.Google Scholar
  168. 166.
    Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH. Infectious tolerance: Human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. Am J Transplant 2002; 2: 857–866.Google Scholar
  169. 167.
    Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 1–producing, contact-independent type 10–like [correction of type 1–like] regulatory T cells. J Exp Med 2002; 196: 247–253.PubMedGoogle Scholar
  170. 168.
    Vella JP, Spadafora-Ferreira M, Murphy B, Alexander SI, Harmon W, Carpenter CB, et al. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation 1997; 64: 795–800.PubMedGoogle Scholar
  171. 169.
    Vasconcellos L, Asher F, Schachter D, Zheng XX, Vasconcellos LHB, Shapiro M, Harmon WE, et al. Cytotoxic lymphocyte gene expression in peripheral blood leukocytes correlates with rejecting renal allografts. Transplantation 1998; 66: 562–566.PubMedGoogle Scholar
  172. 170.
    Han D, Xu X, Pastori RL, Ricordi C, Kenyon NS. Elevation of cytotoxic lymphocyte gene expression is predictive of islet allograft rejection in nonhuman primates. Diabetes 2002; 51: 562–566.PubMedGoogle Scholar
  173. 171.
    Nathan DG, Varmus HE. The National Institutes of Health and clinical research: A progress report. Nat Med 2000; 6: 1201 1204.Google Scholar
  174. 172.
    Morse MA, Califf RM, Sugarman J. Monitoring and ensuring safety during clinical research. JAMA 2001; 285: 1201–1205.Google Scholar
  175. 173.
    Burman WJ, Reyes RR, Cohn DL, Schooley RT. Breaking the camels back: Multicenter clinical trials and local institutional review boards. Ann Intern Med 2001; 134: 152–157.PubMedGoogle Scholar
  176. 174.
    Johnson PR, White SA, London NJ. Collagenase and human islet isolation. Cell Transplant 1996; 5: 437–452.Google Scholar
  177. 175.
    Rosenberg L, Wang R, Paraskevas S, Maysinger D. Structural and functional changes resulting from islet isolation lead to islet cell death. Surgery 1999; 126: 393–398.PubMedGoogle Scholar
  178. 176.
    Bottino R, Balamurugan AN, Bertera S, Pietropaolo M, Trucco M, Piganelli M. Preservation of human islet cell functional mass by anti-oxidative action of a novel SOD mimic compound. Diabetes 2002; 51: 2561–2567.PubMedGoogle Scholar
  179. 177.
    Gruessner AC, Sutherland DER. Analysis of United States (US) and non-US pancreas transplants reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of October 2001. In: Cecka MJ, Terasaki P, eds. Clinical Transplants 2001. Los Angeles: UCLA Immunogenetics Center, 2001: 41–72.Google Scholar
  180. 178.
    Hesse UJ, Sutherland DER, Gores PF, Najarian JS. Experience with 3, 6, and 24 hours of hypothermic storage of the canine pancreas before islet cell preparation and transplantation. Surgery 1987; 102: 460–464.Google Scholar
  181. 179.
    Munn SR, Kaufman DB, Field MJ, Viste AB, Sutherland DE. Cold-storage preservation of the canine and rat pancreas prior to islet isolation. Transplantation 1989; 47: 28–31.PubMedGoogle Scholar
  182. 180.
    Tanioka Y, Sutherland DE, Kuroda Y, Gilmore TR, Asaheim TC, Kronson JW, et al. Excellence of the two-layer method (University of Wisconsin solution/perfluorochemical) in pancreas preservation before islet isolation. Surgery 1997; 122: 435–441.PubMedGoogle Scholar
  183. 181.
    Kneteman NM, Lakey JRT, Warnock GL, Rajotte RV. Human islet isolation after prolonged cold storage. Diabetes Nutr Metab 1992; 5: 33–37.Google Scholar
  184. 182.
    Kneteman NM, Wagner T. Critical components of storage fluid for pancreas preservation before islet isolation. Transplant Proc 1992; 24 (6): 2824.Google Scholar
  185. 183.
    Robertson GS, Chadwick D, Thirdborough S, Swift S, Davies J, James R, et al. Human islet isolation-a prospective randomized comparison of pancreatic vascular perfusion with hyperosmolar citrate or University of Wisconsin solution. Transplantation 1993; 56: 550–553.PubMedGoogle Scholar
  186. 184.
    Ketchum RJ, Nicolae M, Jahr H, Friedman A, Naji A, Barker CF, et al. Analysis of donor age and cold ischemia time as factors in cadaveric human islet isolation. Transplant Proc 1994; 26 (2): 596–597.PubMedGoogle Scholar
  187. 185.
    Lakey JR, Rajotte RV, Warnock GL, Kneteman NM. Human pancreas preservation prior to islet isolation. Cold ischemic tolerance. Transplantation 1995; 59: 689–694.PubMedGoogle Scholar
  188. 186.
    Hiraoka K, Trexler A, Fujioka B, Guo Z, Zhang HJ, Overland A, et al. Optimal temperature in pancreas preservation by the two-layer cold storage method before islet isolation. Transplant Proc 2001; 33 (1/2): 891–892.PubMedGoogle Scholar
  189. 187.
    Bartlett ST, Chin T, Dirden B, Quereshi A, Hadley G. Inclusion of peripancreatic lymph node cells prevents recurrent autoimmune destruction of islet transplants: evidence of donor chimerism. Surgery 1995; 118: 392–397.PubMedGoogle Scholar
  190. 188.
    Stegall MD, Lafferty KJ, Kam I, Gill RG. Evidence of recurrent autoimmunity in human allogeneic islet transplantation. Transplantation 1996; 61: 1272–1274.PubMedGoogle Scholar
  191. 189.
    Terada M, Salzler M, Lennartz K, Mullen Y. The effect of H-2 compatibility on pancreatic beta cell survival in the nonobese diabetic mouse. Transplantation 1988; 45: 622–627.PubMedGoogle Scholar
  192. 190.
    Wang Y, McDuffie M, Nomikos IN, Hao L, Lafferty KJ. Ef-fect of cyclosporine on immunologically mediated diabetes in nonobese diabetic mice. Transplantation 1988; 46 (suppl 2): 101–106.Google Scholar
  193. 191.
    Stegall MD, Loberman Z, Ostrowska A, Coulombe M, Gill RG. Autoimmune destruction of islet grafts in the NOD mouse is resistant to 15–deoxyspergualin but sensitive to anti-CD4 anti body. J Surg Res 1996; 64: 156–160.PubMedGoogle Scholar
  194. 192.
    Bartlett ST, Schweitzer EJ, Kuo PC, Johnson LB, Delatorre A, Hadley, Hadley GA. Prevention of autoimmune islet allograft destruction by engraftment of donor T cells. Transplantation 1997; 63: 299–303.PubMedGoogle Scholar
  195. 193.
    Uchikoshi F, Yang ZD, Rostami S, Yokoi Y, Capocci P, Barker CF, et al. Prevention of autoimmune recurrence and rejection by adenovirus-mediated CTLA4Ig gene transfer to the pancre atic graft in the BB rat. Diabetes 1999; 48: 652–657.PubMedGoogle Scholar
  196. 194.
    Sibley RK, Sutherland DR, Goetz F, Micjael AF. Recurrent di-abetes mellitus in the pancreas iso-and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest 1985; 53: 132.PubMedGoogle Scholar
  197. 195.
    Lampeter EF, Homberg M, Quabeck K, et al. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation. Lancet 1993; 341: 1243.PubMedGoogle Scholar
  198. 196.
    Maki T, Ichikawa T, Blanco R, Porter J. Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum. Proc Natl Acad Sci USA 1992; 89: 3434–3438.PubMedGoogle Scholar
  199. 197.
    Keymeulen B, Ling Z, Gorus FK, Delvaux G, Bouwens L, Grupping A, et al. Implantation of standardized beta-cell grafts in a liver segment of IDDM patients: Graft and recipient characteristics in two cases of insulin-independence under mainte-nance immunosuppression for prior kidney graft. Diabetologia 1998; 41: 452–459.PubMedGoogle Scholar
  200. 198.
    Alegre ML, Peterson LJXD, Sattar HA, Jeyarajah DR,Kowalkowski K, Thistlethwaite JR, et al. A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 1994; 57: 1537–1543.PubMedGoogle Scholar
  201. 199.
    Alegre ML, Tso JY, Sattar HA, Smith J, Desalle F, Cole M, et al. An anti-murine CD3 monoclonal antibody with a low affinity for Fey receptors suppresses transplantation responses while minimizing acute toxcity and immunogenicity. J Immunol 1995; 155: 1544–1555.PubMedGoogle Scholar
  202. 200.
    Woodle ES, Xu D, Zivin RA, Auger J, Charette J, OLaughlin R, et al. Phase I trial of a humanized, Fe receptor nonbinding OKT2 antibody, huOKT3y,(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 1999; 68: 608–616.PubMedGoogle Scholar
  203. 201.
