Effects of Ex Vivo Perfusion and Il-6 Receptor Blockade on Ischemia Reperfusion Injury in Cardiac Transplantation

Purpose In cardiac transplantation, ischemia reperfusion injury (IRI) remains a major problem associated with poor short and long-term outcomes. Since pro-inflammatory cytokines and endothelial activation have been hallmarks of IRI for decades, they can be addressed by recent therapeutic advancements. Normothermic ex vivo heart perfusion using the Organ Care System, but also pre-emptive treatment strategies for highly immunized recipients using the IL-6 receptor antibody tocilizumab, are in current clinical use. Therefore, we retrospectively studied blood samples from our clinical cardiac transplantation cohort for parameters of IRI. Methods In a novel protocol for heart transplantation (HTx) recipients with preformed donor-specific antibodies (pfDSA), an intraoperative application of tocilizumab (10mg/kg) was given together with 5 sessions of plasmapheresis, followed by one infusion of IgGAM (2g/kg) and a single dose of anti-CD20 antibody (rituximab). This protocol was applied to 6 recipients of OCS-preserved hearts. 10 recipients of OCS-preserved hearts without pfDSA did not receive tocilizumab (group 2). 24 recipients of standard heart transplants preserved on ice represent group 3. Donor or recipient demographics did not differ among the groups. Plasma levels of cytokines and endothelial markers were compared before, immediately after transplant surgery (T0), 24h (T24) and 3 weeks after transplantation. Results IRI could be measured in standard heart recipients at T0 and T24 by significantly increased levels of IL-6, CXCL8/IL-8, IL-18, Ang-2 and IGFBP-1 (all p<0.02). Normothermic OCS preservation reduced all of these proteins significantly (all p<0.05). Tocilizumab application increased only IL-6 levels at T0 (p<0.001) without significant changes of other proteins. In recipients of standard and OCS preserved hearts, TNF and sFasL were decreased at T0 (p<0.05) but remained stable in patients also treated with tocilizumab. Conclusion Normothermic ex vivo preservation in the OCS reduces IRI at the cytokine and endothelial level in recipient blood immediately after transplantation. Application of tocilizumab during transplantation blocks binding of IL-6 to its receptor leading to higher plasma levels. These effects may have a clinically relevant impact on ischemia reperfusion injury post cardiac transplantation. In cardiac transplantation, ischemia reperfusion injury (IRI) remains a major problem associated with poor short and long-term outcomes. Since pro-inflammatory cytokines and endothelial activation have been hallmarks of IRI for decades, they can be addressed by recent therapeutic advancements. Normothermic ex vivo heart perfusion using the Organ Care System, but also pre-emptive treatment strategies for highly immunized recipients using the IL-6 receptor antibody tocilizumab, are in current clinical use. Therefore, we retrospectively studied blood samples from our clinical cardiac transplantation cohort for parameters of IRI. In a novel protocol for heart transplantation (HTx) recipients with preformed donor-specific antibodies (pfDSA), an intraoperative application of tocilizumab (10mg/kg) was given together with 5 sessions of plasmapheresis, followed by one infusion of IgGAM (2g/kg) and a single dose of anti-CD20 antibody (rituximab). This protocol was applied to 6 recipients of OCS-preserved hearts. 10 recipients of OCS-preserved hearts without pfDSA did not receive tocilizumab (group 2). 24 recipients of standard heart transplants preserved on ice represent group 3. Donor or recipient demographics did not differ among the groups. Plasma levels of cytokines and endothelial markers were compared before, immediately after transplant surgery (T0), 24h (T24) and 3 weeks after transplantation. IRI could be measured in standard heart recipients at T0 and T24 by significantly increased levels of IL-6, CXCL8/IL-8, IL-18, Ang-2 and IGFBP-1 (all p<0.02). Normothermic OCS preservation reduced all of these proteins significantly (all p<0.05). Tocilizumab application increased only IL-6 levels at T0 (p<0.001) without significant changes of other proteins. In recipients of standard and OCS preserved hearts, TNF and sFasL were decreased at T0 (p<0.05) but remained stable in patients also treated with tocilizumab. Normothermic ex vivo preservation in the OCS reduces IRI at the cytokine and endothelial level in recipient blood immediately after transplantation. Application of tocilizumab during transplantation blocks binding of IL-6 to its receptor leading to higher plasma levels. These effects may have a clinically relevant impact on ischemia reperfusion injury post cardiac transplantation.