TY - JOUR
T1 - Impact of CMV reactivation, treatment approaches, and immune reconstitution in a nonmyeloablative tolerance induction protocol in cynomolgus macaques
AU - Alonso-Guallart, Paula
AU - Duran-Struuck, Raimon
AU - Zitsman, Jonah S.
AU - Sameroff, Stephen
AU - Pereira, Marcus
AU - Stern, Jeffrey
AU - Berglund, Erik
AU - Llore, Nathaly
AU - Pierre, Genevieve
AU - Lopes, Emily
AU - Kofman, Sigal B.
AU - Danton, Makenzie
AU - Sondermeijer, Hugo P.
AU - Woodland, David
AU - Kato, Yojiro
AU - Ekanayake-Alper, Dilrukshi K.
AU - Iuga, Alina C.
AU - Wuu, Cheng Shie
AU - Wu, Anette
AU - Ian Lipkin, W.
AU - Tokarz, Rafal
AU - Sykes, Megan
AU - Griesemer, Adam
N1 - Publisher Copyright:
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2020
Y1 - 2020
N2 - Background. Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. Methods. Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. Results. Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. Conclusions. We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8+ T cells proliferated during CMV viremia.
AB - Background. Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. Methods. Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. Results. Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. Conclusions. We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8+ T cells proliferated during CMV viremia.
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U2 - 10.1097/TP.0000000000002893
DO - 10.1097/TP.0000000000002893
M3 - Article
C2 - 31385931
AN - SCOPUS:85078814444
SN - 0041-1337
SP - 270
EP - 279
JO - Transplantation
JF - Transplantation
ER -