    Smith JA, Bluestone JA. T cell inactivation and cytokine deviation promoted by anti-CD3 mAbs. Curr Opin Immunol 1997; 9: 648–654.PubMedGoogle Scholar
  204. 202.
    Smith JA, Tso JY, Clark MR, Cole MS, Bluestone JA. Non mitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy. J Exp Med 1997; 185: 1413–1422.PubMedGoogle Scholar
  205. 203.
    Chatenoud L, Thervet E, Primo J, Bach JF. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobesediabetic mice. Proc Natl Acad Sci USA 1994; 91: 123–127.PubMedGoogle Scholar
  206. 204.
    Chatenoud L, Primo J, Bach JF. CD3 antibody-induced domi-nant self tolerance in overtly diabetic NOD mice. J Immunol 1997; 158: 2947–2954.PubMedGoogle Scholar
  207. 205.
    Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-on- set type 1 diabetes mellitus. N Engl J Med 2002; 346: 1692–1698.PubMedGoogle Scholar
  208. 206.Waldmann H, Polliak A, Hale G, Or R, Cividalli G, Weiss L, et al. Elimination of graft-versus-host disease by in-vitro de-pletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1). Lancet 1984; 2 (8401): 483–486.Google Scholar
  209. 207.
    Issacs JD, Greer S, Sharma S, Symmons D, Smith M, Johnston J, et al. Morbidity and mortality in rheumatoid arthritis patients with prolonged and profound therapy-induced lymphopenia. Arthritis Rheum 2001; 44: 1998–2008.Google Scholar
  210. 208.
    Naparstek E, Delukina M, Or R, Nagler A, Kapelushnik J, Varadi G, et al. Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies. Exp Hematol 1999; 27: 1210–1218.PubMedGoogle Scholar
  211. 209.
    Cull GM, Haynes AP, Byrne JL, Carter GI, Miflin G, Rebello P, et al. Preliminary experience of allogeneic stem cell trans-plantation for lymphoproliferative disorders using BEAM- CAMPATH conditioning: An effective regimen with low pro- cedure-related toxicity. Br J Haematol 2000; 108: 754–760.PubMedGoogle Scholar
  212. 210.
    Hale G, Jacobs P, Wood L, Fibbe WE, Barge R, Novitzky N, et al. CD52 antibodies for prevention of graft-versus-host dis-ease and graft rejection following transplantation of allogeneic peripheral blood stem cells. Bone Marrow Transplant 2000; 26: 69–76.PubMedGoogle Scholar
  213. 211.
    Lockwood CM, Thiru S, Isaacs JD, Hale G, Waldmann H. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 1993; 341 (8861): 1620–1622.PubMedGoogle Scholar
  214. 212.
    Coles M, Wing MG, Compston DA. Disease activity and the immune set in multiple sclerosis: Blood markers for im- munotherapy. Mult Scler 1998; 4: 232–238.PubMedGoogle Scholar
  215. 213.
    Lim SH, Hale G, Marcus RE, Waldmann H, Baglin TP. CAM-PATH-1 monoclonal antibody therapy in severe refractory au-toimmune thrombocytopenic purpura. Br J Haematol 1993; 84: 542–544.PubMedGoogle Scholar
  216. 214.
    Killick SB, Marsh JC, Hale G, Waldmann H, Kelly SJ, Gor-don-Smith EC. Sustained remission of severe resistant autoim-mune neutropenia with Campath-1H. Br J Haematol 1997; 97: 306–308.PubMedGoogle Scholar
  217. 215.
    Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Trans-plantation 1999; 68: 1613–1616.Google Scholar
  218. 216.
    Stuart FP, Leventhal JR, Kaufman DB, Stuart L, Abecassis M, Flyer JP, et al. Alemtuzumab (Campath-1H) facilitates pred-nisone free immunosuppression in kidney transplant recipients. Transplantation 2002; 74 (suppl): 121.Google Scholar
  219. 217.
    Knechtle SJ, Pirsch JD, Becker BN, Odorico JS, DAlessandro AM, Chin LT, et al. A pilot study of Campath-1H induction plus rapamycin monotherapy in renal transplantation. Trans-plantation 2002; 74 (suppl 4): 32–33.Google Scholar
  220. 218.
    Kirk AD, Swanson SJ, Mannon RB, Batty DS, Bernstein W, Brettman L, et al. Preliminary results from a human tolerance trial using Campath-1H. Am J Transplant 2001; 1 (suppl 1): 136–137.Google Scholar
  221. 219.
    Thomas JM, Neville DM, Contreras JL, Eckhoff DE, Meng G, Lobashevsky AL, et al. Preclinical studies of allograft tolerance in rhesus monkeys: A novel anti-CD3–immunotoxin given per-itransplant with donor bone marrow induces operational tolerance to kidney allografts. Transplantation 1997; 64: 124–135.PubMedGoogle Scholar
  222. 220.
    Contreras JL, Wang PX, Eckhoff DE, Lobashevsky AL, Asiedu C, Frenette L, et al. Peritransplant tolerance induction with antiCD3–immunotoxin: A matter of proinflammatory cytokine control. Transplantation 1998; 65: 1159–1169.PubMedGoogle Scholar
  223. 221.
    Knechtle SJ, Vargo D, Fechner J, Zhai Y, Wang J, Hanaway MJ, et al. FN18–CRM9 immunotoxin promotes tolerance in primate renal allografts. Transplantation 1997; 63: 1–6.PubMedGoogle Scholar
  224. 222.
    Contreras JL, Eckhoff DE, Cartner S, Frenette L, Thomas FT, Robbin ML, et al. Tolerability and side effects of anti-CD3–immunotoxin in preclinical testing in kidney and pancreatic islet transplant recipients. Transplantation 1999; 68: 215–219.PubMedGoogle Scholar
  225. 223.
    Thomas JM, Eckhoff DE, Contreras JL, Lobashevsky AL, Hubbard WJ, Moore JK, et al. Durable donor-specific T and B cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin: Absence of chronic allograft nephropathy. Transplantation 2000; 69: 2497 2503.Google Scholar
  226. 224.
    Thomas JM, Contreras JL, Jiang XL, Eckhoff DE, Wang PX, Hubbard WJ, et al. Peritransplant tolerance induction in macaques: Early events reflecting the unique synergy between immunotoxin and deoxyspergualin. Transplantation 1999; 68 (11): 1660–1673.PubMedGoogle Scholar
  227. 225.
    Thomas JM, Neville DM, Contreras JL, Eckhoff DE, Meng G, Lobashevsky AL, et al. Preclinical studies of allograft tolerance in rhesus monkeys: A novel anti-CD3–immunotoxin given peritransplant with donor bone marrow induces operational tolerance to kidney allografts. Transplantation 1997; 64: 124–135.PubMedGoogle Scholar
  228. 226.
    Hubbard WJ, Moore JK, Contreras JL, Smyth CA, Chen ZW, Lobashevsky AL, et al. Phenotypic and functional analysis of T-cell recovery after anti-CD3 immunotoxin treatment for tolerance induction in rhesus macaques. Hum Immunol 2001; 62: 479–487.PubMedGoogle Scholar
  229. 227.
    Thomas F, Contreras J, Ricordi C, Ranuneolia A, Cartner S, Eckhoff D, et al. Reversal of naturally occurring insulinopenic diabetes and induction of isolated islet xenograft tolerance in a preclinical study. Transplant Proc 1999; 31 (1/2): 637–638.PubMedGoogle Scholar
  230. 228.
    Contreras JL, Eckhoff DE, Cartner S, Bilbao G, Ricordi C, Neville DMJ, et al. Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. Transplantation 2000; 69: 195–201.PubMedGoogle Scholar
  231. 229.
    Fernandez LA, Lehmann R, Luzi L, Battezzati A, Angelico MC, Ricordi C, et al. The effects of maintenance doses of FK506 versus cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation. Transplantation 1999; 68: 1532 1541.Google Scholar
  232. 230.
    Morris RJ, Wang J, Blum MG, et al. Immunosuppressive effects of morpholinoethyl ester of mycophenolic acid (RS-61443) in rat and nonhuman primate recipients of heart allografts. Transplant Proc 1991; 23 (suppl 2): 19.PubMedGoogle Scholar
  233. 231.
    Platzer C, Bechstein WO, Eckhoff DE, Susuki Y, Sollinger HW. RS-61443 reverses acute rejection in dogs. Surgery 1991; 110: 736.Google Scholar
  234. 232.
    Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029.Google Scholar
  235. 233.
    Sievers TM, Rossi SJ, Ghobrial RM, et al. Mycophenolate mofetil. Pharmacotherapy 1997; 17: 1178.PubMedGoogle Scholar
  236. 234.
    Hodge EE. The role of mycophenolate mofetil in clinical renal transplantation. World J Surg 1996; 14: 249.Google Scholar
  237. 235.
    Vu MD, Qi S, Xu J, Wu J, Peng J, Daloze P, et al. Synergistic effects of mycophenolate mofetil and sirolimus in prevention of acute heart, pancreas, and kidney allograft rejection and in reversal of ongoing heart allograft rejection in the rat. Transplantation 1998; 66: 1575–1580.PubMedGoogle Scholar
  238. 236.
