Factors Related to the Development of CMV-Specific CD8+ T cell Response in CMV-Seropositive Solid Organ Transplant Candidates

Cantisán, Sara; Rodelo-Haad, Cristian; Páez-Vega, Aurora; Nieto, Antonio; Vaquero, José M.; Poyato, Antonio; Montejo, Miguel; Fariñas, María Carmen; Rivero, Antonio; Solana, Rafael; Martín‐Malo, Alejandro; Torre‐Cisneros, Julián

doi:10.1111/ajt.13012

Cited by 26 publications

(16 citation statements)

References 35 publications

(50 reference statements)

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“…We would like to thank Fern andez-Ruiz et al (1) for their interest in our manuscript (2) and welcome the opportunity to address their comments on the factors influencing CMVspecific T cell response in transplant candidates.…”

Section: To the Editormentioning

confidence: 99%

Response to “Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates”

Cantisán

Solana

Torre‐Cisneros

2015

American Journal of Transplantation

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We would like to thank Fern andez-Ruiz et al (1) for their interest in our manuscript (2) and welcome the opportunity to address their comments on the factors influencing CMVspecific T cell response in transplant candidates.Whereas we show an association between HLA-A1 and/or HLA-A2 alleles and age older than 50 with CMV-specific CD8þ T cell response, their results did not show this association. Although the studies are apparently contradictory, they have considerable methodological differences which impact the results and their interpretation.Regarding the data analysis, we used logistic regression analysis and the results were given in terms of odds ratios. Thus, we reported that HLA-A1 and/or HLA-A2 candidates and those older than 50 have a higher probability of having CMV-specific CD8þ T cell response (IFNg !0.2 IU/mL) than non-HLA-A1/non-HLA-A2 candidates and those younger than 50. Fern andez-Ruiz and coworkers, however, analyze the association of HLA alleles and age with the magnitude of CMV-specific T cell response (absolute count of IFNgproducing T cells) using linear regression analysis.They also argue that the intracellular staining (ICS) method is the reference procedure for assessing CMV-specific T cell response, whereas the QuantiFERON-CMV (QF-CMV) assay used in our study introduces a bias because it primes the response against pp65 and IE-1 restricted by HLA-A1 and HLA-A2. However, the QF-CMV assay also includes pp50, gB, IE-2, and pp28 peptides. In fact, the immunodominant peptide restricted by HLA-A1 (VTEHDTLLY) derives from pp50, and not from pp65 or IE-1 (3-4). In contrast, they used peptide libraries of pp65 and IE-1 and not from other CMV proteins. Thus, each method uses different peptides for stimulation with its pros and cons. In addition, the QF-CMV assay has a well-established cut-off that classifies individuals as reactive (IFNg !0.2 IU/mL) and nonreactive in contrast to the ICS method, which does not have a standardized cut-off to define nonresponding individuals.Our results (2) are in line with those published by Giest and coworkers, who analyzed levels of CMV-specific CD8þ T cells in hematopoietic stem cell transplant (HSCT) patients and CMV-seropositive volunteers using HLA-A1/pp50, HLA-A1/pp65, HLA-A2/pp65, HLA-A24/pp65, and HLA-B35/pp65 combinations (5). In both healthy volunteers and HSCT patients, frequencies of CMV-specific CD8þ T cells targeting HLA-A1/pp50 or HLA-A2/pp65 were significantly higher than those targeting HLA-B35/pp65 or HLA-A24/pp65. The authors suggest that different HLA alleles provide protection against CMV reactivation in HSCT patients at different thresholds. Thus, the higher level of HLA-A1/pp50 and HLA-A2/pp65 CD8þ T cells might indicate that these responses are less efficient in the protection from CMV and higher number of cells is required to obtain the same protection.Finally, it is unquestionable that larger samples increase the chance of statistical significance because they more reliably reflect the population mean. Therefore, the lower sample size in...

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Section: To the Editormentioning

confidence: 99%

Response to “Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates”

Cantisán

Solana

Torre‐Cisneros

2015

American Journal of Transplantation

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“… SOT setting: Although there are only a few studies testing CMV‐specific CMI before SOT, all of them coincide in its utility for individualizing the post‐transplantation risk of CMV infection. Cantisan et al demonstrated that patients lacking pretransplant CMI (ie, nonreactive QuantiFERON‐CMV test) were more likely to develop post‐transplant CMV replication than those with a reactive assay at that point . Ritta et al and Bestard et al found that having low pretransplant CMV‐specific T‐cell responses was associated with a higher risk of post‐transplant CMV replication .…”

Section: Introductionmentioning

confidence: 99%

Going beyond serology for stratifying the risk of CMV infection in transplant recipients

Navarro

Fernández‐Ruiz

Aguado

et al. 2018

Reviews in Medical Virology

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Summary Knowledge of donor and recipient (D/R) cytomegalovirus (CMV) serostatus is critical for risk stratification of CMV infection and disease in transplant recipients, particularly in the solid organ transplantation (SOT) setting. Despite its broad availability and the success of it use, the risk stratification based on the D/R serostatus is not free of limitations since there are a nondepreciable number of patients that are not accurately categorized by this approach. In fact, up to 20% of seropositive SOT recipients, classically considered at intermediate risk, develop episodes of CMV infection and disease after transplantation. Here, we provide an overview of additional donor and recipient factors that may have utility in identifying patients at risk for post‐transplant CMV infection. Specifically, we summarize our current understanding regarding the potential use of use CMV‐specific T‐cell‐mediated immunity, neutralizing antibodies and host genetics that may influence the risk of CMV infection and disease. We provide an overview of the benefits and limitations associated with using these immunological factors in risk stratification and propose specific variables that could be analyzed at the pretransplant evaluation to improve the identification of patients with increased individual susceptibility.

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“…Despite the importance of humoral immunity, cellular immunity is considered more important in the virus control [1], with both CD8+ cytotoxic and CD4+ helper cells playing a central role in the resolution of acute infection and in the maintenance of long-term memory. In vitro studies demonstrated the association between production of IFN-gamma by the CD8 T lymphocytes and the risk of infection/CMV disease after transplantation [2], [3], [4], [5].…”

Section: Introductionmentioning

confidence: 99%

Cytomegalic hepatitis in a patient receiving omalizumab

Gonçalves

Valente

Ferreira

et al. 2016

IDCases

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Cytomegalovirus is a double stranded DNA virus that can be present in nearly all organs and body fluids. The primary infection is usually asymptomatic in the immunocompetent host and it is common among adolescents and young adults. The symptomatic form appears, in the majority of cases, as a mononucleosis syndrome with full recovery without specific treatment. We report a case of a 25 years old woman who presented with hepatitis due to CMV infection and history of omalizumab administration one month earlier. This recombinant monoclonal antibody is used to control refractory asthma and chronic spontaneous urticarial as it inhibits human IgE. Despite that, the long course of the disease lead us to initiate treatment with valganciclovir. The improvement after that was rapid and complete.

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Factors Related to the Development of CMV-Specific CD8+ T cell Response in CMV-Seropositive Solid Organ Transplant Candidates

Cited by 26 publications

References 35 publications

Response to “Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates”

Response to “Influence of Age and HLA Alleles on the CMV-Specific Cell-Mediated Immunity Among CMV-Seropositive Kidney Transplant Candidates”

Going beyond serology for stratifying the risk of CMV infection in transplant recipients

Cytomegalic hepatitis in a patient receiving omalizumab

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