Functional patterns of cytomegalovirus (<scp>CMV</scp>) pp65 and immediate early‐1‐specific <scp>CD</scp>8<sup>+</sup> T cells that are associated with protection from and control of <scp>CMV DNA</scp>emia after allogeneic stem cell transplantation

Giménez, Estela; Muñoz-Cobo, Beatriz; Solano, Carlos; Amat, Paula; Cámara, Rafael de la; Nieto, José; López, Javier; Remigia, María José; García‐Noblejas, Ana; Navarro, David

doi:10.1111/tid.12391

Cited by 27 publications

(24 citation statements)

References 33 publications

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“…Similar observations have been made in other studies utilizing quantitative or semi-quantitative methods for measurement of CMV immunity. 57,93,94 All of these methods are technically demanding and standardisation has not been achieved thus far. Studies using cut-off thresholds for CMV immunity are therefore not easily applied in routine clinical use.…”

Section: Measurement Of CMV Specific Immune Function In the Clinicmentioning

confidence: 99%

“…Multimer-based assessment provides no indication of functional responsiveness, and thus numeric thresholds may provide false reassurance of immunity in the early post-HSCT population. [90][91][92] Functional assays include the enzyme linked immunoassay (ELISPOT), 60 cytokine production assays 57,93,94 57 This study had a relatively high threshold CMV copy number for initiation of pre-emptive treatment (>30,000 copies/ml) so is helpful in understanding the natural history of CMV immune recovery in the absence of therapeutic intervention. It should be noted that the majority of patients were young recipients of bone marrow grafts and few had cord blood or T cell depleted transplants that are associated with higher risk of uncontrolled CMV infection.…”

Section: Measurement Of CMV Specific Immune Function In the Clinicmentioning

confidence: 99%

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CMV-specific immune reconstitution following allogeneic stem cell transplantation

et al. 2016

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Cytomegalovirus (CMV) remains a major contributor to morbidity and mortality following allogeneic haemopoietic stem cell transplant (HSCT) despite widespread use of viraemia monitoring and preemptive antiviral therapy. Uncontrolled viral replication occurs primarily in the first 100 d post transplant but this high risk period can extend to many months if immune recovery is delayed. The re-establishment of a functional population of cellular effectors is essential for control of virus replication and depends on recipient and donor serostatus, the stem cell source, degree of HLA matching and post-transplant factors such as CMV antigen exposure, presence of GVHD and ongoing use of immune suppression. A number of immune monitoring assays exist but have not yet become widely accessible for routine clinical use. Vaccination, adoptive transfer of CMV specific T cells and a number of graft engineering processes are being evaluated to enhance of CMV specific immune recovery post HSCT.

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Section: Measurement Of CMV Specific Immune Function In the Clinicmentioning

confidence: 99%

Section: Measurement Of CMV Specific Immune Function In the Clinicmentioning

confidence: 99%

CMV-specific immune reconstitution following allogeneic stem cell transplantation

et al. 2016

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“…Giménez et al reported that functional CMV-specific CD8 ? T cell responses, measured by IFNc and TNFa production, were found in patients without CMV viremia compared to recipients who developed it after allo-HSCT [109]. Besides, polyfunctional CD8 ?…”

Section: Intracellular Cytokine Stainingmentioning

confidence: 86%

The immune response to cytomegalovirus in allogeneic hematopoietic stem cell transplant recipients

Ciáurriz

Zabalza

Beloki

et al. 2015

Cell. Mol. Life Sci.

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Approximately, up to 70 % of the human population is infected with cytomegalovirus (CMV) that persists for life in a latent state. In healthy people, CMV reactivation induces the expansion of CMV-specific T cells up to 10 % of the entire T cell repertoire. On the contrary, CMV infection is a major opportunistic viral pathogen that remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Due to the delayed CMV-specific immune recovery, the incidence of CMV reactivation during post-transplant period is very high. Several methods are currently available for the monitoring of CMV-specific responses that help in clinical monitoring. In this review, essential aspects in the immune recovery against CMV are discussed to improve the better understanding of the immune system relying on CMV infection and, thereby, helping the avoidance of CMV disease or reactivation following hematopoietic stem cell transplantation with severe consequences for the transplanted patients.

