Cytomegalovirus-specific T cells restricted for shared and donor human leukocyte antigens differentially impact on cytomegalovirus reactivation risk after allogeneic hematopoietic stem cell transplantation

After allogeneic hematopoietic stem cell transplantation (HSCT), the emergence of circulating cytomegalovirus (CMV)- specific T cells correlates with protection from CMV reactivation, an important risk factor for non-relapse mortality. However, functional assays measuring CMV-specific cells are time...

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Vydané v:Haematologica (Roma) Ročník 108; číslo 6; s. 1530 - 1543
Hlavní autori: Tassi, Elena, Noviello, Maddalena, De Simone, Pantaleo, Lupo-Stanghellini, Maria T., Doglio, Matteo, Serio, Francesca, Abbati, Danilo, Beretta, Valeria, Valtolina, Veronica, Oliveira, Giacomo, Racca, Sara, Campodonico, Edoardo, Ruggiero, Eliana, Clerici, Daniela, Giglio, Fabio, Lorentino, Francesca, Dvir, Roee, Xue, Elisabetta, Farina, Francesca, Oltolini, Chiara, Manfredi, Francesco, Vago, Luca, Corti, Consuelo, Bernardi, Massimo, Clementi, Massimo, Brix, Liselotte, Ciceri, Fabio, Peccatori, Jacopo, Greco, Raffaella, Bonini, Chiara
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Italy Fondazione Ferrata Storti 01.06.2023
Ferrata Storti Foundation
Predmet:
CD8-Positive T-Lymphocytes
Cell Therapy & Immunotherapy
Cytomegalovirus - physiology
Cytomegalovirus Infections - etiology
Hematopoietic Stem Cell Transplantation - adverse effects
Hematopoietic Stem Cell Transplantation - methods
HLA Antigens
Humans
Prospective Studies
T-Lymphocytes
Transplantation, Homologous
ISSN:0390-6078, 1592-8721, 1592-8721
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Popis
Shrnutí:After allogeneic hematopoietic stem cell transplantation (HSCT), the emergence of circulating cytomegalovirus (CMV)- specific T cells correlates with protection from CMV reactivation, an important risk factor for non-relapse mortality. However, functional assays measuring CMV-specific cells are time-consuming and often inaccurate at early time-points. We report the results of a prospective single-center, non-interventional study that identified the enumeration of Dextramerpositive CMV-specific lymphocytes as a reliable and early predictor of viral reactivation. We longitudinally monitored 75 consecutive patients for 1 year after allogeneic HSCT (n=630 samples). The presence of ≥0.5 CMV-specific CD8+ cells/mL at day +45 was an independent protective factor from subsequent clinically relevant reactivation in univariate (P<0.01) and multivariate (P<0.05) analyses. Dextramer quantification correlated with functional assays measuring interferon-γ production, and allowed earlier identification of high-risk patients. In mismatched transplants, the comparative analysis of lymphocytes restricted by shared, donor- and host-specific HLA revealed the dominant role of thymic-independent CMV-specific reconstitution. Shared and donor-restricted CMV-specific T cells reconstituted with similar kinetics in recipients of CMV-seropositive donors, while donor-restricted T-cell reconstitution from CMV-seronegative grafts was impaired, indicating that in primary immunological responses the emergence of viral-specific T cells is largely sustained by antigen encounter on host infected cells rather than by cross-priming/presentation by non-infected donor-derived antigen-presenting cells. Multiparametric flow cytometry and high-dimensional analysis showed that shared-restricted CMV-specific lymphocytes display a more differentiated phenotype and increased persistence than donor-restricted counterparts. In this study, monitoring CMV-specific cells by Dextramer assay after allogeneic HSCT shed light on mechanisms of immune reconstitution and enabled risk stratification of patients, which could improve the clinical management of post-transplant CMV reactivations.
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Disclosures
ET and MN designed the study, conducted laboratory experiments, analyzed and interpreted data and wrote the paper; PDS designed the study, conducted laboratory experiments, and analyzed and interpreted data; MTLS, FS, EC, DC, FG, FL, EX, FF, CO, CC and MB provided clinical data and samples and participated in the data interpretation; MD performed statistical analyses; DA and FM participated in the high dimensional analysis of flow cytometry data; VB and VV participated in the laboratory experiments; GO participated in the design of the study; SR, RD and MC performed the QuantiFERON-CMV, and analyzed and interpreted the results; ER and LV participated in the discussion and interpretation of data; LB participated in the study design and reviewed the paper; FC and JP designed and supervised the study; RG and CB designed and supervised the study and wrote the paper.
Contributions
CB has received research support from Intellia Therapeutics and is a member of advisory boards or a consultant or speaker for Molmed, Intellia, TxCell, Novartis, GSK, Allogene, Kite/Gilead, Miltenyi, Kiadis, QuellTX, and Janssen. RG discloses honoraria for speaking at educational events supported by Biotest, Medac, Pfizer and Magenta.
The datasets generated for this study are available on request to the corresponding author.
Data-sharing statement
ISSN:0390-6078
1592-8721
1592-8721
DOI:10.3324/haematol.2022.280685