Prospective and challenges of islet transplantation for the therapy of autoimmune diabetes.

Pancreatic islet cell transplantation is an attractive treatment of type 1 diabetes (T1D). The success enhanced by the Edmonton protocol has fostered phenomenal progress in the field of clinical islet transplantation in the past 5 years, with 1-year rates of insulin independence after transplantation near 80%. Long-term function of the transplanted islets, however, even under the Edmonton protocol, seems difficult to accomplish, with only 10% of patients maintaining insulin independence 5 years after transplantation. These results differ from the higher metabolic performance achieved by whole pancreas allotransplantation, and autologous islet cell transplantation, and form the basis for a limited applicability of islet allografts to selected adult patients. Candidate problems in islet allotransplantation deal with alloimmunity, autoimmunity, and the need for larger islet cell masses. Employment of animal islets and stem cells, as alternative sources of insulin production, will be considered to face the problem of human tissue shortage. Emerging evidence of the ability to reestablish endogenous insulin production in the pancreas even after the diabetic damage occurs envisions the exogenous supplementation of islets to patients also as a temporary therapeutic aid, useful to buy time toward a possible self-healing process of the pancreatic islets. All together, islet cell transplantation is moving forward.

[1]  P. Lacy,et al.  Automated Islet Isolation From Human Pancreas , 1989, Diabetes.

[2]  E. Livingston,et al.  Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase. , 2000, American journal of physiology. Cell physiology.

[3]  R. Holman,et al.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. , 1998 .

[4]  F. Bach,et al.  Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. , 2001, Diabetes.

[5]  J F Elliott,et al.  Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. , 2001, Diabetes.

[6]  F. Andreelli,et al.  Evidence of recurrent type I diabetes following HLA-mismatched pancreas transplantation. , 2000, Diabetes & metabolism.

[7]  O. Domínguez,et al.  Endotoxin contamination may be responsible for the unexplained failure of human pancreatic islet transplantation. , 1998, Transplantation.

[8]  G. Cameron Regeneration of the pancreas , 1927 .

[9]  A. Shapiro,et al.  Influence of Pancreas Preservation on Human Islet Isolation Outcomes: Impact of the Two-Layer Method , 2004, Transplantation.

[10]  P. Robbins,et al.  Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. , 2000, The Journal of biological chemistry.

[11]  T. Maki,et al.  Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T. Berney,et al.  Pancreas allocation in the era of islet transplantation , 2005, Transplant international : official journal of the European Society for Organ Transplantation.

[13]  D. Dunn,et al.  Transplant options for patients undergoing total pancreatectomy for chronic pancreatitis. , 2004, Journal of the American College of Surgeons.

[14]  T. Starzl,et al.  Pancreatic islet transplantation after upper abdominal exeriteration and liver replacement , 1990, The Lancet.

[15]  P. Morris,et al.  A Method for Isolation of Islets of Langerhans from the Human Pancreas , 1984, Diabetes.

[16]  L. Wicker,et al.  Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice1 , 2003, The Journal of Immunology.

[17]  P. Lacy,et al.  The use of ficoll in the preparation of viable islets of langerhans from the rat pancreas. , 1973, Transplantation.

[18]  Zhiguang Guo,et al.  Immunotherapy with nondepleting anti-CD4 monoclonal antibodies but not CD28 antagonists protects islet graft in spontaneously diabetic nod mice from autoimmune destruction and allogeneic and xenogeneic graft rejection. , 2001, Transplantation.

[19]  K. Ekdahl,et al.  Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation. , 2002, Diabetes.

[20]  C. Ricordi,et al.  Improved human islet isolation outcome from marginal donors following addition of oxygenated perfluorocarbon to the cold-storage solution , 2003, Transplantation.

[21]  B. Wolf,et al.  The use of non-heart-beating donors for isolated pancreatic islet transplantation , 2003, Transplantation.

