Bone marrow as an alternative site for islet transplantation.

The liver is the current site for pancreatic islet transplantation, but has many drawbacks due to immunologic and nonimmunologic factors. We asked whether pancreatic islets could be engrafted in the bone marrow (BM), an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. Syngeneic islets engrafted efficiently in the BM of C57BL/6 mice rendered diabetic by streptozocin treatment. For more than 1 year after transplantation, these animals showed parameters of glucose metabolism that were similar to those of nondiabetic mice. Islets in BM had a higher probability to reach euglycemia than islets in liver (2.4-fold increase, P = .02), showed a compact morphology with a conserved ratio between alpha and beta cells, and affected bone structure only very marginally. Islets in BM did not compromise hematopoietic activity, even when it was strongly induced in response to a BM aplasia-inducing infection with lymphocytic choriomeningitis virus. In conclusion, BM is an attractive and safe alternative site for pancreatic islet transplantation. The results of our study open a research line with potentially significant clinical impact, not only for the treatment of diabetes, but also for other diseases amenable to treatment with cellular transplantation.

[1]  E. Bonifacio,et al.  Intrahepatic Islet Transplant in the Mouse: Functional and Morphological Characterization , 2008, Cell transplantation.

[2]  M. Gobbi,et al.  Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. , 2008, The Lancet. Oncology.

[3]  B. Torbett,et al.  Switching-On Survival and Repair Response Programs in Islet Transplants by Bone Marrow–Derived Vasculogenic Cells , 2008, Diabetes.

[4]  R. Robertson,et al.  Intrahepatic Glucose Flux as a Mechanism for Defective Intrahepatic Islet α-Cell Response to Hypoglycemia , 2008, Diabetes.

[5]  L. Benítez-Bribiesca,et al.  Pancreatic islet transplantation into the bone marrow of the rat. , 2008, American journal of surgery.

[6]  G. Karsenty,et al.  Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice , 2008, Proceedings of the National Academy of Sciences.

[7]  J. Permert,et al.  Intramuscular Autotransplantation of Pancreatic Islets in a 7‐Year‐Old Child: A 2‐Year Follow‐Up , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  F. Chisari,et al.  Platelets prevent IFN-α/β-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus , 2008, Proceedings of the National Academy of Sciences.

[9]  J. Permert,et al.  Optimising islet engraftment is critical for successful clinical islet transplantation , 2008, Diabetologia.

[10]  H. Nakauchi,et al.  Bone marrow (BM) transplantation promotes beta-cell regeneration after acute injury through BM cell mobilization. , 2007, Endocrinology.

[11]  E. Bonifacio,et al.  Relevance of Hyperglycemia on the Timing of Functional Loss of Allogeneic Islet Transplants: Implication for Mouse Model , 2007, Transplantation.

[12]  Philippe Morel,et al.  International trial of the Edmonton protocol for islet transplantation. , 2006, The New England journal of medicine.

[13]  P. Carlsson,et al.  Islets Transplanted Intraportally into the Liver are Stimulated to Insulin and Glucagon Release Exclusively through the Hepatic Artery , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  C. Mathieu,et al.  Hepatocellular neoplasms induced by low-number pancreatic islet transplants in autoimmune diabetic BB/Pfd rats. , 2006, Cancer research.

[15]  M. Hara,et al.  Liver Ischemia Contributes to Early Islet Failure Following Intraportal Transplantation: Benefits of Liver Ischemic‐Preconditioning , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  M. Taniguchi,et al.  Natural killer T-cells participate in rejection of islet allografts in the liver of mice. , 2006, Diabetes.

[17]  S. Messinger,et al.  Immunosuppression and Procedure-Related Complications in 26 Patients with Type 1 Diabetes Mellitus Receiving Allogeneic Islet Cell Transplantation , 2005, Transplantation.

[18]  G. Marchal,et al.  Feasibility, Safety, and Efficacy of Percutaneous Transhepatic Injection of β-Cell Grafts , 2005 .

[19]  O. Ohara,et al.  Vα14 NK T cell–triggered IFN-γ production by Gr-1+CD11b+ cells mediates early graft loss of syngeneic transplanted islets , 2005, The Journal of experimental medicine.

