Thrombomodulin Improves Early Outcomes After Intraportal Islet Transplantation

Abstract

Primary islet nonfunction due to an instant blood mediated inflammatory reaction (IBMIR) leads to an increase in donor islet mass required to achieve euglycemia. In the presence of thrombin, thrombomodulin generates activated protein C (APC), which limits procoagulant and proinflammatory responses. In this study, we postulated that liposomal formulations of thrombomodulin (lipo-TM), due to its propensity for preferential uptake in the liver, would enhance intraportal engraftment of allogeneic islets by inhibiting the IBMIR. Diabetic C57BL/6J mice underwent intraportal transplantation with B10.BR murine islets. In the absence of treatment, conversion to euglycemia was observed among 29% of mice receiving 250 allo-islets. In contrast, a single infusion of lipo-TM led to euglycemia in 83% of recipients (p = 0.0019). Fibrin deposition (p < 0.0001), neutrophil infiltration (p < 0.0001), as well as expression TNF-a and IL-b (p < 0.03) were significantly reduced. Significantly, thrombotic responses mediated by human islets in contact with human blood were also reduced by this approach. Lipo-TM improves the engraftment of allogeneic islets through a reduction in local thrombotic and inflammatory processes. As an enzyme-based pharmacotherapeutic, this strategy offers the potential for local generation of APC at the site of islet infusion, during the initial period of elevated thrombin production.

Beneficial Effects of Desferrioxamine on Encapsulated Human Islets—In Vitro and In Vivo Study

“…Human islets are subjected to both immunological and nonimmunological insults in the immediate posttransplantation period leading to islet cell death and graft failure (30)(31)(32)(33). VEGF is an angiogenic factor that is known to enhance survival of both endothelial and other cell types.…”

The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies

“…Consistent with this approach, a monoclonal anti-TF antibody (CNTO859) has been shown to enhance engraftment in a non-human primate marginal mass model (Berman et al, 2007). In addition to direct inhibition of TF, inhibition of the coagulation system at various stages of activation, for example by using the thrombin inhibitor Melagatran (Ozmen et al, 2002), active siteinactivated FVII (iFVIIa) (Moberg et al, 2002a), N-acetylcysteine (Beuneu et al, 2007), activated protein C (APC) (Contreras et al, 2004), anti-GP IIb/IIIa in combination with APC (Akima et al, 2009) or thrombomodulin (Cui et al, 2009), is able inhibit thromboinflammation in vitro or in vivo. As already mentioned, the complement inhibitor compstatin inhibits the release of C-peptide from pancreatic cells exposed to human plasma .…”

Islet surface PEGylation attenuate the instant blood-mediated inflammatory reaction in intrahepatic islet transplantation

“…High doses of heparin and complement inhibitors such as low molecular weight dextran sulfate and melagatran were able to overcome the islet destruction by inhibiting the IBMIR. [6][7][8][9][10] However, these drugs are limited in terms of their efficacy and safety because of a narrow therapeutic window and poor penetration into the thrombus. Furthermore, several literatures have demonstrated that isolated islets express at least 50 inflammation-associated genes, including those for monocyte chemotactic protein-1, interleukin-8, vascular DOI 10.1007/s13233-011-0904-y *Corresponding Author.…”