Inhibition of Thrombin Abrogates the Instant Blood-Mediated Inflammatory Reaction Triggered by Isolated Human Islets

Abstract

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 mol/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 mol/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.

Composite Islet‐Endothelial Cell Grafts: A Novel Approach to Counteract Innate Immunity in Islet Transplantation

“…IBMIR is characterized by a number of events including platelet consumption, activation of the coagulation and complement cascade systems, and leukocyte infiltration (1,3). The thrombin inhibitor, melagatran, inhibits IBMIR in an in vitro blood loop model (4). Similar beneficial effects were obtained using an antibody against TF or inactivated factor VII as a means to block TF-induced coagulation (2).…”

Thrombin-Activatable Fibrinolysis Inhibitor Is Activated in an Instant Blood-Mediated Inflammatory Reaction After Intraportal Islet Transplant

“…3,[16][17][18] However, it is difficult to apply these anticoagulants in the clinical environment because systemic administration is associated with an increased risk of severe bleeding. 19 Therefore, there is an urgent need to explore new therapeutic target for treating IBMIR with fewer bleeding complications.…”

Blood vessels of human islets of Langerhans are surrounded by a double basement membrane

“…Human islet isolation and short-term culture Human pancreas was processed and islets were isolated as described earlier [22] in the Central Laboratory of the Nordic Network for Clinical Islet Transplantation in Uppsala, Sweden. After Ficoll gradient purification, fractions rich in islets (60-85%) were collected and shipped on ice to Helsinki.…”