[22]  D. Greiner,et al.  Autoimmune Destruction of Islets Transplanted Into RT6-Depleted Diabetes-Resistant BB/Wor Rats , 1990, Diabetes.

[23]  S. Matsumoto Clinical Application of Perfluorocarbons for Organ Preservation , 2005, Artificial cells, blood substitutes, and immobilization biotechnology.

[24]  P. Lacy,et al.  Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas , 1967, Diabetes.

[25]  G. Maddern,et al.  Islet yield remains a problem in islet autotransplantation. , 2002, Archives of surgery.

[26]  D. Kendall,et al.  Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. , 2001, Diabetes.

[27]  J. Tuomilehto,et al.  Worldwide increase in incidence of Type I diabetes – the analysis of the data on published incidence trends , 1999, Diabetologia.

[28]  A. Shapiro,et al.  Strategic opportunities in clinical islet transplantation. , 2005, Transplantation.

[29]  A. Shapiro,et al.  Five-year follow-up after clinical islet transplantation. , 2005, Diabetes.

[30]  K. Ekdahl,et al.  Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation , 2002, The Lancet.

[31]  C. Ricordi,et al.  Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center , 2002, Transplantation.

[32]  C. Ferran,et al.  DEPLETING ANTI-CD4 MONOCLONAL ANTIBODY CURES NEW-ONSET DIABETES, PREVENTS RECURRENT AUTOIMMUNE DIABETES, AND DELAYS ALLOGRAFT REJECTION IN NONOBESE DIABETIC MICE1 , 2004, Transplantation.

[33]  S. Wild,et al.  Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. , 2004, Diabetes care.

[34]  Technical aspects of islet preparation and transplantation , 2003, Transplant international : official journal of the European Society for Organ Transplantation.

[35]  R. van Schilfgaarde,et al.  An analysis of the role of collagenase and protease in the enzymatic dissociation of the rat pancreas for islet isolation , 1992, Diabetologia.

[36]  E. Ryan,et al.  Human islet transplantation from pancreases with prolonged cold ischemia using additional preservation by the two-layer (UW solution/perfluorochemical) cold-storage method , 2002, Transplantation.

[37]  A. Shapiro,et al.  Risks and side effects of islet transplantation , 2004, Current diabetes reports.

[38]  G. Korbutt,et al.  SERINE-PROTEASE INHIBITION DURING ISLET ISOLATION INCREASES ISLET YIELD FROM HUMAN PANCREASES WITH PROLONGED ISCHEMIA1 , 2001, Transplantation.

[39]  G. Warnock,et al.  Successful autotransplantation of isolated islets of Langerhans in the cynomolgus monkey , 1986, Transplantation proceedings.

[40]  S. Paraskevas,et al.  Cell Loss in Isolated Human Islets Occurs by Apoptosis , 2000, Pancreas.

[41]  Ames,et al.  Islet Transplantation in Seven Patients with Type 1 Diabetes Mellitus Using a Glucocorticoid-Free Immunosuppressive Regimen , 2000 .

[42]  I. Leykin,et al.  Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. , 2004, Diabetes.

[43]  T. Tanaka,et al.  Pancreatic secretory trypsin inhibitor as a marker for early detection of rejection in canine pancreas allotransplantation. , 1988, Transplantation.

[44]  G. Warnock,et al.  Normoglycemia after implantation of purified islet cells in dogs. , 1988, Canadian journal of surgery. Journal canadien de chirurgie.

[45]  M. Rosen,et al.  Magnetic resonance-defined periportal steatosis following intraportal islet transplantation: a functional footprint of islet graft survival? , 2003, Diabetes.

[46]  S. Matsumoto,et al.  Perfluorocarbon for organ preservation before transplantation. , 2002, Transplantation.

[47]  R. Bottino,et al.  Preservation of human islet cell functional mass by anti-oxidative action of a novel SOD mimic compound. , 2002, Diabetes.

[48]  A. Tingle,et al.  The use of hypaque-ficoll in the isolation of pancreatic islets in rats. , 1976, Transplantation.

