Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection

Abstract

Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction. Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1β maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.

Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients

“…The innate immune system can be activated by several different cytokines resulting in rejection episode, 26,27 and activation of IL-1R pathway has a central role in ischemic reperfusion injury. 28 However, despite the overall higher proportion of CH patients experiencing acute cellular rejection, it failed to reach statistical significance. One possibility is that based on the 16% absolute increase observed, a sample size of over 400 patients would be required to reach statistical significance.…”

“…The complex relationship of immune phenomena and inflammation promoted by CH could be responsible for other outcomes in OHT recipients. The innate immune system can be activated by several different cytokines resulting in rejection episode, 26,27 and activation of IL‐1R pathway has a central role in ischemic reperfusion injury 28 . However, despite the overall higher proportion of CH patients experiencing acute cellular rejection, it failed to reach statistical significance.…”

Hypothermia-Triggered Mesoporous Silica Particles for Controlled Release of Hydrogen Sulfide to Reduce the I/R Injury of the Myocardium

“…Compared to PBS and NaHS groups, HE staining revealed less inflammatory cell infiltration in the donor heart treated with HT-MSN (Figure ). The level of IL-1β in donor hearts was found to be significantly elevated . Donor hearts were protected by genetic deletion or pharmacologic IL-1β blockade .…”

“…The level of IL-1β in donor hearts was found to be significantly elevated. 50 Donor hearts were protected by genetic deletion or pharmacologic IL-1β blockade. 51 Another factor affecting donor heart function is inflammation following prolonged myocardial ischemia.…”

Targeting IL-6 to prevent cardiac allograft rejection

“…Despite the increasing use of normothermic machine perfusion, static cold storage remains the most common preservation method in heart transplantation and further contributes to IL‐6‐related allograft injury in the form of IRI 22–26 . Prolonged ischemic times, which exacerbate IRI, are known risk factors for primary graft dysfunction (PGD), acute and chronic rejection, CAV, and poorer 30‐day survival 27–33 . Following implantation, graft‐derived IL‐6 serves as an innate danger signal that promotes the activation of peripheral CD4+ and CD8+ effector T cells (T eff ) through an antigen‐independent mechanism 34 …”