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“…To study the cellular response to the entire pp65 protein in HCT recipients, we measured expression (%) of the 4-1BB (CD137) functional activation marker on CD3 + CD8 + and CD3 + CD4 + T cells stimulated for 24 hours with a peptide library encompassing the full sequence of the pp65 protein, including the pp65 495À503 epitope [25]. The IE1 protein is also highly recognized in CMV-seropositive HCT recipients, and both pp65 and IE1 CMV antigens are considered to play prominent roles in protective immunity [27,[31][32][33][34][35]. Thus, we also monitored the CD137 surface marker on CD3 + CD8 + and CD3 + CD4 + T cells stimulated with the IE1 peptide library, following previously described techniques [25].…”

Section: Functional Activation Markers and T Cell Memory Profiles Formentioning

confidence: 99%

Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax

Rosa

Longmate

Lingaraju

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T Early cytomegalovirus (CMV) reactivation remains a significant cause of morbidity and mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine designed to control CMV infection in HCT recipients seropositive for CMV by stimulating the expansion of T cell subsets that target the CMV tegument protein pp65. In a randomized Phase Ib pilot trial (ClinicalTrials.gov NCT01588015), two injections of CMVPepVax (at days 28 and 56 post-HCT) demonstrated safety, immunogenicity, increased relapse-free survival, and reduced CMV reactivation and use of antivirals. In the present study, we assessed the phenotypes and time courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. The functionality and antiviral role of CMV-specific T cells have been linked to immune reconstitution profiles characterized predominantly by differentiated effector memory T (TEM) subsets that have lost membrane expression of the costimulatory molecule CD28 and often reexpress the RA isoform of CD45 (TEMRA). Major histocompatibility complex class I pp65 495-503 multimers, as well as CD28 and CD45 memory markers, were used to detect immune reconstitution in blood specimens from HCT recipients enrolled in the Phase Ib clinical trial. Specimens from the 10 (out of 18) vaccinated patients who had adequate (.2%) multimer binding to allow for memory analysis showed highly differentiated TEM and TEMRA phenotypes for pp65 495-503 -specific CD8 T cells during the first 100 days post-transplantation. In particular, by day 70, during the period of highest risk for CMV reactivation, combined TEM and TEMRA phenotypes constituted a median of 90% of pp65 495-503 -specific CD8 T cells in these vaccinated patients. CMV viremia was not detectable in the patients who received CMVPepVax, although their pp65 495-503 -specific CD8 T cell profiles were strikingly similar to those observed in viremic patients who did not receive the vaccine. Collectively, our findings indicate that in the absence of clinically relevant viremia, CMVPep-Vax reconstituted significant levels of differentiated pp65 495-503 -specific CD8 TEMs early post-HCT. Our data indicate that the rapid reconstitution of CMV-specific T cells with marked levels of effector phenotypes may have been key to the favorable outcomes of the CMVPepVax clinical trial.

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Functional patterns of cytomegalovirus (CMV) pp65 and immediate early‐1‐specific CD8⁺ T cells that are associated with protection from and control of CMV DNAemia after allogeneic stem cell transplantation

Cited by 27 publications

References 33 publications

CMV-specific immune reconstitution following allogeneic stem cell transplantation

CMV-specific immune reconstitution following allogeneic stem cell transplantation

The immune response to cytomegalovirus in allogeneic hematopoietic stem cell transplant recipients

Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax

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Functional patterns of cytomegalovirus (CMV) pp65 and immediate early‐1‐specific CD8+ T cells that are associated with protection from and control of CMV DNAemia after allogeneic stem cell transplantation

Cited by 27 publications

References 33 publications

CMV-specific immune reconstitution following allogeneic stem cell transplantation

CMV-specific immune reconstitution following allogeneic stem cell transplantation

The immune response to cytomegalovirus in allogeneic hematopoietic stem cell transplant recipients

Rapid Acquisition of Cytomegalovirus-Specific T Cells with a Differentiated Phenotype, in Nonviremic Hematopoietic Stem Transplant Recipients Vaccinated with CMVPepVax

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Product

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Functional patterns of cytomegalovirus (CMV) pp65 and immediate early‐1‐specific CD8⁺ T cells that are associated with protection from and control of CMV DNAemia after allogeneic stem cell transplantation