    Kreis H, Durand D, Land W, Wramner L, Squifflet JP, Abramowicz D, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252–1260.PubMedGoogle Scholar
  239. 237.
    Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS, et al. CTLA4–Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94: 8789–8794.PubMedGoogle Scholar
  240. 238.
    Levisetti MG, Padrid PA, Szot GL, Mittal N, Meehan SM, Wardrip CL, et al. Immunosuppressive effects of human CTLA41g in a non-human primate model of allogeneic pancreatic islet transplantation. J Immunol 1997; 59 (11): 5187–5191.Google Scholar
  241. 239.
    Adams AB, Shirasugi N, Durham MM, Strobert E, Anderson D, Rees P, et al. Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates. Diabetes 2002; 51: 265–270.PubMedGoogle Scholar
  242. 240.
    Kenyon NS, Chatzipetrou M, Masetti M, Ranuncoli A, Oliveira M, Wagner JL, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA 1999; 96: 8132–8137.PubMedGoogle Scholar
  243. 241.
    Wijkstrom M, Kirchhof N, Harmon JV, Clemmings SM, Hardstedt M, Gebauer BS, et al. Effect of combined immunotherapy and pretransplant donor splenocyte transfusion on islet allograft survival in nonhuman primates. Unpublished.Google Scholar
  244. 242.
    Kenyon NS, Fernandez LA, Lehmann R, Masetti M, Ranuncoli A, Chatzipetrou M, et al. Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154. Diabetes 1999; 48: 1473–1481.PubMedGoogle Scholar
  245. 243.
    Brams P, Black A, Padlan EA, Hariharan K, Leonard J, Chambers-Slater K, et al. A humanized anti-human CD154 monoclonal antibody blocks CD154–CD40 mediated human B cell activation. Int Immunopharmacol 2001; 1 (2): 277–294.PubMedGoogle Scholar
  246. 244.
    Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine 1–phosphate receptors. J Biol Chem 2002; 277: 21453–21457.PubMedGoogle Scholar
  247. 245.
    Dragun D, Bohler T, Waiser J, et al. Pretreatment with FTY720 protects renal allografts against preservation-reperfusion injury. Transplantation 2000; 69: S127.Google Scholar
  248. 246.
    Brinkmann V, Pinschewer DD, Feng L, Chen S. FTY720: Altered lymphocyte traffic results in allograft protection. Transplantation 2001; 72: 764–769.PubMedGoogle Scholar
  249. 247.
    Fu F, Hu S, DeLeo J, Li S, Hopf C, Hoover J, et al. Longterm islet graft survival in streptozocin-and autoimmune-induced diabetes models by immunosuppressive and potential insulino-tropic agent FTY720. Transplantation 2002; 73: 1425–1430.PubMedGoogle Scholar
  250. 248.
    Ferguson RM, Mulgaonkar S, Tedesco H, Oppenheimer F, Walker R, Kunzendor U, et al. FTY720 with reduced-exposure Neoral provides adequate rejection prophylaxis in de novo renal transplant recipients. Interim results. Transplantation 2002; 74 (suppl 4): 34.Google Scholar
  251. 249.
    Wijkstrom M, Kenyon NS, Kirchhof N, Kenyon N, Mullon C, Lake P, et al. Insulin independence and rejection-free allograft survival in nonhuman primate allograft recipients immunosup-pressed with basiliximab, RAD001, and FTY720. Am J Transplant 2002; 2 (suppl 3): 362.Google Scholar
  252. 250.
    Kenyon NS, Wijkstrom M, Kirchhof N, Kenyon NM, Mullon C, Lake P, et al. Development of a non-human primate mar ginal mass model and preliminary demonstrations of enhanced metabolic control in allogeneic islet recipients treated with TP10 and immunosuppressed with basiliximab, RAD001, and FTY720. Am J Transplant 2002; 2 (suppl 3): 362.Google Scholar
  253. 251.
    Preiksaitis JK, Lakey JRT, LeBlanc BA, Fenton JM, Ryan EA, Bigam DL, et al. Cytomegalovirus (CMV) is not transmitted by pancreatic islet transplantation. Am J Transplant 2002; 2 (suppl 3): 308.Google Scholar
  254. 252.
    Jamil B, Nicholls K, Becker GJ, Walker RG. Impact of acute rejection therapy on infections and malignancies in renal trans plant recipients. Transplantation 1999; 68: 1597–1603.PubMedGoogle Scholar
  255. 253.
    Stratta RJ, Cushing KA, Frisbie K, Miller SA. Analysis of hospital charges after simultaneous pancreas-kidney transplanta tion in the era of managed care. Transplantation 1997; 64: 287–292.PubMedGoogle Scholar
  256. 254.
    Auchincloss H Jr. In search of the elusive Holy Grail: The mechanisms and prospects for achieving clinical transplanta tion tolerance. Am J Transplant 2001; 1: 6–12.PubMedGoogle Scholar
  257. 255.
    Kirk AD, Harlan DM. Challenges for the clinical application of transplant tolerance strategies. Curr Organ Transplant 2000; 5: 108–113.Google Scholar
  258. 256.
    Li XC, Strom TB, Turka LA, Wells AD. T cell death and trans plantation tolerance. Immunity 2001; 14: 407–416.PubMedGoogle Scholar
  259. 257.
    Sachs DH. Mixed chimerism as an approach to transplantation tolerance. Clin Immunol 2000; 95: S63.PubMedGoogle Scholar
  260. 258.
    Ikehara S. Bone marrow transplantation for autoimmune dis eases. Acta Haematol 1998; 99: 116–132.PubMedGoogle Scholar
  261. 259.
    Seung E, Iwakoshi N, Woda N, Markees TG, Mordes JP,Rossini AA, 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-al lografted NOD/Lt mice. Blood 2000; 95: 2175–2182.PubMedGoogle Scholar
  262. 260.
    McSweeney PA, Storb R. Mixed chimerism: Preclinical stud ies and clinical applications. Biol Blood Marrow Transplant 1999; 5: 192–203.PubMedGoogle Scholar
  263. 261.
    McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina M, Maloney DG, et al. Hematopoietic cell transplan- tation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor ef-fects. Blood 2001; 97: 3390–3400.PubMedGoogle Scholar
  264. 262.
    Ildstad ST, Sachs DH. Reconstitution with syngeneic plus al logeneic or xenogeneic bone marrow leads to specific ac ceptance of allografts or xenografts. Nature 1984; 307 (5947): 168.PubMedGoogle Scholar
  265. 263.
    Sharabi Y, Sachs DH. Mixed chimerism and permanent spe cific transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med 1989; 169: 493.PubMedGoogle Scholar
  266. 264.
    Huang CA, Fuchimoto Y, Scheier-Dolberg R, Murphy MC, Neville DMJ, Sachs DH. Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large animal model. J Clin Invest 2000; 105: 173.PubMedGoogle Scholar
  267. 265.
    Kawai T, Cosimi B, Colvin R, Powelson J, Eason J, Kozlowski T, et al. Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation 1995; 59: 256–262.PubMedGoogle Scholar
  268. 266.
    Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Buhlman J, Xu J, Flavell RA, et al. Blockade of CD40 ligand-CD40 interac-tion impairs CD4+ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation J Immunol 1997; 158: 29–39.Google Scholar
  269. 267.
    Wekerle T, Sayegh MH, Hill J, Zhao Y, Chandraker A, Swen-son KG, et al. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is fol-lowed by center T cell tolerance. J Exp Med 1998; 187: 2037–2044.PubMedGoogle Scholar
  270. 268.
    Wekerle T, Sayegh MH, Ito H, Hill J, Chandraker A, Pearson DA, et al. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and toler-ance. Transplantation 1999; 68: 1348–1355.PubMedGoogle Scholar
  271. 269.
    Taylor PA, Lees CJ, Waldmann H, Noelle RJ, Blazar BR. Re-quirements for the promotion of allogeneic engraftment by anti-CD154 (anti-CD40L) monoclonal antibody under nonmye-loablative conditions. Blood 2001; 98: 467–474.PubMedGoogle Scholar
  272. 270.
    Durham MM, Bingaman AW, Adams AB, Ha J, Waitze SY, Pearson TC, et al. Cutting edge: Administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive condition-ing. J Immunol 2000; 165: 1–4.PubMedGoogle Scholar
  273. 271.
    Quesenberry PJ, Zhong S, Wang H, Stewart M. Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice. Blood 2001; 97 (2): 557–564.PubMedGoogle Scholar
  274. 272.
    Adams AB, Durham MM, Kean L, Shirasugi N, Ha J, Williams MA, et al. Costimulation blockade, busulfan, and bone marrow promote titratable macrochimerism, induce transplantation tol-erance, and correct genetic hemoglobinopathies with minimal myelosuppression. J Immunol 2001; 167 (2): 1103–1111.PubMedGoogle Scholar
  275. 273.
