Islet transplantation: a brave new world.

It has indeed been a distinct honor to be the recipient of the 2002 Outstanding Scientific Achievement Award, and I was happy to accept it, on behalf of the entire islet transplant field, as there have been many surgeons, physicians, and scientists who have worked as a team, moving this field forward. I was born the year the Lilly Lecture was established, 1957, and since then, this is the first time that the award goes to islet transplantation, representing indeed a very important recognition to all of us in the field. Therefore, I’d like to outline the major steps in the development of islet transplantation, from a hypothesis, to its clinical application, through what we call translational research, bench to bedside. At the end, some of the challenges ahead, including novel immunomodulatory strategies, tolerance induction, and the development of alternative sources of insulin-producing tissue, are discussed. The challenge, as you may predict, is diabetes. A syndrome well known since over 3,500 years ago, even if the term “diabetes” was coined in the first century by Arataeus from the Greek “siphon” or “pipe-like.” Arataeus described diabetes as “a melting down of flesh and limbs into urine.” It took over 3,500 years to link diabetes to the pancreas, and until insulin was discovered, diabetes remained a devastating, deadly disease, often treated by starvation. The discovery of insulin, by Banting and Best in 1922, changed the course of history in the treatment of the disease, and suddenly children with diabetes could be offered a new chance at life. While definitely a life-saving breakthrough, insulin treatment still cannot fully prevent chronic complications, and intensive insulin treatment to improve metabolic control has paralleled an increased risk of severe hypoglycemia (1). The hypothesis that replacement of the endocrine pancreas by transplantation of insulin-producing tissue could represent …

[1]  P. Lacy,et al.  Transplantation of cryopreserved human pancreatic islets into diabetic nude mice , 1988, World Journal of Surgery.

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

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

[4]  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.

[5]  E. Bonifacio,et al.  Succesful transplantation of human islets in recipients bearing a kidney graft , 2002, Diabetologia.

[6]  A. F. Stewart,et al.  Transgenic overexpression of hepatocyte growth factor in the beta-cell markedly improves islet function and islet transplant outcomes in mice. , 2001, Diabetes.

[7]  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.

[8]  L. Turka,et al.  Primer on Transplantation , 2001 .

[9]  C. Ricordi,et al.  Proteins linked to a protein transduction domain efficiently transduce pancreatic islets. , 2001, Diabetes.

[10]  C. Ricordi,et al.  SIX-YEAR CLINICAL EFFECT OF DONOR BONE MARROW INFUSIONS IN RENAL TRANSPLANT PATIENTS1 , 2001, Transplantation.

[11]  M. Redondo,et al.  Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. , 2001, The Journal of clinical investigation.

[12]  C. Ricordi,et al.  Prolonged islet graft survival in NOD mice by blockade of the CD40-CD154 pathway of T-cell costimulation. , 2001, Diabetes.

[13]  C. Ricordi,et al.  ENDOTOXIN-MEDIATED DELAYED ISLET GRAFT FUNCTION IS ASSOCIATED WITH INCREASED INTRA-ISLET CYTOKINE PRODUCTION AND ISLET CELL APOPTOSIS1 , 2001, Transplantation.

[14]  E. Ryan,et al.  Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. , 2000, The New England journal of medicine.

[15]  C. Ricordi,et al.  The human bone marrow as an immunoregulatory organ. , 1999, Transplantation.

[16]  D. Harlan,et al.  Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  D. Harlan,et al.  Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154. , 1999, Diabetes.

[18]  C. Ricordi,et al.  The effects of maintenance doses of FK506 versus cyclosporin A on glucose and lipid metabolism after orthotopic liver transplantation. , 1998, Transplantation.

[19]  C. Ricordi,et al.  Long-Term Function (6 Years) of Islet Allografts in Type 1 Diabetes , 1997, Diabetes.

[20]  C. Ricordi,et al.  Improved Human Islet Isolation Using a New Enzyme Blend, Liberase , 1997, Diabetes.

[21]  C. Ricordi,et al.  The effects of chimeric cells following donor bone marrow infusions as detected by PCR-flow assays in kidney transplant recipients. , 1997, The Journal of clinical investigation.

[22]  C. Mathieu,et al.  Protection against autoimmune diabetes in mixed bone marrow chimeras: mechanisms involved. , 1997, Journal of immunology.

[23]  E. Schiff,et al.  High-dose donor bone marrow infusions to enhance allograft survival: the effect of timing. , 1997, Transplantation.

[24]  S. Boggs,et al.  Mixed allogeneic chimerism induced by a sublethal approach prevents autoimmune diabetes and reverses insulitis in nonobese diabetic (NOD) mice. , 1996, Journal of immunology.

