Ex vivo treatment of cytomegalovirus in human donor lungs using a novel chemokine-based immunotoxin

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Documents

  • Rafaela V.P. Ribeiro
  • Terrance Ku
  • Aizhou Wang
  • Layla Pires
  • Victor H. Ferreira
  • Vinicius Michaelsen
  • Aadil Ali
  • Marcos Galasso
  • Sajad Moshkelgosha
  • Anajara Gazzalle
  • Mads G. Jeppesen
  • Rosenkilde, Mette
  • Mingyao Liu
  • Lianne G. Singer
  • Deepali Kumar
  • Shaf Keshavjee
  • John Sinclair
  • Thomas N. Kledal
  • Atul Humar
  • Marcelo Cypel

Background: Transmission of latent human cytomegalovirus (HCMV) via organ transplantation with post-transplant viral reactivation is extremely prevalent and results in substantial adverse impact on outcomes. Therapies targeting the latent reservoir within the allograft to mitigate viral transmission would represent a major advance. Here, we delivered an immunotoxin (F49A-FTP) that targets and kills latent HCMV aiming at reducing the HCMV reservoir from donor lungs using ex-vivo lung perfusion (EVLP). Methods: HCMV seropositive human lungs were placed on EVLP alone or EVLP + 1mg/L of F49A-FTP for 6 hours (n = 6, each). CD14+ monocytes isolated from biopsies pre and post EVLP underwent HCMV reactivation assay designed to evaluate viral reactivation capacity. Off-target effects of F49A-FTP were studied evaluating cell death markers of CD34+ and CD14+ cells using flow cytometry. Lung function on EVLP and inflammatory cytokine production were evaluated as safety endpoints. Results: We demonstrate that lungs treated ex-vivo with F49A-FTP had a significant reduction in HCMV reactivation compared to controls, suggesting successful targeting of latent virus (76% median reduction in F49A-FTP vs 15% increase in controls, p = 0.0087). Furthermore, there was comparable cell death rates of the targeted cells between both groups, suggesting no off-target effects. Ex-vivo lung function was stable over 6 hours and no differences in key inflammatory cytokines were observed demonstrating safety of this novel treatment. Conclusions: Ex-vivo F49A-FTP treatment of human lungs targets and kills latent HCMV, markedly attenuating HCMV reactivation. This approach demonstrates the first experiments targeting latent HCMV in a donor organ with promising results towards clinical translation.

Original languageEnglish
JournalJournal of Heart and Lung Transplantation
Volume41
Issue number3
Pages (from-to)287-297
ISSN1053-2498
DOIs
Publication statusPublished - 2022

Bibliographical note

Publisher Copyright:
© 2021 International Society for Heart and Lung Transplantation

    Research areas

  • chemokine-based immunotoxin, ex vivo lung perfusion, human cytomegalovirus, latent cytomegalovirus, lung transplantation

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