Liposomal Formulations of Thrombomodulin Increase Engraftment after Intraportal Islet Transplantation

Abstract

Early destruction of donor islet grafts due to an instant blood-mediated inflammatory reaction (IBMIR) remains a major obstacle in islet transplantation. Thrombomodulin plays an important role in limiting coagulation and inflammatory events through a variety of effects. In this study, we investigated the ability of thrombomodulin (TM), when reconstituted as a liposomal formulation, to enhance early syngeneic islet engraftment by minimizing or abrogating the IBMIR. Administration of TM significantly improved early engraftment of syngeneic islets after intraportal transplantation in diabetic mice. In the absence of treatment, conversion to euglycemia was observed among 46.6% (7/15) of recipients. In contrast, administration of TM led to euglycemia in 93.3% (14/15) of recipients ( p = 0.0142). Recipients that received TM exhibited a lower incidence of primary nonfunction and better glucose control over a 30-day period after transplantation. Fibrin deposition ( p < 0.05), neutrophil infiltration ( p < 0.05), expression of TNF-α and IL-β mRNA ( p < 0.05), as well as NF-κB activity ( p < 0.05) were significantly reduced in the liver of islet recipients having been treated with liposomal TM. These data demonstrate that TM significantly improves early syngeneic islet engraftment through effects that target both coagulation and inflammatory pathways.