[49]  E. Ho,et al.  Administration of NF‐κB decoy inhibits pancreatic activation of NF‐κB and prevents diabetogenesis by alloxan in mice , 2001 .

[50]  H. Auchincloss,et al.  The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade. , 2002, Diabetes.

[51]  Norman Fleischer,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. , 1993 .

[52]  Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. , 1998, Annals of internal medicine.

[53]  T. Berney,et al.  Assessment of a Novel Two-Component Enzyme Preparation for Human Islet Isolation and Transplantation , 2005, Transplantation.

[54]  B. Hering,et al.  The evaluation of neutral density separation utilizing Ficoll-sodium diatrizoate and Nycodenz and centrifugal elutriation in the purification of bovine and canine islet preparations. , 1990, Hormone and metabolic research. Supplement series.

[55]  Å. Lernmark,et al.  Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. , 1999, Diabetes.

[56]  T. Mandel,et al.  Prevention of autoimmunity in nonobese diabetic (NOD) mice by neonatal transfer of allogeneic thymic macrophages. , 1995, Autoimmunity.

[57]  D. Sutherland,et al.  Combined hepatic and pancreaticoduodenal procurement for transplantation. , 1989, Surgery, gynecology & obstetrics.

[58]  Yuval Dor,et al.  Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. , 2004, Nature.

[59]  C. Ricordi,et al.  Protecting Pancreatic ß‐cells , 2004 .

[60]  A. Secchi,et al.  Islet transplantation in type 1 diabetic patients. , 2004, Transplantation proceedings.

[61]  P. Lacy,et al.  Low-temperature culture of human islets isolated by the distention method and purified with Ficoll or Percoll gradients. , 1987, Surgery.

[62]  N. Barshes,et al.  islet transplantation: implications for intrahepatic grafts , 2022 .

[63]  A. Matas,et al.  Human islet autotransplantation following pancreatectomy. , 1979, Transplantation proceedings.

[64]  D. Dunn,et al.  Lessons Learned From More Than 1,000 Pancreas Transplants at a Single Institution , 2001, Annals of surgery.

[65]  D. Stolz,et al.  Harmful Delayed Effects of Exogenous Isolation Enzymes on Isolated Human Islets: Relevance to Clinical Transplantation , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[66]  P. Pour,et al.  Are There Any Stem Cells in the Pancreas? , 2005, Pancreas.

[67]  Simon C Watkins,et al.  Gene transfer of manganese superoxide dismutase extends islet graft function in a mouse model of autoimmune diabetes. , 2003, Diabetes.

[68]  R. Robertson Islet transplantation as a treatment for diabetes - a work in progress. , 2004, The New England journal of medicine.

[69]  M. Trucco,et al.  Protection of Human Islets from the Effects of Interleukin-1β by Adenoviral Gene Transfer of an IκB Repressor* , 2000, The Journal of Biological Chemistry.

[70]  J. Fung,et al.  Flexible Management of Enzymatic Digestion Improves Human Islet Isolation Outcome from Sub‐Optimal Donor Pancreata , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[71]  R. Nakhleh,et al.  Characterization of T Lymphocytes Infiltrating Human Pancreas Allograft Affected by Isletitis and Recurrent Diabetes , 1992, Diabetes.

[72]  P. Liss,et al.  Measurements of oxygen tension in native and transplanted rat pancreatic islets. , 1998, Diabetes.

[73]  P. Morel,et al.  Human islet transplantation: lessons from 13 autologous and 13 allogeneic transplantations. , 2000, Transplantation.

[74]  B. Hering,et al.  Endotoxin-mediated activation of cytokine production in human PBMCs by collagenase and Ficoll , 1999, Journal of Molecular Medicine.

[75]  Zhaohui Geng,et al.  CD40/154 blockade and rejection of islet allografts in the streptozotocin and autoimmune diabetic rat , 2001, Pediatric diabetes.