[20]  Johannes D Veldhuis,et al.  Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. , 2005, Diabetes.

[21]  Hua Yang,et al.  Effect of glucose toxicity on intraportal tilapia islet xenotransplantation in nude mice , 2005, Xenotransplantation.

[22]  Rajesh Balkrishnan,et al.  Transaminitis after pancreatic islet transplantation. , 2005, Journal of the American College of Surgeons.

[23]  M. Salvioni,et al.  Technique, complications, and therapeutic efficacy of percutaneous transplantation of human pancreatic islet cells in type 1 diabetes: the role of US. , 2005, Radiology.

[24]  A. Shapiro,et al.  The Portal Immunosuppressive Storm: Relevance to Islet Transplantation? , 2005, Therapeutic drug monitoring.

[25]  W. Waldhäusl,et al.  Insulin production rate following glucose ingestion estimated by splanchnic C-peptide output in normal man , 1979, Diabetologia.

[26]  G. Marchal,et al.  Feasibility, safety, and efficacy of percutaneous transhepatic injection of beta-cell grafts. , 2005, Journal of vascular and interventional radiology : JVIR.

[27]  E. Bonifacio,et al.  Tissue factor and CCL2/monocyte chemoattractant protein-1 released by human islets affect islet engraftment in type 1 diabetic recipients. , 2004, The Journal of clinical endocrinology and metabolism.

[28]  A. Shapiro,et al.  Prevalence of hepatic steatosis after islet transplantation and its relation to graft function. , 2004, Diabetes.

[29]  G. Mattsson,et al.  Evidence of functional impairment of syngeneically transplanted mouse pancreatic islets retrieved from the liver. , 2004, Diabetes.

[30]  P. Argibay,et al.  Effect of the Embolization of Completely Unpurified Islets on Portal Vein Pressure and Hepatic Biochemistry in Clinical Practice , 2004, Cell transplantation.

[31]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

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

[33]  B. Wolf,et al.  Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity? , 2003, Transplantation.

[34]  A. Shapiro,et al.  Percutaneous transhepatic pancreatic islet cell transplantation in type 1 diabetes mellitus: radiologic aspects. , 2003, Radiology.

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

[36]  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.

[37]  E. Ryan,et al.  Portal venous pressure changes after sequential clinical islet transplantation , 2002, Transplantation.

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

[39]  K Thomaseth,et al.  Contribution to glucose tolerance of insulin-independent vs. insulin-dependent mechanisms in mice. , 2001, American journal of physiology. Endocrinology and metabolism.

[40]  P. Liss,et al.  Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. , 2001, Diabetes.

[41]  J. Altman,et al.  Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. , 1998, Immunity.

[42]  R. Zinkernagel,et al.  Virus-induced Transient Bone Marrow Aplasia: Major Role of Interferon-α/β during Acute Infection with the Noncytopathic Lymphocytic Choriomeningitis Virus , 1997, The Journal of experimental medicine.

[43]  D. Kendall,et al.  The Defective Glucagon Response From Transplanted Intrahepatic Pancreatic Islets During Hypoglycemia Is Transplantation Site–Determined , 1997, Diabetes.

[44]  D. Kendall,et al.  Defective Glucagon Secretion During Sustained Hypoglycemia Following Successful Islet Allo- and Autotransplantation in Humans , 1997, Diabetes.

[45]  M. Oldstone,et al.  Virus-induced autoimmune disease , 1996, Current Opinion in Immunology.

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

[47]  B H Frank,et al.  Quantitative study of insulin secretion and clearance in normal and obese subjects. , 1988, The Journal of clinical investigation.

[48]  A. Matas,et al.  Total or Near Total Pancreatectomy and Islet Autotransplantation for Treatment of Chronic Pancreatitis , 1980, Annals of surgery.

[49]  A. Matas,et al.  Transplantation of Dispersed Pancreatic Islet Tissue in Humans: Autografs and Allografts , 1980, Diabetes.

[50]  U. Binswanger,et al.  A long-term functioning human pancreatic islet allotransplant. , 1980, Transplantation.