Ex vivo treatment of cytomegalovirus in human donor lungs using a novel chemokine-based immunotoxin
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Ex vivo treatment of cytomegalovirus in human donor lungs using a novel chemokine-based immunotoxin. / Ribeiro, Rafaela V.P.; Ku, Terrance; Wang, Aizhou; Pires, Layla; Ferreira, Victor H.; Michaelsen, Vinicius; Ali, Aadil; Galasso, Marcos; Moshkelgosha, Sajad; Gazzalle, Anajara; Jeppesen, Mads G.; Rosenkilde, Mette M.; Liu, Mingyao; Singer, Lianne G.; Kumar, Deepali; Keshavjee, Shaf; Sinclair, John; Kledal, Thomas N.; Humar, Atul; Cypel, Marcelo.
In: Journal of Heart and Lung Transplantation, Vol. 41, No. 3, 2022, p. 287-297.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Ex vivo treatment of cytomegalovirus in human donor lungs using a novel chemokine-based immunotoxin
AU - Ribeiro, Rafaela V.P.
AU - Ku, Terrance
AU - Wang, Aizhou
AU - Pires, Layla
AU - Ferreira, Victor H.
AU - Michaelsen, Vinicius
AU - Ali, Aadil
AU - Galasso, Marcos
AU - Moshkelgosha, Sajad
AU - Gazzalle, Anajara
AU - Jeppesen, Mads G.
AU - Rosenkilde, Mette M.
AU - Liu, Mingyao
AU - Singer, Lianne G.
AU - Kumar, Deepali
AU - Keshavjee, Shaf
AU - Sinclair, John
AU - Kledal, Thomas N.
AU - Humar, Atul
AU - Cypel, Marcelo
N1 - Publisher Copyright: © 2021 International Society for Heart and Lung Transplantation
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - chemokine-based immunotoxin
KW - ex vivo lung perfusion
KW - human cytomegalovirus
KW - latent cytomegalovirus
KW - lung transplantation
U2 - 10.1016/j.healun.2021.10.010
DO - 10.1016/j.healun.2021.10.010
M3 - Journal article
C2 - 34802874
AN - SCOPUS:85119489160
VL - 41
SP - 287
EP - 297
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
SN - 1053-2498
IS - 3
ER -
ID: 286300632