Evaluation of cytomegalovirus-specific cytotoxic T-lymphocytes in patients with the HLA-A*02 or HLA-A*24 phenotype undergoing hematopoietic stem cell transplantation

Morita, Yuriko; Hosokawa, Mami; Ebisawa, Michiko; Sugita, Takahisa; Miura, Osamu; Takaue, Yoichi; Heike, Yuji

doi:10.1038/sj.bmt.1705133

Cited by 21 publications

(25 citation statements)

References 36 publications

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“…We detected no CMV-CTLs using the HLA-A*2402 tetramer in 73% of the tests. This is in agreement with data published by others, who detected low levels of CMV-CTLs using the HLA-A*2402 tetramer when monitoring CMV-CTL reconstitution [19], [27], [28], [29], [30], [31], [32]. We also identified no correlation between the immune reconstitution of CD3 + CD8 + T cells and CMV-CTL levels detected using the HLA-A*2402 tetramer.…”

Section: Discussionsupporting

confidence: 93%

“…Since CMV reactivation did not occur more frequently in patients expressing the HLA-A*2402 molecule. We speculate that either lower levels of HLA-A*2402-corresponding CMV-CTLs are needed provide protection [19] or the immune-response in HLA-A*2402-positive individuals is dominated by other epitopes [27]. In addition to the different median levels of CMV-CTLs, we found that expression of different HLA alleles may interfere with the expansion of T cells specific for other HLA peptide combinations.…”

Section: Discussionmentioning

confidence: 79%

“…However, analyzing additional HLA molecules in our large patient cohort showed that different HLA types yield quite different median values of detectable CMV-CTLs (Figure 2). We and others observed that CMV-CTL levels detected by HLA-A*0101 (pp50 243–255 ) or HLA-B*3501 (pp65 123–131 ) were considerably higher or much lower than CMV-CTL levels detected by HLA-A*2402 (pp65 341–349 ), which yielded a mean of 4 per µl blood (Figure 2) [15], [18], [19], [27]. We detected no CMV-CTLs using the HLA-A*2402 tetramer in 73% of the tests.…”

Section: Discussionmentioning

confidence: 85%

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Sequential Anti-Cytomegalovirus Response Monitoring May Allow Prediction of Cytomegalovirus Reactivation after Allogeneic Stem Cell Transplantation

et al. 2012

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BackgroundReconstitution of cytomegalovirus-specific CD3+CD8+ T cells (CMV-CTLs) after allogeneic hematopoietic stem cell transplantation (HSCT) is necessary to bring cytomegalovirus (CMV) reactivation under control. However, the parameters determining protective CMV-CTL reconstitution remain unclear to date.Design and MethodsIn a prospective tri-center study, CMV-CTL reconstitution was analyzed in the peripheral blood from 278 patients during the year following HSCT using 7 commercially available tetrameric HLA-CMV epitope complexes. All patients included could be monitored with at least CMV-specific tetramer.ResultsCMV-CTL reconstitution was detected in 198 patients (71%) after allogeneic HSCT. Most importantly, reconstitution with 1 CMV-CTL per µl blood between day +50 and day +75 post-HSCT discriminated between patients with and without CMV reactivation in the R+/D+ patient group, independent of the CMV-epitope recognized. In addition, CMV-CTLs expanded more daramtaically in patients experiencing only one CMV-reactivation than those without or those with multiple CMV reactivations. Monitoring using at least 2 tetramers was possible in 63% (n = 176) of the patients. The combinations of particular HLA molecules influenced the numbers of CMV-CTLs detected. The highest CMV-CTL count obtained for an individual tetramer also changed over time in 11% of these patients (n = 19) resulting in higher levels of HLA-B*0801 (IE-1) recognizing CMV-CTLs in 14 patients.ConclusionsOur results indicate that 1 CMV-CTL per µl blood between day +50 to +75 marks the beginning of an immune response against CMV in the R+/D+ group. Detection of CMV-CTL expansion thereafter indicates successful resolution of the CMV reactivation. Thus, sequential monitoring of CMV-CTL reconstitution can be used to predict patients at risk for recurrent CMV reactivation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 85%

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Sequential Anti-Cytomegalovirus Response Monitoring May Allow Prediction of Cytomegalovirus Reactivation after Allogeneic Stem Cell Transplantation

et al. 2012

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“…Furthermore, it is essential that we should develop a universal monitoring method, which is not limited to HLA to cover larger populations, since an epitope that is potent enough for immunomonitoring is not obtained in some HLA types such as HLA-A24. 12 In this study, simultaneous functional analysis of CMV-specific lymphocytes by intracellular cytokine assay upon stimulation with CMV lysate and antigen peptide were performed with tetramer-based CTL quantification in patients who underwent HSCT to identify an optimal monitoring system.…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of cytomegalovirus-specific T lymphocytes compared to tetramer assay in patients undergoing hematopoietic stem cell transplantation

