Tirofiban and Activated Protein C Synergistically Inhibit the Instant Blood Mediated Inflammatory Reaction (IBMIR) from Allogeneic Islet Cells Exposure to Human Blood

Akima, Satoshi; Hawthorne, Wayne J.; Favaloro, Emmanuel J.; Patel, Anita; Blyth, Katrina; Mudaliar, Yugan; Chapman, Jeremy R.; O’Connell, Philip J.

doi:10.1111/j.1600-6143.2009.02673.x

Cited by 29 publications

(24 citation statements)

References 21 publications

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“…Low-molecular-weight dextran sulfate (24) and a combination of Tirofiban and activated protein C (37) have also been tested in an ex vivo loop model and proved effective in ameliorating the thrombotic reaction in IBMIR. However, to date, neither of these treatment strategies has been reported.…”

Section: Discussionmentioning

confidence: 99%

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

et al. 2017

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Islet cell transplantation has limited effectiveness because of an instant blood-mediated inflammatory reaction (IBMIR) that occurs immediately after cell infusion and leads to dramatic β-cell death. In intraportal islet transplantation models using mouse and human islets, we demonstrated that α-1 antitrypsin (AAT; Prolastin-C), a serine protease inhibitor used for the treatment of AAT deficiency, inhibits IBMIR and cytokine-induced inflammation in islets. In mice, more diabetic recipients reached normoglycemia after intraportal islet transplantation when they were treated with AAT compared with mice treated with saline. AAT suppressed blood-mediated coagulation pathways by diminishing tissue factor production, reducing plasma thrombin-antithrombin complex levels and fibrinogen deposition on islet grafts, which correlated with less graft damage and apoptosis. AAT-treated mice showed reduced serum tumor necrosis factor-α levels, decreased lymphocytic infiltration, and decreased nuclear factor (NF)-κB activation compared with controls. The potent anti-inflammatory effect of AAT is possibly mediated by suppression of c-Jun N-terminal kinase (JNK) phosphorylation. Blocking JNK activation failed to further reduce cytokine-induced apoptosis in β-cells. Taken together, AAT significantly improves islet graft survival after intraportal islet transplantation by mitigation of coagulation in IBMIR and suppression of cytokine-induced JNK and NF-κB activation. AAT-based therapy has the potential to improve graft survival in human islet transplantation and other cellular therapies on the horizon.

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Section: Discussionmentioning

confidence: 99%

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

et al. 2017

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“…The safety of LMWDS administration and its mechanism of action by the induction of hepatocyte growth factor has been demonstrated in a recent phase I clinical trial (40). Furthermore, recombinant human-activated protein C and the platelet inhibitor tirofiban have successfully inhibited IBMIR (41). Those modifications and/or drugs might also inhibit IBMIR during TP-AIT.…”

Section: Moberg Et Almentioning

confidence: 99%

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

Naziruddin

Iwahashi

Kanak

et al. 2014

American Journal of Transplantation

172

149

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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.

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“…IBMIR has been connected to a variety of inflammatory mediators; binding of antibody and complement, rapid activation of the coagulation cascade and innate cellular infiltration all contribute to islet destruction and nonengraftment (13,17). The mechanistic understanding of IBMIR has developed over time via extensive in vitro assays measuring isolated variables suspected to play a part in this process (18)(19)(20)(21)(22)(23)(24). However, the redundancy of the immune system demands a dedicated in vivo evaluation of IBMIR performed using a rigorous and clinically relevant model.…”

Section: Introductionmentioning

confidence: 99%

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

Martin

Samy

et al. 2015

American Journal of Transplantation

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Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. Wild-type (WT) and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets (NPIs) were studied in non-immunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at one and 24 hours after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages, and platelets. Insulin, complement, antibody, neutrophils, macrophages, and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 hours in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.

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Tirofiban and Activated Protein C Synergistically Inhibit the Instant Blood Mediated Inflammatory Reaction (IBMIR) from Allogeneic Islet Cells Exposure to Human Blood

Cited by 29 publications

References 21 publications

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

α-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction

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

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

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