Evidence for Instant Blood-Mediated Inflammatory Reaction in Clinical Autologous Islet Transplantation

Abstract

y These authors contributed equally.A nonspecific inflammatory and thrombotic reaction termed instant blood-mediated inflammatory reaction (IBMIR) has been reported when allogenic or xenogenic islets come into contact with blood. This reaction is known to cause significant loss of transplanted islets. We hypothesized that IBMIR occurs in patients undergoing total pancreatectomy followed by autologous islet transplantation (TP-AIT) and tested this hypothesis in 24 patients and in an in vitro model. Blood samples drawn during the peritransplant period showed a significant and rapid increase of thrombinanti-thrombin III complex (TAT) and C-peptide during islet infusion, which persisted for up to 3 h, along with a decreased platelet count. A concomitant increase in levels of inflammatory proteins IL-6, IL-8 and interferoninducible protein-10 was observed. An in vitro model composed of pure islets plus autologous blood also demonstrated significantly increased levels of TAT (p < 0.05), C-peptide (p < 0.05), tumor necrosis factoralpha (p < 0.05) and MCP-1 (p < 0.05), as well as strong tissue factor expression in islets. Islet viability decreased significantly but was rescued by the presence of low-molecular-weight dextran sulfate. In conclusion, AIT-induced elevation of TAT and destruction of islets suggests that IBMIR might occur during AIT. Modulating this process may help improve islet engraftment and the insulin independence rate in TP-AIT patients.

Clinical Islet Cell Transplantation – Recent Advances

“…Further examination on the presentation of islets to autologous blood utilizing a miniaturized in vitro tube model resulted in the expression of TF, verified by our previous in vivo findings 22 . Hence, it was evident that IBMIR is an issue in allogenic and xenogenic islet transplantation as well as in autologous islet transplantation.…”

“…Compstatin -a complement inhibitor treatment significantly improved the graft survival under in vivo conditions 26 . In contrast, there was no significant impact of complement proteins during IBMIR in clinical autologous islet transplantation 22 .…”

“…It attracts innate immune cells, resulting in the release of proinflammatory cytokines prompting the islet damage further by apoptosis 21 . The occurrence of IBMIR under allogeneic and xenogeneic combinations is well studied 19,20 , but its importance and existence in autologous islet infusion has not been clinically or experimentally illustrated 22 . Recently, our group observed IBMIR in patients undergoing total pancreatectomy followed by autologous islet transplantation.…”

Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet‐transplantation enhances immediate post‐transplant islet graft function but not long‐term normoglycemia

“…The liver as transplantation side is considered to be a major contributor to these low success rates. Inadequate revascularization,5 the large numbers of natural killer T cells in the liver,6 high concentrations of immunosuppressive drugs,7, 8 and the instant blood‐mediated inflammatory reaction9 play a role in islet graft failure after intraportal transplantation. Therefore, a more adequate transplantation site is required for this technology to gain widespread acceptance and practice.…”

Strategies in Preventing Diabetes after Pancreatectomy Using Islet Auto- and Allo-Transplantation

“…Instant Blood-Mediated Inflammatory Reaction (IBMIR) was previously found to be common in recipient of islet allo-or xenograft, however, recent study showed its incidence in islet autograft as well, indicated by elevated c-peptide and Thrombin-Anti-Thrombin III Complex (TAT) in blood post-operatively. In the case of TP-IAT, the cytokine release leading to IBMIR may have occurred because of the surgery process itself [57]. Despite these chances for failure, TP-IAT has been found to be safe overall, with low mortality, morbidity, and a good rate of achieving insulin independence [58].…”