Morita-Hoshi

Heike

Kawakami

et al. 2007

Bone Marrow Transplant

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In order to evaluate whether we could predict reactivation of CMV by monitoring the number of CMV-specific cytotoxic T-lymphocytes (CTL), tetramer analysis was performed in 37 patients who underwent hematopoietic stem cell transplantation (HSCT). The results disclosed that the mean number of CMV-specific CTL at day 30 did not differ among patients who developed CMV antigenemia (22/ll) and those who did not (12/ll). Serial tetramer analysis showed that 21% of the patients had 410/ll CMV-specific CTL at the first detection of CMV antigenemia and 67% of the patients had more than 10/ll CMV-specific CTL at the onset of CMV disease. Intracellular staining upon stimulation by CMV lysates and peptide in patients with CMV colitis revealed that both IFN-c producing CD4 þ and CD8 þ lymphocytes were suppressed at the onset of CMV colitis (1.6 and 8/ll), which increased with recovery of the disease (19 and 47/ll). These data suggest that it is difficult to predict CMV reactivation solely by the number of CMV-specific CTL. We suggest that additional functional analysis by intracellular cytokine assay may be useful for immunomonitoring against CMV.

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“…Ozdemir et al demonstrated that frequencies of CMV-specific CD8 + T cells were significantly higher in those subjects who experienced early antigenemia relative to those who did not (2.2 vs 0.75%) (17). Meanwhile, HLA-A * 2402-CMVpp65 peptide (QYDPVAALF) tetramer was also shown to be effective for the early detection and specific and sensitive monitoring of blood CMV-specific CD8 + T cells in allogeneic SCT patients (18,19). More importantly, Gondo et al demonstrated that CMV-specific CD8 + T cells were constructed earlier in allogeneic peripheral blood SCT patients than allogeneic bone marrow SCT patients (18).…”

Section: Discussionmentioning

confidence: 99%

Characterization of cytomegalovirus pp65-HLA-A24 peptide-specific CTL lines from metastatic melanoma patients

Akiyama

Tai²,

Komiyama³

et al. 2009

Oncol Rep

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Abstract. Because of advances in immunological technology for detecting a very small number of blood CTL cells, clinicians have been able to monitor cellular immunity against CMV and evaluate the status of CMV infections in highly advanced cancer patients or transplant recipients. Our previous study using healthy volunteer PBLs revealed a significant increase in CMV HLA-A24 tetramer + CTLs after stimulation in vitro with autologous DCs. However, the efficiency of CMV A24 peptide-specific CTL expansion in highly advanced cancer patients has yet to be studied in detail. In the present study, we tried to characterize and expand HLA-A * 2402 CMVpp65 peptide (QYDPVAALF)-specific tetramer + CTLs from HLA-A * 2402 + metastatic melanoma patients, and eventually demonstrated that expansion efficiency was closely related to both post-stimulation CMV tetramer frequency and anti-CMV IgG titer. This is a novel finding regarding in vitro CMVpp65-A24 peptide-specific CTL expansion based on metastatic cancer patient-derived PBLs. Interestingly, the current results using metastatic melanoma PBLs showed a much higher frequency of CMVpp65-A24 tetramer + CTLs and expansion efficiency than in healthy volunteers. Finally, we were successful in cloning CMVpp65 HLA-A24 peptidespecific TCR cDNAs from in vitro expanded CTL lines derived from melanoma patients. Additionally, CMVpp65 HLA-A24 peptide-specific TCR cDNA was transduced into naive T cells from patients and functionally reconstructed. The results showed that cloned CMV-specific TCR genes were efficient in reconstituting specific anti-CMV activity and might be good tools for adoptive immunotherapy against CMV infections.

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Evaluation of cytomegalovirus-specific cytotoxic T-lymphocytes in patients with the HLA-A02 or HLA-A24 phenotype undergoing hematopoietic stem cell transplantation

Cited by 21 publications

References 36 publications

Sequential Anti-Cytomegalovirus Response Monitoring May Allow Prediction of Cytomegalovirus Reactivation after Allogeneic Stem Cell Transplantation

Sequential Anti-Cytomegalovirus Response Monitoring May Allow Prediction of Cytomegalovirus Reactivation after Allogeneic Stem Cell Transplantation

Functional analysis of cytomegalovirus-specific T lymphocytes compared to tetramer assay in patients undergoing hematopoietic stem cell transplantation

Characterization of cytomegalovirus pp65-HLA-A24 peptide-specific CTL lines from metastatic melanoma patients

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