[25]  A G Tzakis,et al.  Long-term in vivo function of human mantled islets obtained by incomplete pancreatic dissociation and purification. , 1995, Transplantation proceedings.

[26]  Ana D. Lopez,et al.  Growth Factor/Matrix-Induced Proliferation of Human Adult β-Cells , 1995, Diabetes.

[27]  R. Noelle,et al.  Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D. Dunn,et al.  Autologous Islet Transplantation to Prevent Diabetes After Pancreatic Resection , 1995, Annals of surgery.

[29]  C. Ricordi Methods in cell transplantation , 1995 .

[30]  C. Ricordi,et al.  Acceleration of chronic failure of intrahepatic canine islet autografts by a short course of prednisone. , 1994, Transplantation.

[31]  C. Ricordi,et al.  Human islet allograft follow-up: long-term islet function and over 3 years of insulin independence. , 1994, Transplantation proceedings.

[32]  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.

[33]  T. Starzl,et al.  CHIMERISM AND DONOR‐SPECIFIC NONREACTIVITY 27 TO 29 YEARS AFTER KIDNEY ALLOTRANSPLANTATION , 1993, Transplantation.

[34]  C. Ricordi,et al.  Donor cell chimerism permitted by immunosuppressive drugs: a new view of organ transplantation. , 1993, Immunology today.

[35]  T. Starzl,et al.  Islet xenografts in fully xenogeneic (rat----mouse) chimeras: evidence for normal regulation of function in a xenogeneic mouse environment. , 1992, Surgery.

[36]  T. Starzl,et al.  Donor dendritic cell repopulation in recipients after rat-to-mouse bone-marrow transplantation , 1992, The Lancet.

[37]  T. Starzl,et al.  Cell migration, chimerism, and graft acceptance , 1992, The Lancet.

[38]  T. Starzl,et al.  Induction of Pancreatic Islet Graft Acceptance: The Role of Antigen Presenting Cells. , 1992, Transplantation science.

[39]  T. Starzl,et al.  HUMAN ISLET ISOLATION AND ALLOTRANSPLANTATION IN 22 CONSECUTIVE CASES 1, 2 , 1992, Transplantation.

[40]  T. Starzl,et al.  Long-term survival of donor-specific pancreatic islet xenografts in fully xenogeneic chimeras (WF rat----B10 mouse). , 1992, Transplantation.

[41]  T. Starzl,et al.  Islet cell allotransplantation in diabetic patients. Histologic findings in four adults simultaneously receiving kidney or liver transplants. , 1992, The American journal of pathology.

[42]  T. Starzl,et al.  Histologic finding of pancreatic islet tissue following intraportal human islet allotransplantation. , 1992, Transplantation proceedings.

[43]  T. Starzl,et al.  In vivo effect of FK506 on human pancreatic islets. , 1991, Transplantation.

[44]  T. Starzl,et al.  Detection of pancreatic islet tissue following islet allotransplantation in man. , 1991, Transplantation.

[45]  T. Starzl,et al.  Human islet isolation and purification from pediatric-age donors. , 1991, Transplantation proceedings.

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

[47]  P. Lacy,et al.  Insulin Independence After Islet Transplantation Into Type I Diabetic Patient , 1990, Diabetes.

[48]  C. Ricordi,et al.  Isolation of the elusive pig islet. , 1990, Surgery.

[49]  D. Laface,et al.  Reciprocal Allogeneic Bone Marrow Transplantation Between NOD Mice and Diabetes-Nonsusceptible Mice Associated With Transfer and Prevention of Autoimmune Diabetes , 1989, Diabetes.

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

[51]  P. Lacy,et al.  REVERSAL OF DIABETES IN NUDE MICE AFTER TRANSPLANTATION OF FRESH AND 7‐DAY‐CULTURED (24°C) HUMAN PANCREATIC ISLETS , 1988 .

[52]  Camillo Ricordi,et al.  Automated Method for Isolation of Human Pancreatic Islets , 1988, Diabetes.

[53]  R. Alejandro,et al.  A simple method of staining fresh and cultured islets. , 1988, Transplantation.

[54]  P. Lacy,et al.  Low-temperature culture of human islets or in vivo treatment with L3T4 antibody produces a marked prolongation of islet human-to-mouse xenograft survival. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

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

[56]  M. Bliss The Discovery of Insulin , 2021 .

[57]  A. Matas,et al.  Pancreatic islet cell transplantation. , 1978, The Surgical clinics of North America.

[58]  P. Lacy,et al.  Transplantation of intact pancreatic islets in rats. , 1972, Surgery.

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

[60]  P. Medawar,et al.  ‘Actively Acquired Tolerance’ of Foreign Cells , 1953, Nature.