    Blazar BR, Taylor PA, Sehgal SN, Vallera DA. Rapamycin, a potent inhibitor of T-cell function, prevents graft rejection in murine recipients of allogeneic T-cell-depleted donor marrow. Blood 1994; 83 (2): 600–609.PubMedGoogle Scholar
  276. 274.
    Hale DA, Gottschalk R, Fukuzaki T, Wood ML, Maki T, Monaco AP. Superiority of sirolimus (rapamycin) over cy-closporine in augmenting allograft and xenograft survival in mice treated with antilymphocyte serum and donor-specific bone marrow. Transplantation 1997; 63: 359–364.PubMedGoogle Scholar
  277. 275.
    Wekerle T, Sykes M. Mixed chimerism and transplantation tol-erance. Annu Rev Med 2001; 52: 353–370.PubMedGoogle Scholar
  278. 276.
    Wekerle T, Kurtz J, Sayegh M, Ito H, Wells A, Bensinger S, et al. Peripheral deletion after bone marrow transplantation with cos-timulatory blockade has features of both activation-induced cell death and passive cell death. J Immunol 2001; 166: 2311–2316.PubMedGoogle Scholar
  279. 277.
    Taylor PA, Noelle RJ, Blazar BR. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to al-loantigen via costimulatory blockade. J Exp Med 2001; 193: 1311–1318.PubMedGoogle Scholar
  280. 278.
    Kawai T, Sogawa H, Koulmanda M, Smith RN, ONeil JJ, Wee SL, et al. Long-term islet allograft function in the absence of chronic immunosuppression: A case report of a nonhuman pri-mate previously made tolerant to a renal allograft from the same donor. Transplantation 2001; 72: 351–354.PubMedGoogle Scholar
  281. 279.
    Kenyon NS, Yu C, Kenyon NM, Storb R, Ricordi C. Accep-tance of DLA matched allogeneic islets in the absence of immunosuppression in dogs with stable hematopoietic chimerism. Acta Chirurgica Austriaca 2001; 33 (suppl 174): 51.Google Scholar
  282. 280.
    Wekerle T, Kurtz J, Ito H, et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000; 6: 464.PubMedGoogle Scholar
  283. 281.
    Durham MM, Bingaman AW, Adams AB, Ha J, Waitze SY, Pearson TC, et al. Cutting edge: Administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning J Immunol 2000; 165: 1–4.Google Scholar
  284. 282.
    Fuchimoto Y, Huang CA, Yamada K, Shimizu A, Kitamura H, Colvin RB, et al. Mixed chimerism and tolerance without whole body irradiation in a large animal model. J Clin Invest 2000; 105: 1779–1789.PubMedGoogle Scholar
  285. 283.
    Reich-Zeliger S, Zhao Y, Krauthgamer R, Bachar-Lustig E, Reisner Y. Anti-third party CD8+ CTLs as potent veto cells: Coexpression of CD8 and FasL is a prerequisite. Immunity 2000; 13: 507–515.Google Scholar
  286. 284.
    Rachamim N, Gan J, Segall H, Krauthgamer R, Marcus H, Berrebi A, et al. Tolerance induction by “megadose” hematopoietic transplants: Donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation 1998; 65: 1386–1393.PubMedGoogle Scholar
  287. 285.
    Reisner Y, Martelli MF. Transplantation tolerance induced by “mega dose” CD34+ cell transplants. Exp Hematol 2000; 28: 119–127.PubMedGoogle Scholar
  288. 286.
    Fandrich F, Lin X, Chai GX, Schulze M, Ganten D, Bader M, et al. Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning. Nat Med 2002; 8: 171–178.PubMedGoogle Scholar
  289. 287.
    Lim F, Sun AM. Microencapsulated islets as bioartificial endocrine pancreas. Science 1980; 210 (4472): 908–910.PubMedGoogle Scholar
  290. 288.
    Colton CK. Implantable biohybrid artificial organs. Cell Transplant 1995; 4: 415–436.PubMedGoogle Scholar
  291. 289.
    Lanza RP, Chick WL. Transplantation of pancreatic islets. Ann NY Acad Sci 1997; 831: 323–331.PubMedGoogle Scholar
  292. 290.
    de Vos P, Hamel AF, Tatarkiewicz K. Considerations for successful transplantation of encapsulated pancreatic islets. Diabetologia 2002; 45: 159–173.PubMedGoogle Scholar
  293. 291.
    OShea GM, Goosen MF, Sun AM. Prolonged survival of transplanted islets of Langerhans encapsulated in a biocompatible membrane. Biochim Biophys Acta 1984; 804: 133–136.Google Scholar
  294. 292.
    Lacy PE, Hegre OD, Gerasimidi-Vazeou A, Gentile FT, Dionne KE. Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets. Science 1991; 254 (5039): 1782–1784.PubMedGoogle Scholar
  295. 293.
    ArRajab A, Bengmark S, Ahren B. Insulin secretion in streptozocin-diabetic rats transplanted with immunoisolated islets. Transplantation 1991; 51: 570–574.Google Scholar
  296. 294.
    Sun YL, Ma X, Zhou D, Vacek I, Sun AM. Porcine pancreatic islets: isolation, microencapsulation, and xenotransplantation. Artif Organs 1993; 17: 727–733.PubMedGoogle Scholar
  297. 295.
    Lanza RP, Jackson R, Sullivan A, Ringeling J, McGrath C, Kuhtreiber W, et al. Xenotransplantation of cells using biodegradable microcapsules. Transplantation 1999; 67: 1105 1111.Google Scholar
  298. 296.
    Weber CJ, Hagler MK, Chryssochoos JT, Kapp JA, Korbutt GS, Rajotte RV, et al. CTLA4–Ig prolongs survival of microencapsulated neonatal porcine islet xenografts in diabetic NOD mice. Cell Transplant 1997; 6: 505–508.PubMedGoogle Scholar
  299. 297.
    Duvivier-Kali VF, Omer A, Parent RJ, ONeil JJ, Weir GC. Complete protection of islets against allorejection and autoimmunity by a simple barium-alginate membrane. Diabetes 2001; 50: 1698–1705.PubMedGoogle Scholar
  300. 298.
    Maki T, Lodge JP, Carretta M, Ohzato H, Borland KM, Sullivan SJ, et al. Treatment of severe diabetes mellitus for more than one year using a vascularized hybrid artificial pancreas. Transplantation 1993; 55: 713–717.PubMedGoogle Scholar
  301. 299.
    Sun Y, Ma X, Zhou D, Vacek I, Sun AM. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J Clin Invest 1996; 98: 1417–1422.PubMedGoogle Scholar
  302. 300.
    Soon-Shiong P, Feldman E, Nelson R, Komtebedde J, Smids-rod O, Skjak-Braek G, et al. Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets. Transplantation 1992; 54: 769–774.PubMedGoogle Scholar
  303. 301.
    Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, et al. Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 1994; 343 (8903): 950–951.PubMedGoogle Scholar
  304. 302.
    Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418 (6893): 41–49.PubMedGoogle Scholar
  305. 303.
    Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, et al. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000; 97: 79998004.Google Scholar
  306. 304.
    Newgard CB, Clark S, Beltrandelrio H, Hohmeier HE, Quaade C, Normington K. Engineered cell lines for insulin replacement in diabetes-current status and future prospects. Diabetologia 1997; 40 (suppl 2): 42–47.Google Scholar
  307. 305.
    Efrat S. Cell replacement therapy for type 1 diabetes. Trends Mol Med 2002; 8 (7): 334–340.PubMedGoogle Scholar
  308. 306.
    Hering BJ. Islet xenotransplantation. In: Ricordi C, ed. Pancreatic Islet Transplantation: 1892–1992: One Century of Transplantation for Diabetes. Austin, TX: R.G. Landes Co; 1992: 313–335.Google Scholar
  309. 307.
    Kirchhof N, Matsumoto S, Shibata S, Hiraoka K, Sageshima J, Zhang XW, et al. Immediate reversal of diabetes in primates following intraportal transplantation of porcine islets purified on a new histidine-lactobionate-iodixanol gradient. Transplantation 1999; 67: 5220.Google Scholar
  310. 308.
    Wijkstrom M, Kirchhof N, Pilon KJ, Kandaswamy R, Clemmings S, Trexler A, et al. Xenogeneic pig islets escape rejection in immunosuppressed primates but fail to sustain normoglycemia. Am J Transplant 2001; 1: 153.Google Scholar
  311. 309.
    Mandel TE, Koulmanda M, Cozzi E, Waterworth P, Tolan M, Langford G, et al. Transplantation of normal and DAF-transgenic fetal pig pancreas into cynomolgus monkeys. Transplant Proc 1997; 29 (1/2): 940.PubMedGoogle Scholar
  312. 310.
    Mandel TE. Fetal islet xenotransplantation in rodents and primates. J Mol Med 1999; 77: 155–160.PubMedGoogle Scholar
  313. 311.
    Rijkelijkhuizen JKRA, Ossevort M, Ringers J, van der Burg MP, Kuhn EM, Wubben J, et al. Xenografting of pig islets in monkeys does not result in hyperacute rejection. Transplant Proc 2000; 32: 1064.PubMedGoogle Scholar
  314. 312.