[76]  C. Ricordi,et al.  Long-term islet allograft survival in nonobese diabetic mice treated with tacrolimus, rapamycin, and anti-interleukin-2 antibody1 , 2003, Transplantation.

[77]  F. Brunicardi,et al.  Development of a human pancreatic islet-transplant program through a collaborative relationship with a remote islet-isolation center , 2004, Transplantation.

[78]  P. Kuo,et al.  Prevention of autoimmune islet allograft destruction by engraftment of donor T cells. , 1997, Transplantation.

[79]  R. Robertson,et al.  Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. , 2003, Diabetes.

[80]  R. Bottino,et al.  Response of human islets to isolation stress and the effect of antioxidant treatment. , 2004, Diabetes.

[81]  C. Kaufman,et al.  Allogeneic chimerism induces donor-specific tolerance to simultaneous islet allografts in nonobese diabetic mice. , 1995, Surgery.

[82]  J. Connolly Pancreatic whole organ transplantation. , 1978, The Surgical clinics of North America.

[83]  P. Lacy,et al.  A Method for the Mass Isolation of Islets From the Adult Pig Pancreas , 1986, Diabetes.

[84]  S. Bonner-Weir,et al.  New sources of pancreatic beta-cells. , 2005, Nature biotechnology.

[85]  R. James,et al.  Successful Reversal of Diabetes in Nude Rats by Transplantation of Isolated Adult Human Islets of Langerhans , 1989, Diabetes.

[86]  R. Bottino,et al.  Islet/pancreas transplantation: challenges for pediatrics , 2002, Pediatric diabetes.

[87]  J. Bluestone,et al.  Transplantation of Cultured Islets from Two‐Layer Preserved Pancreases in Type 1 Diabetes with Anti‐CD3 Antibody , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[88]  H. Auchincloss,et al.  Allorecognition and effector pathways of islet allograft rejection in normal versus nonobese diabetic mice. , 2003, Journal of the American Society of Nephrology : JASN.

[89]  T. Starzl,et al.  Pancreas and islet cell transplantation. , 2002, Best practice & research. Clinical gastroenterology.

[90]  W. Tamborlane,et al.  Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. , 1999, Diabetes care.

[91]  I. Chaudry,et al.  Brain death significantly reduces isolated pancreatic islet yields and functionality in vitro and in vivo after transplantation in rats. , 2003, Diabetes.

[92]  B. Woda,et al.  Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. , 2000, Blood.

[93]  R. Stratta,et al.  Pancreas transplantation in type 1 diabetes. , 2004, Diabetes care.

[94]  C. Ricordi,et al.  The Bag Method for Islet Cell Infusion , 2003, Cell transplantation.

[95]  I. Weissman,et al.  Purified allogeneic hematopoietic stem cell transplantation blocks diabetes pathogenesis in NOD mice. , 2003, Diabetes.

[96]  R. Curi,et al.  Improvement of the mitochondrial antioxidant defense status prevents cytokine-induced nuclear factor-kappaB activation in insulin-producing cells. , 2003, Diabetes.

[97]  R. James,et al.  Large-Scale Purification of Human Islets Utilizing Discontinuous Albumin Gradient on IBM 2991 Cell Separator , 1989, Diabetes.

[98]  C. Ricordi,et al.  Prolonged islet allograft survival in diabetic NOD mice by targeting CD45RB and CD154. , 2003, Diabetes.

[99]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[100]  P. Morel,et al.  HUMAN ISLET TRANSPLANTATION , 2000 .

[101]  C. Ricordi,et al.  Protecting pancreatic beta-cells. , 2004, IUBMB life.

[102]  J. Lakey,et al.  A Prospective Comparison of Discontinuous Euroficoll and Eurodextran Gradients for Islet Purification , 1998, Cell transplantation.

[103]  R. Bottino,et al.  Recovery of the Endogenous β Cell Function in the NOD Model of Autoimmune Diabetes , 2003, Stem cells.

