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

Iris K.A. Jones, Susan Orloff, Jennifer M. Burg, Nicole N. Haese, Takeshi F. Andoh, Ashley Chambers, Suzanne S. Fei, Lina Gao, Craig N. Kreklywich, Zachary J. Streblow, Kristian Enesthvedt, Alan Wanderer, James Baker, Daniel N. Streblow

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)44-59
Number of pages16
JournalAmerican Journal of Transplantation
Volume21
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • animal models
  • basic (laboratory) research/science
  • complication: infectious
  • heart (allograft) function/dysfunction
  • heart transplantation/cardiology
  • immune regulation
  • immunobiology
  • infection and infectious agents – viral: cytomegalovirus (CMV)
  • infectious disease

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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