    Korsgren O. Acute cellular xenograft rejection. Xenotrans plantation 1997; 4: 11–19.Google Scholar
  315. 313.
    Lalain S, Chaillous L, Gouin E, Sai P. Intensity and mechanisms of in vitro xenorecognition of adult pig pancreatic islet cells by CD4+ and CD8+ lymphocytes from type 1 diabetic or healthy subjects. Diabetologia 1999; 42: 330–335.PubMedGoogle Scholar
  316. 314.
    Olack BJ, Manna P, Jaramillo A, Steward N, Swanson C, Kaes-berg K, et al. Indirect recognition of porcine swine leucocyte Ag class I molecules expressed on islets by human CD4+T lymphocytes. J Immunol 2000; 165: 1294–1299.PubMedGoogle Scholar
  317. 315.
    Krook H, Hagberg A, Song Z, Landegren U, Wennberg L, Korsgren O. A distinct Thl immune response precedes the de scribed Th2 response in islet xenograft rejection. Diabetes 2002; 51: 79–86.PubMedGoogle Scholar
  318. 316.
    Soderlund J, Wennberg L, Castanos-Velez E, Biberfeld P, Zhu S, Tibell A, et al. Fetal porcine islet-like cell clusters trans planted to cynomolgus monkeys: An immunohistochemical study. Transplantation 1999; 67: 784–791.PubMedGoogle Scholar
  319. 317.
    Shishido S, Naziruddin B, Howard T, Mohanakumar T. Recognition of porcine major histocompatibility complex class I antigens by human CD8+ cytolytic T cell clones. Transplantation 1997; 64: 340–346.PubMedGoogle Scholar
  320. 318.
    Friedman T, Shimizu A, Smith RN, Colvin RB, Seebach JD, Sachs DH, et al Human CD4+ T cells mediate rejection of porcine xenografts. J Immunol 1999; 162: 5256–5262.PubMedGoogle Scholar
  321. 319.
    Yi S, Feng X, Hawthorne W, Patel A, Walters S, O’Connell PJ. CD8+ T cells are capable of rejecting pancreatic islet xenografts. Transplantation 2000; 70: 896–906.PubMedGoogle Scholar
  322. 320.
    Oldmixon BA, Wood JC, Ericsson TA, Wilson CA, White-Scharf ME, Andersson G, et al. Porcine endogenous retrovirus transmission characteristics of an inbred herd of miniature swine. J Virol 2002; 76: 3045–3048.PubMedGoogle Scholar
  323. 321.
    van der Laan LJ, Lockey C, Griffeth BC, Frasier FS, Wilson CA, Onions DE, et al. Infection by porcine endogenous retro-virus after islet xenotransplantation in SCID mice. Nature 2000; 407 (6800): 90–94.PubMedGoogle Scholar
  324. 322.
    Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. Science 1999; 285 (5431): 1236–1241.PubMedGoogle Scholar
  325. 323.
    Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001; 292 (5520): 1389–1394.PubMedGoogle Scholar
  326. 324.
    Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, Tzukerman M. Insulin production by human embryonic stem cells. Diabetes 2001; 50: 1691–1697.PubMedGoogle Scholar
  327. 325.
    Bonner-Weir S, Sharma A. Pancreatic stem cells. J Pathol 2002; 197: 519–526.PubMedGoogle Scholar
  328. 326.
    Beattie GM, Itkin-Ansari P, Cirulli V, Leibowitz G, Lopez AD, Bossie S, et al. Sustained proliferation of PDX-1+ cells de rived from human islets. Diabetes 1999; 48: 1013–1019.PubMedGoogle Scholar
  329. 327.
    Zulewski H, Abraham EJ, Gerlach MJ, Daniel PB, Moritz W,Muller B, et al. Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pan-creatic endocrine, exocrine, and hepatic phenotypes. Diabetes 2001; 50: 521–533.PubMedGoogle Scholar
  330. 328.
    Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF. Insulinotropic hormone glucagon-like peptide-1 differentia-tion of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology 2002; 143: 3152–3161.PubMedGoogle Scholar
  331. 329.
    Guz Y, Nasir I, Teitelman G Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes. Endocrinology 2001; 142: 4956–4968.PubMedGoogle Scholar
  332. 330.
    Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cor-nelius JG. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat Med 2000; 6: 278–282.PubMedGoogle Scholar
  333. 331.
    Gu D, Sarvetnick N. Epithelial cell proliferation and islet neo-genesis in IFN-g transgenic mice. Development 1993; 118: 33–46.PubMedGoogle Scholar
  334. 332.
    Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291–1302.PubMedGoogle Scholar
  335. 333.
    Efrat S, Fusco-DeMane D, Lemberg H, Emran OA, Wang S. Conditional transformation of a pancreatic beta cell line derived from transgenic mice expressing a tetracycline-regulated onco-gene. Proc Natl Acad Sci USA 1995; 92: 3576–3580.PubMedGoogle Scholar
  336. 334.
    Simpson AM, Marshall GM, Tuch BE, Maxwell L, Szyman- ska B, Tu J, et al. Gene therapy of diabetes: Glucose-stimu- lated insulin secretion in a human hepatoma cell line (HEP G2ins/g) Gene Ther 1997; 4: 1202–1215.Google Scholar
  337. 335.
    Najarian JS, Sutherland DE, Matas AJ, Steffes MW, Simmons RL, Goetz FC, et al. Human islet transplantation: A prelimi-nary report. Transplant Proc 1977; 9 (1): 233–236.PubMedGoogle Scholar
  338. 336.
    Sutherland DE, Matas AJ, Goetz FC, Najarian JS. Transplan-tation of dispersed pancreatic islet tissue in humans: Autografts and allografts. Diabetes 1980; 29 (suppl 1): 31–44.PubMedGoogle Scholar
  339. 337.
    Largiader F, Kolb E, Binswanger U. A long-term functioning human pancreatic islet allotransplant. Transplantation 1980; 29: 76–77.PubMedGoogle Scholar
  340. 338.
    Valente U, Ferro M, Campisi C, Parodi F, Tosatti E. Allogeneic pancreatic islet transplantation by means of artificial membrane chambers in 13 diabetic recipients. Transplant Proc 1980; 12 (4, suppl 2): 223–226.PubMedGoogle Scholar
  341. 339.
    Gores PF, Najarian JS, Sutherland DR. Clinical islet allotrans-lantation-the University of Minnesota experience. In: Ri-cordi C, ed. Pancreatic Islet Cell Transplantation. Austin, TX: R.G. Landes, Co; 1992: 423–433.Google Scholar
  342. 340.
    Toledo-Pereyra LH. Practical immunologic aspects of clinical pancreas and islet cell transplantation. Dialy Transplant 1986; 15: 514–522.Google Scholar
  343. 341.
    Alejandro R, Latif Z, Noel J, Shienvold FL, Mintz DH. Ef-fect of anti-Ia antibodies, culture, and cyclosporin on pro-longation of canine islet allograft survival. Diabetes 1987; 36: 269–273.PubMedGoogle Scholar
  344. 342.
    Altman JJ, Cugnenc PH, Tessier C, Capeau J, Adam R, Bis- muth H, et al. Epiploic flap: A new site for islet implantation in man. Hormone Metab Res 1990; 25 (suppl): 136–137.Google Scholar
  345. 343.
    Altman JJ, Tessier C, Bethoux JP, Cugnenc PH, Legrelle M, Journois D, et al. Human islet cotransplantation with liver or kidney. Transplant Proc 1992; 24 (3): 967–968.PubMedGoogle Scholar
  346. 344.
    Warnock GL, Kneteman NM, Ryan EA, Evans MG, Seelis RE, Halloran PF, et al. Continued function of pancreatic islets af- ter transplantation in type I diabetes. Lancet 1989; 2 (8662): 570–572.PubMedGoogle Scholar
  347. 345.
    Ricordi C, Tzakis A, Carroll P, Zeng Y, Rilo HL, Alejandro R, et al. Human islet allotransplantation under FK 506. Transplant Proc 1991; 23 (6): 3207.PubMedGoogle Scholar
  348. 346.
    London NJM, Robertson GSM, Chadwick DR. Purification of human pancreatic islets by large-scale continuous density gradient centrifugation. Hormone Metab Res 1993; 25: 61.Google Scholar
  349. 347.
    London NJM, James RFL, Robertson GM, Chadwick D, Feehlay J, Burden F, et al. Human islet transplantation: The Leicester experience. In: Ricordi C, ed. Pancreatic Islet Transplantation: 1892–1992: One Century of Transplantation for Diabetes. Austin, TX: R.G. Landes Co; 1992: 454–461.Google Scholar
  350. 348.
    Brunicardi FC, Atiya A, Stock P, Kenmochi T, Une S, Benhamou PY, et al. Clinical islet transplantation experience of the University of California Islet Transplant Consortium. Surgery 1995; 118: 967–971.PubMedGoogle Scholar
  351. 349.
