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.
A thrombotic/inflammatory reaction is elicited when isolated islets of Langerhans come in contact with ABO-compatible blood. The detrimental effects of this instant blood-mediated inflammatory reaction (IBMIR) provide a reasonable explanation for the observation that an unexpectedly high number of islets, from several donors, are needed to produce normoglycemia in transplant patients with type 1 diabetes. In this study, the hypothesis that a specific thrombin inhibitor, Melagatran, could reduce IBMIR in an in vitro model in which human islets are exposed to ABO-compatible blood was tested. The administration of Melagatran abrogated IBMIR dose-dependently. Islets exposed to blood, in the absence or presence of 0.4 micromol/l Melagatran, exhibited a loss of integrity and were found to be trapped in macroscopic clots containing platelets and CD11b(+) leukocytes. At concentrations from 1 to 10 micromol/l, Melagatran inhibited both coagulation and complement activation. Also, platelet and leukocyte activation and consumption were decreased. Islet morphology was maintained with almost no platelets adhering to the surface, and infiltration by CD11b(+) leukocytes was considerably reduced. In conclusion, Melagatran significantly reduced IBMIR in this model system. This protective effect indicates that thrombin plays a pivotal role in IBMIR and suggests that thrombin inhibition can improve the outcome of clinical islet transplantation.
Ozmen
Lisa
L
Department of Radiology, Oncology and Clinical Immunology, Division of Clinical Immunology, the Rudbeck Laboratory, University Hospital, Uppsala, Sweden.
Ekdahl
Kristina Nilsson
KN
Elgue
Graciela
G
Larsson
Rolf
R
Korsgren
Olle
O
Nilsson
Bo
B
D000017:ABO Blood-Group System; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000627:therapeutic use; D001384:Azetidines; D001596:Benzylamines; D001792:Blood Platelets / Q000473:pathology; D018845:CD11 Antigens / Q000032:analysis; D002102:Cadaver; D005260:Female; D005337:Fibrin / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood* / Q000473:pathology / Q000517:prevention & control*; D007515:Islets of Langerhans / Q000503:physiopathology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000032:analysis; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control
D000017:ABO Blood-Group System; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D018845:CD11 Antigens; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C109573:melagatran; D005337:Fibrin; D013917:Thrombin; D005998:Glycine