[104]  P. Lacy,et al.  Effect of transplantation site on the results of pancreatic islet isografts in diabetic rats , 1973, Diabetologia.

[105]  R. Kandaswamy,et al.  CLINICAL APPLICATION OF THE TWO-LAYER (UNIVERSITY OF WISCONSIN SOLUTION/PERFLUOROCHEMICAL PLUS O 2) METHOD OF PANCREAS PRESERVATION BEFORE TRANSPLANTATION , 1999, Transplantation.

[106]  B. Hering,et al.  Impact of two-layer pancreas preservation on islet isolation and transplantation. , 2002, Transplantation.

[107]  M. Trucco Regeneration of the pancreatic β cell , 2005 .

[108]  T. Berney,et al.  Serva collagenase NB1: a new enzyme preparation for human islet isolation. , 2004, Transplantation proceedings.

[109]  G. Wolters,et al.  The efficacy of density gradients for islet purification: a comparison of seven density gradients , 1989, Transplant international : official journal of the European Society for Organ Transplantation.

[110]  R. Stratta,et al.  Combined liver and pancreas procurement with Belzer-UW solution. , 1989, Surgery.

[111]  D. Sutherland Current status of beta-cell replacement therapy (pancreas and islet transplantation) for treatment of diabetes mellitus. , 2003, Transplantation proceedings.

[112]  R. Bretzel,et al.  Endotoxin impairs the engraftment of rat islets transplanted beneath the kidney capsule of C57BL/6-mice , 1999, Journal of Molecular Medicine.

[113]  Y. Tabata,et al.  Bioartificial Pancreas Transplantation at Prevascularized Intermuscular Space: Effect of Angiogenesis Induction on Islet Survival , 2003, Pancreas.

[114]  J. Markmann,et al.  Prevention of Recurrent Diabetes in BB Rats After Islet Transplantation by Monoclonal Antibody Therapy , 1989, Diabetes.

[115]  G. Korbutt,et al.  Intraductal collagenase delivery into the human pancreas using syringe loading or controlled perfusion. , 1998, Cell transplantation.

[116]  E. Ho,et al.  Administration of NF-kappaB decoy inhibits pancreatic activation of NF-kappaB and prevents diabetogenesis by alloxan in mice. , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[117]  R. James,et al.  Bovine serum albumin density gradient isolation of rat pancreatic islets. , 1987, Transplantation.

[118]  M. Trucco Regeneration of the pancreatic beta cell. , 2005, The Journal of clinical investigation.

[119]  G. Warnock,et al.  Prevention of Recurrence of IDDM in Islet-Transplanted Diabetic NOD Mice by Adjuvant Immunotherapy , 1992, Diabetes.

[120]  G. Klöppel,et al.  Proliferation and hypertrophy of liver cells surrounding islet grafts in diabetic recipient rats , 1995, Hepatology.

[121]  R. Gruessner Immunosuppression after pancreas transplantation. , 2005, Transplantation proceedings.

[122]  J. Lakey,et al.  Effect of core pancreas temperature during cadaveric procurement on human islet isolation and functional viability1 , 2002, Transplantation.

[123]  Y. Kuroda,et al.  A new, simple method for cold storage of the pancreas using perfluorochemical. , 1988, Transplantation.

[124]  R. van Schilfgaarde,et al.  Factors influencing the isolation process of islets of Langerhans. , 1990, Hormone and metabolic research. Supplement series.

[125]  W. Bry,et al.  Total abdominal evisceration: an en bloc technique for abdominal organ harvesting. , 1992, Surgery.

[126]  M. Stegall,et al.  Evidence of recurrent autoimmunity in human allogeneic islet transplantation. , 1996, Transplantation.

[127]  M. Field,et al.  Beneficial and detrimental effects of RBC-adsorbed antilymphocyte globulin and prednisone on purified canine islet autograft and allograft function. , 1991, Transplantation.

[128]  A. Matas,et al.  Human islet transplantation: a preliminary report. , 1977, Transplantation proceedings.