    Arias-Diaz J, Vara E, Balibrea JL, Garcia C, Maranes A, Diaz A, et al. CT-guided fine-needle approach for intrathymic islet transplantation in a diabetic patient. Pancreas 1996; 12: 100102.Google Scholar
  352. 350.
    Fontes P, Rao AS, Demetris AJ, Zeevi A, Trucco M, Carroll P, et al. Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation. Lancet 1994; 344 (8916): 151–155.PubMedGoogle Scholar
  353. 351.
    Linetsky E, Selvaggi G, Bottino R, Kong SS, Qian T, Alejandro R, et al. Comparison of collagenase type P and Liberase during human islet isolation using the automated method. Transplant Proc 1995; 27 (6): 3264.PubMedGoogle Scholar
  354. 352.
    Birkeland SA, Beck-Nielsen H, Rohr N, Socci C, Christensen J, Dieperink H, et al. Islet and kidney transplantation using ATG and cyclosporin monotherapy and a central facility for islet isolation and purification. Transplant Proc 1995; 27 (6): 3150–3157.PubMedGoogle Scholar
  355. 353.
    Rastellini C, Shapiro R, Corry R, Fung JJ, Starzl TE, Rao AS. An attempt to reverse diabetes by delayed islet cell transplantation in humans. Transplant Proc 1997; 29 (4): 2238–2239.PubMedGoogle Scholar
  356. 354.
    Leone JP, Kendall DM, Reinsmoen N, Hering BJ, Sutherland DR. Immediate insulin-independence after retransplantation of islets prepared from an allograft pancreatectomy in a type 1 diabetic patient. Transplant Proc 1998; 30: 319.PubMedGoogle Scholar
  357. 355.
    London NJM. Clinical studies of human islet transplantation. Ann Roy Coll Surg Engl 1995;77:263–269. Comments.Google Scholar
  358. 356.
    Brendel MD, Eckhard M, Brandhorst D, Brandhorst H, Bretzel RG. Clinical islet transplantation after allogeneic orthotopic liver transplantation. Transplant Proc 1998; 30: 309–311.PubMedGoogle Scholar
  359. 357.
    Maffi P, Aldrighetti L, Nano R, Socci C, Guiducci D, Salvioni M, et al. Human islet allotransplantation in the cure of type 1 diabetes: 11 years experience. Acta Chirurgica Austriaca 2001; 33 (suppl 174): 30.Google Scholar
  360. 358.
    Alejandro R, Caulfield AM, Froud T, Ferreira JV, Rothenberg LC, al-Abdullah IH, et al. Solitary islet cell transplantation from a single donor for patients with type 1 diabetes and hypoglycemia unawareness. Acta Chir Austriaca 2001; 33 (suppl 174): 30.Google Scholar
  361. 359.
    Matsumoto S, Rigley T, Marsh CL, Strong DM, Stevens RB. Inhibition of trypsin activity during islet isolation improves islet yields from human and non-human pancreata. Acta Chir Austriaca 2001; 33 (suppl 174): 33.Google Scholar
  362. 360.
    Lakey JR, Helms LM, Kin T, Korbutt GS, Rajotte RV, Shapiro AM, et al. Serine-protease inhibition during islet isolation increases islet yield from human pancreases with prolonged ischemia. Transplantation 2001; 72 (4): 565–570.PubMedGoogle Scholar
  363. 361.
    Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hypoglycemia in adults with IDDM. Diabetes Care 1995; 18: 517–528.PubMedGoogle Scholar
  364. 362.
    Gray DW, Gohde W, Carter N, Heiden T, Morris PJ. Separation of pancreatic islets by fluorescence-activated sorting. Diabetes 1989; 38 (suppl 1): 133–135.PubMedGoogle Scholar
  365. 363.
    Lacy PE, Davie JM, Finke EH, Scharp DW. Prolongation of islet allograft survival. Transplantation 1979; 27: 171–174.PubMedGoogle Scholar
  366. 364.
    Nash JR, Everson NW, Wood RF, Bell PR. Effect of silica and carrageenan on the survival of islet allografts. Transplantation 1980; 29 (3): 206–208.PubMedGoogle Scholar
  367. 365.
    Kaufman DB, Platt JL, Rabe FL, Dunn DL, Bach FH, Sutherland DE. Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts. J Exp Med 1990; 172: 291–302.PubMedGoogle Scholar
  368. 366.
    Nomikos IN, Prowse SJ, Carotenuto P, Lafferty KJ. Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice. Diabetes 1986; 35: 1302 1304.Google Scholar
  369. 367.
    Sandler S, Andersson A. Stimulation of cell replication in transplanted pancreatic islets by nicotinamide treatment. Transplantation 1988; 46: 30–31.PubMedGoogle Scholar
  370. 368.
    Ueki M, Yasunami Y, Motoyama K, Funakoshi A, Ikeda S, Tanaka M. The amelioration of hyperglycemia in streptozocininduced diabetic rats after the intraportal transplantation of an insufficient number of islets by nicotinamide treatment. Transplantation 1995; 60: 313–317.PubMedGoogle Scholar
  371. 369.
    Shibata S, Matsumoto S, Sageshima J, Hiraoka K, Sutherland DER, Kirchhof N, 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.PubMedGoogle Scholar
  372. 370.
    Bradley B, Prowse SJ, Bauling P, Lafferty KJ. Desferrioxamine treatment prevents chronic islet allograft damage. Diabetes 1986; 35: 550–555.PubMedGoogle Scholar
  373. 371.
    Shin SJ, Taniguchi H, Hara Y, Ejiri K, Morimoto Y, Yamashiro Y, et al. Effect of dimethylthiourea on syngeneic rodent islet transplantation. Diabetes Res Clin Pract 1989; 6 (3): 167–171.PubMedGoogle Scholar
  374. 372.
    Kaufman DB, Field MJ, Gruber SA, Farney AC, Stephanian E, Gores PF, et al. Extended functional survival of murine islet allografts with 15–deoxyspergualin. Transplant Proc 1992; 24 (3): 1045–1047.PubMedGoogle Scholar
  375. 373.
    Sandberg JO, Eizirik DL, Sandler S, Tracey DE, Andersson A. Treatment with an interleukin-1 receptor antagonist protein prolongs mouse islet allograft survival. Diabetes 1993; 42: 1845 1851.Google Scholar
  376. 374.
    Farney AC, Xenos E, Sutherland DE, Widmer M, Stephanian E, Field MJ, 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): 865–866.PubMedGoogle Scholar
  377. 375.
    Marquet RL, Bonthuis F, van Ijken M, Bouwman E, Wolvekamp MC, Van Rooijen N, et al. Primary nonfunction of islet xenografts: The role of macrophages. Transplant Int 1994; 7 (suppl 1): S660–S662.Google Scholar
  378. 376.
    Xenos ES, Stevens RB, Sutherland DE, Lokeh A, Ansite JD, Casanova D, et al. The role of nitric oxide in IL-1 beta-mediated dysfunction of rodent islets of Langerhans. Implications for the function of intrahepatic islet grafts. Transplantation 1994; 57: 1208–1212.PubMedGoogle Scholar
  379. 377.
    Marquet RL, Bouwman E, Bonthuis F, Wolvekamp MC, Kouwenhoven E, van Rooijen N, et al. Local immunologic fac tors determine the occurrence of primary nonfunction of islet xenografts. Transplant Proc 1994; 26 (2): 766–767.PubMedGoogle Scholar
  380. 378.
    Bottino R, Fernandez LA, Ricordi C, Lehmann R, Tsan MF, Oliver R, et al. Transplantation of allogeneic islets of Langer-hans in the rat liver-effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 1998; 47: 316–323.PubMedGoogle Scholar
  381. 379.
    Faust A, Rothe H, Schade U, Lampeter E, Kolb H. Primary nonfunction of islet grafts in autoimmune diabetic nonobese diabetic mice is prevented by treatment with interleukin-4 and interleukin-10. Transplantation 1996; 62: 648–652.PubMedGoogle Scholar
  382. 380.
    Arita S, Saul J, Joh S, Kasraie A, Atiya A, Une S, et al. Islet protective effect of pravastatin from nonspecific inflammation in mouse pancreatic islet isografts. Transplant Proc 1996; 28 (2): 924.PubMedGoogle Scholar
  383. 381.
    Bleich D, Chen S, Bursten SL, Nadler JL. Lisofylline, an in hibitor of unsaturated phosphatidic acid generation, amelioratesinterleukin-1 beta-induced dysfunction in cultured rat islets. En-docrinology 1996; 137: 4871–4877.Google Scholar
  384. 382.
    Jansen A, Rosmalen JG, Homo-Delarche F, Dardenne M, Drex hage HA. Effect of prophylactic insulin treatment on the num ber of ER-MP23 + macrophages in the pancreas of NOD mice.Is the prevention of diabetes based on beta-cell rest? J Au toimmunol 1996; 9: 341–348.Google Scholar
  385. 383.
    Vargas F, Vivespi M, Somoza N, Fernandezllamazares J, Pu jolborrell R. Endotoxin activity of collagenase and human islet transplantation. Lancet 1997; 350 (9078): 641.PubMedGoogle Scholar
  386. 384.
