Islet surface heparinization prevents the instant blood-mediated inflammatory reaction in islet transplantation.
OBJECTIVE
In clinical islet transplantation, the instant blood-mediated inflammatory reaction (IBMIR) is a major factor contributing to the poor initial engraftment of the islets. This reaction is triggered by tissue factor and monocyte chemoattractant protein (MCP)-1, expressed by the transplanted pancreatic islets when the islets come in contact with blood in the portal vein. All currently identified systemic inhibitors of the IBMIR are associated with a significantly increased risk of bleeding or other side effects. To avoid systemic treatment, the aim of the present study was to render the islet graft blood biocompatible by applying a continuous heparin coating to the islet surface.


METHODS
A biotin/avidin technique was used to conjugate preformed heparin complexes to the surface of pancreatic islets. This endothelial-like coating was achieved by conjugating barely 40 IU heparin per full-size clinical islet transplant.


RESULTS
Both in an in vitro loop model and in an allogeneic porcine model of clinical islet transplantation, this heparin coating provided protection against the IBMIR. Culturing heparinized islets for 24 h did not affect insulin release after glucose challenge, and heparin-coated islets cured diabetic mice in a manner similar to untreated islets.


CONCLUSIONS
This novel pretreatment procedure prevents intraportal thrombosis and efficiently inhibits the IBMIR without increasing the bleeding risk and, unlike other pretreatment procedures (e.g., gene therapy), without inducing acute or chronic toxicity in the islets.
Cabric
Sanja
S
Division of Clinical Immunology, Department of Oncology, Radiology, and Clinical Immunology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Sanchez
Javier
J
Lundgren
Torbjörn
T
Foss
Aksel
A
Felldin
Marie
M
Källen
Ragnar
R
Salmela
Kaija
K
Tibell
Annika
A
Tufveson
Gunnar
G
Larsson
Rolf
R
Korsgren
Olle
O
Nilsson
Bo
B
D000017:ABO Blood-Group System / Q000276:immunology; D000818:Animals; D042783:Endothelial Cells / Q000187:drug effects; D006085:Graft Survival; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000473:pathology* / Q000601:surgery; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods* / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D010477:Perfusion; D013552:Swine; D046509:Tissue Culture Techniques; D014182:Transplantation, Autologous / Q000276:immunology / Q000379:methods / Q000473:pathology; D014183:Transplantation, Heterologous / Q000276:immunology / Q000379:methods / Q000473:pathology
D000017:ABO Blood-Group System; D006493:Heparin