    Vargas F, Vives-Pi M, Somoza N, Armengol P, Alcalde L, Marti M, et al. Endotoxin contamination may be responsible for the unexplained failure of human pancreatic islet trans-plantation. Transplantation 1998; 65 (5): 722–727.PubMedGoogle Scholar
  387. 385.
    Eckhardt T, Jahr H, Federlin K, Bretzel RG. Endotoxin impairs the engraftment of rat islets transplanted beneath the kidney capsule of C57BL/6–mice. J Mol Med 1999; 77: 123–125.PubMedGoogle Scholar
  388. 386.
    Berney T, Molano RD, Cattan P, Pileggi A, Vizzardelli C, Oliver R, et al. Endotoxin-mediated delayed islet graft function is associated with increased intra-islet cytokine production and islet cell apoptosis. Transplantation 2001; 71: 125–132.PubMedGoogle Scholar
  389. 387.
    Stevens RB, Sutherland DR, Ansite JD, Saxena M, Rossini TJ, Levayyoung BK, et al. Insulin down-regulates the inducible nitric oxide synthase pathway-nitric oxide as cause and effect of diabetes. J Immunol 1997; 159: 5329–5335.PubMedGoogle Scholar
  390. 388.
    Hyon SH, Tracey KJ, Kaufman DB. Specific inhibition of macrophage-derived proinflammatory cytokine synthesis with a tetravalent guanylhydrazone CNI-1493 accelerates early islet graft function posttransplant. Transplant Proc 1998; 30 (2): 409–410.PubMedGoogle Scholar
  391. 389.
    Katz SM, Bennett F, Stecker K, Clark JH, Pham T, Wang ME, et al. ICAM-1 antisense oligodeoxynucleotide improves islet allograft survival and function. Cell Transplant 2000; 9: 817 828.Google Scholar
  392. 390.
    Hsu BR, Juang JH, Fu SH, Kuo CH, Lu WT. Reduction in pri mary nonfunction of syngeneic islet transplants with nordihydroguaiaretic acid, a lipoxygenase inhibitor. Cell Transplant 2001; 10: 255–262.PubMedGoogle Scholar
  393. 391.
    Brandhorst D, Brandhorst H, Zwolinski A, Nahidi F, Bretzel RG. Prevention of intraportal islet failure by a highly selective factor. iNOS inhibitor in the pig-to-nude rat model. Transplant Proc 2001; 33 (112): 523.PubMedGoogle Scholar
  394. 392.
    Brown M, Braun M, Mercado P, Cicalese L, Benedetti E, Rastellini C. Pyruvate improves pancreatic islet engraftment and functionality. Transplant Proc 2001; 33 (7/8): 3523.PubMedGoogle Scholar
  395. 393.
    Nomikos IN, Wang Y, Lafferty KJ. Involvement of 02 radi-cals in “autoimmune” diabetes. Immunol Cell Biol 1989; 67: 85–87.PubMedGoogle Scholar
  396. 394.
    Gunther L, Berberat PO, Haga M, Brouard S, Smith RN, Soares MP, et al. Carbon monoxide protects pancreatic beta-cells from apoptosis and improves islet function/survival after transplan-tation. Diabetes 2002; 51: 994–999.PubMedGoogle Scholar
  397. 395.
    Longo C, Grey ST, Parent R, Czismadia E, Ferran C. Genetic engineering of islets with A20 overcomes primary non-func- tion. Am J Transplant 2002; 2 (suppl 3): 391.Google Scholar
  398. 396.
    Rutzky LP, Bilinski S, Kloc M, Phan T, Zhang H, Katz SM, et al. Microgravity culture condition reduces immunogenicity and improves function of pancreatic islets. Transplantation 2002; 74: 13–21.PubMedGoogle Scholar
  399. 397.
    Unger RH, Grundy S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin re-sistance: Implications for the management of diabetes. Dia-betologia 1985; 28: 119–121.Google Scholar
  400. 398.
    Sandler S, Jansson L. Blood flow measurements in autotrans- planted pancreatic islets of the rat. Impairment of the blood per- fusion of the graft during hyperglycemia. J Clin Invest 1987; 80: 17–21.PubMedGoogle Scholar
  401. 399a.
    Ohzato H, Porter J, Monaco AP, Montana E, Maki T. Mini- mum number of islets required to maintain euglycemia and their reduced immunogenicity after transplantation into diabetic mice. Transplantation 1993; 56: 270–274.PubMedGoogle Scholar
  402. 399b.
    Keymeulen B, Vetri M, Gorus F, Vanbrabandt B, Pipeleers DG. The effect of insulin treatment on function of intrapor- tally grafted islets in streptozotocin-diabetic rats. Transplanta-tion 1993; 56 (1): 60–64.Google Scholar
  403. 399c.
    Papalois B, Sutherland DE, Leone J, Nelson L, Wahoff D. In-fluence of delayed completion pancreatectomy on engraftment of islets isolated from the previously excised segment in dogs: histological findings. Transplant Proc 1995; 27 (6): 3025–3026.PubMedGoogle Scholar
  404. 400.
    Nagai T, Yasunami Y, Nagata N, Ryu S, Ono J, Ikeda S. Ame-lioration of hyperglycemia in streptozocin-induced diabetic rats receiving a marginal mass of islet grafts by troglitazone, an oral antidiabetic agent. Pancreas 1996; 13: 381–387.PubMedGoogle Scholar
  405. 401.
    Rooth P, Dawidson I, Lafferty K, et al. Prevention of detri-mental effect of cyclosporin A on vascular ingrowth of trans-planted pancreatic islets with verapamil. Diabetes 1989; 38 (suppl 1): 202–205.PubMedGoogle Scholar
  406. 402.
    Stagner JI, Samols E. The induction of capillary bed develop-ment by endothelial cell growth factor before islet transplanta-tion may prevent islet ischemia. Transplant Proc 1990; 22 (2): 824–828.PubMedGoogle Scholar
  407. 403.
    Stagner JI, Mokshagundam S, Samols E. Induction of mild hy-poglycemia by islet transplantation to the pancreas. Transplant Proc 1998; 30: 635–636.PubMedGoogle Scholar
  408. 404.
    Trivedi N, Steil GM, Colton CK, Bonner-Weir S, Weir GC. Improved vascularization of planar membrane diffusion devices following continuous infusion of vascular endothelial growth Cell Transplant 2000; 9: 115–124.Google Scholar
  409. 405.
    Hayek A, Lopez AD, Beattie GM. Angiogenic peptides in pancreatic islet transplantation to diabetic rats. Transplantation 1990; 50: 931–933.PubMedGoogle Scholar
  410. 406.
    Ye J, Laychock SG. A protective role for heme oxygenase expression in pancreatic islets exposed to interleukin-lbeta. Endocrinology 1998; 139: 4155–4163.PubMedGoogle Scholar
  411. 407.
    Pileggi A, Molano RD, Berney T, Cattan P, Vizzardelli C, Oliver R, et al. Herne oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. Diabetes 2001; 50: 1983–1991.PubMedGoogle Scholar
  412. 408.
    Tobiasch E, Gunther L, Bach FH. Heme oxygenase-1 protects pancreatic beta cells from apoptosis caused by various stimuli. J Invest Med 2001; 49: 566–571.Google Scholar
  413. 409.
    Nakano M, Yasunami Y, Maki T, Kodama S, Ikehara Y, Nakamura T, et al. Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts. Transplantation 2000; 69: 214–221.PubMedGoogle Scholar
  414. 410.
    Garcia-Ocana A, Takane KK, Syed MA, Philbrick WM, Vasavada RC, Stewart AF. Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J Biol Chem 2000; 275: 1226–1232.PubMedGoogle Scholar
  415. 411.
    Garcia-Ocana A, Vasavada RC, Cebrian A, Reddy V, Takane KK, Lopez-Talavera JC, et al. Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. Diabetes 2001; 50: 2752–2762.PubMedGoogle Scholar
  416. 412.
    Shapiro AM, Hao E, Rajotte RV, Kneteman NM. Impact of Lazaroid U74006F on ischemia and reperfusion injury of islets after transplantation in the rat. Transplant Proc 1996; 28: 85–86.PubMedGoogle Scholar
  417. 413.
    Yasuda H, Nagata M, Arisawa K, Yoshida R, Fujihira K, Okamoto N, et al. Local expression of immunoregulatory IL-12p40 gene prolonged syngeneic islet graft survival in diabetic NOD mice. J Clin Invest 1998; 102: 1807–1814.PubMedGoogle Scholar
  418. 414.
    Rabinovitch A, Suarez-Pinzon W, Strynadka K, Ju Q, Edelstein D, Brownlee M, et al. Transfection of human pancreatic islets with an anti-apoptotic gene (bc1–2) protects beta-cells from cytokine-induced destruction. Diabetes 1999; 48: 1223–1229.PubMedGoogle Scholar
  419. 415.
    Contreras JL, Bilbao G, Smyth C, Eckhoff DE, Xiang XL, Jenkins S, et al. Gene transfer of the Bc1–2 gene confers cytoprotection to isolated adult porcine pancreatic islets exposed to xenoreactive antibodies and complement. Surgery 2001; 130: 166–174.PubMedGoogle Scholar
  420. 416.
    Giannoukakis N, Rudert WA, Ghivizzani SC, Gambotto A, Ricordi C, Trucco M, et al. Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-lbeta-induced beta-cell impairment and activation of islet cell apoptosis in vitro. Diabetes 1999; 48: 1730–1736.PubMedGoogle Scholar
  421. 417.
    Han X, Sun Y, Scott S, Bleich D. Tissue inhibitor of metalloproteinase-1 prevents cytokine-mediated dysfunction and cytotoxicity in pancreatic islets and beta-cells. Diabetes 2001; 50: 1047–1055.PubMedGoogle Scholar
  422. 418.
    Ozmen L, Ekdahl KN, Elgue G, Larsson R, Korsgren O, Nilsson B. 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: 1779–1784.PubMedGoogle Scholar
  423. 419.
    Piemonti L, Leone BE, Nano R, Saccani A, Monti P, Maffi P, et al. Human pancreatic islets produce and secrete MCP-1/CCL2: Relevance in human islet transplantation. Diabetes 2002; 51: 55–65.PubMedGoogle Scholar
  424. 420.
    Vasavada RC, Cavaliere C, DErcole AJ, Dann P, Burtis WJ, Madlener AL, et al. Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia. J Biol Chem 1996; 271: 1200–1208.PubMedGoogle Scholar
  425. 421.
    Otonkoski T, Cirulli V, Beattie M, Mally MI, Soto G, Rubin JS, et al. A role for hepatocyte growth factor/scatter factor in fetal mesenchyme-induced pancreatic beta-cell growth. Endocrinology 1996; 137: 3131–3139.PubMedGoogle Scholar
  426. 422.
    van der Burg MP, van Suylichem PT, Guicherit OR, Frolich M, Lemkes HH, Gooszen HG. Glucoregulation after canine islet transplantation: Contribution of insulin secretory capacity, insulin action, and the entero-insular axis. Cell Transplant 1997; 6: 497–503.PubMedGoogle Scholar
  427. 423.
    Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48: 2270–2276.PubMedGoogle Scholar
  428. 424.
    Davalli AM, Scaglia L, Brevi M, Sanvito F, Freschi M, Cavallaro U, et al. Pituitary cotransplantation significantly improves the performance, insulin content, and vascularization of renal subcapsular islet grafts. Diabetes 1999; 48: 59–65.PubMedGoogle Scholar
  429. 425.
    Giannoukakis N, Mi Z, Rudert WA, Gambotto A, Trucco M, Robbins P. Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I. Gene Ther 2000; 7: 2015–2022.PubMedGoogle Scholar
  430. 426.
    Devedjian JC, George M, Casellas A, Pujol A, Visa J, Pelegrin M, et al. Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. J Clin Invest 2000; 105: 731–740.PubMedGoogle Scholar
  431. 427a.
    Vasavada RC, Garcia-Ocana A, Zawalich WS, Sorenson RL, Dann P, Syed M, et al. Targeted expression of placental lactogen in the beta cells of transgenic mice results in beta cell proliferation, islet mass augmentation, and hypoglycemia. J Biol Chem 2000; 275: 15399–15406.PubMedGoogle Scholar
  432. 427b.
    Hering BJ, Kandaswamy R, Ansite JD, Eckman PM, Nakano M, Sawada T et al. Successful single donor islet transplantation in type 1 diabetes. Am J Transplant 2003; 3 (Suppl. 5): 296.Google Scholar
  433. 428.
    Lacy PE, Davie JM, Finke EH. Prolongation of islet allograft survival following in vitro culture (24 degrees C) and a single injection of ALS. Science 1979; 204 (4390): 312–313.PubMedGoogle Scholar
  434. 429.
    Bowen KM, Andrus L, Lafferty KJ. Successful allotransplantation of mouse pancreatic islets to nonimmunosuppressed recipients. Diabetes 1980; 29 (suppl 1): 98–104.PubMedGoogle Scholar
  435. 430.
    Britt LD, Scharp DW, Lacy PE, Slavin S. Transplantation of islet cells across major histocompatibility barriers after total lymphoid irradiation and infusion of allogeneic bone marrow cells. Diabetes 1982; 31 (suppl 4): 63–68.PubMedGoogle Scholar
  436. 431.
    Li H, Kaufman CL, Ildstad ST. Allogeneic chimerism induces donor-specific tolerance to simultaneous islet allografts in nonobese diabetic mice. Surgery 1995; 118: 192–197.PubMedGoogle Scholar
  437. 432.
    Lau H, Reemtsma K, Hardy MA. Pancreatic islet allograft prolongation by donor-specific blood transfusions treated with ultraviolet irradiation. Science 1983; 221 (4612): 754–756.PubMedGoogle Scholar
  438. 433.
    Lau H, Reemtsma K, Hardy MA. Prolongation of rat islet allograft survival by direct ultraviolet irradiation of the graft. Science 1984; 223 (4636): 607–609.PubMedGoogle Scholar
  439. 434.
    Lau H, Reemtsma K, Hardy MA. The use of direct ultraviolet irradiation and cyclosporine in facilitating indefinite pancreatic islet allograft acceptance. Transplantation 1984; 38: 566–569.PubMedGoogle Scholar
  440. 435.
    Selawry HP, Whittington K. Extended allograft survival of islets grafted into intra-abdominally placed testis. Diabetes 1984; 33: 405–406.PubMedGoogle Scholar
  441. 436.
    James RF, Lake SP, Chamberlain J, Thirdborough S, Bassett PD, Mistry N, et al. Gamma irradiation of isolated rat islets pre-transplantation produces indefinite allograft survival in cyclosporine-treated recipients. Transplantation 1989; 47: 929–933.PubMedGoogle Scholar
  442. 437.
    Posselt AM, Barker CF, Tomaszewski JE, Markmann JF, Choti MA, Naji A. Induction of donor-specific unresponsiveness by intrathymic islet transplantation. Science 1990; 249 (4974): 1293–1295.PubMedGoogle Scholar
  443. 438.
    Shizuru JA, Gregory AK, Chao CT, Fathman CG. Islet allograft survival after a single course of treatment of recipient with antibody to L3T4. Science 1987; 237 (4812): 278–280.PubMedGoogle Scholar
  444. 439.
    Parker DC, Greiner DL, Phillips NE, Appel MC, Steele AW, Dude FH, et al. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Nail Acad Sci USA 1995; 92: 9560–9564.Google Scholar
  445. 440.
    Lau HT, Yu M, Fontana A, Stoeckert CJ Jr. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 1996; 273 (5271): 109–112.PubMedGoogle Scholar
  446. 441.
    Korbutt GS, Elliott JF, Rajotte RV. Cotransplantation of allogeneic islets with allogeneic testicular cell aggregates allows long-term graft survival without systemic immunosuppression. Diabetes 1997; 46: 317–322.PubMedGoogle Scholar
  447. 442.
    Basadonna GP, Auersvald L, Khuong CQ, Zheng XX, Kashio N, Zekzer D, et al. Antibody-mediated targeting of CD45 isoforms: A novel immunotherapeutic strategy. Proc Natl Acad Sci USA 1998; 95: 3821–3826.PubMedGoogle Scholar
  448. 443.
    Nicolls MR, Coulombe M, Yang H, Bolwerk A, Gill RG. AntiLFA-1 therapy induces long-term islet allograft acceptance in the absence of IFN-gamma or IL-4. J Immunol 2000; 164: 36273634.Google Scholar
  449. 444.
    Nicolls MR, Coulombe M, Beilke J, Gill RG. Dominant transplantation tolerance does not require elimination of donor-specific T cells in vivo. Am J Transplant 202;2(suppl 3 ): 212.Google Scholar
  450. 445.
    Ikebukuro K, Adachi Y, Yamada Y, Fujimoto S, Seino Y, Oyaizu H, et al. Treatment of streptozocin-induced diabetes mellitus by transplantation of islet cells plus bone marrow cells via portal vein in rats. Transplantation 2002; 73: 512–518.PubMedGoogle Scholar
  451. 446.
    Li XC, Ima A, Li Y, Zheng XX, Malek TR, Strom TB. Blocking the common gamma-chain of cytokine receptors induces T cell apoptosis and long-term islet allograft survival. J Immunol 2000; 164: 1193–1199.PubMedGoogle Scholar
  452. 447.
    Oluwole 00, Depaz HA, Gopinathan R, Ali A, Garrovillo M, Jin MX, et al. Indirect allorecognition in acquired thymic tolerance: Induction of donor-specific permanent acceptance of rat islets by adoptive transfer of allopeptide-pulsed host myeloid and thymic dendritic cells. Diabetes 2001; 50: 1546–1552.Google Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Bernhard J. Hering
  • Martin Wijkstrom
  • Peter M. Eckman

There are no affiliations available

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