scholarly journals Paradoxical Effect of Donor Cytomegalovirus (CMV) Status on CMV Reactivation after T-Cell Depleted (TCD) Stem Cell Transplantation (SCT)

2015 ◽  
Vol 21 (2) ◽  
pp. S302-S303
Author(s):  
Yao-Ting Huang ◽  
Julia Foldi ◽  
Kun Xiao ◽  
Dick Chung ◽  
Dionysios Neofytos ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Paradoxical Effect ◽  
Cmv Reactivation ◽  
Cmv Status

scholarly journals Letermovir Administration to Prevent Cytomegalovirus Reactivation Is the Potential Risk of Chronic Graft-Versus-Host Disease in Patients Who Received Haploidentical Stem-Cell Transplantation With Post-Transplant Cyclophosphamide

2021 ◽  
Vol 11 ◽  
Author(s):  
Toshiki Terao ◽  
Ken-ichi Matsuoka ◽  
Kentaro Narita ◽  
Takafumi Tsushima ◽  
Satoshi Yuyama ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Recovery ◽  
Activated T Cells ◽  
Post Transplant ◽  
Hla Dr ◽  
Cmv Reactivation

The prevention of chronic graft-versus-host disease (cGVHD) is important for recipients of hematopoietic stem-cell transplantation (HSCT). As one of the etiologies, the relationship between early T-cell recovery and subsequent cGVHD development has been the focus of attention. Recently, letermovir (LTV) was approved for preventing cytomegalovirus (CMV) reactivation in the early transplantation phase. Although CMV affects the immune reconstitution after HSCT, the impacts of LTV to prevent CMV reactivation on early T-cell recovery and cGVHD have not been fully investigated. We aimed to identify early T-cell recovery under LTV at day 30 in 15 and 33 recipients from matched related donors (MRDs) and haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo), respectively. Early increases in the levels of total lymphocytes and HLA-DR+ activated T-cells at day 30 were observed under CMV prophylaxis by LTV only in PTCy-haplo recipients and not in MRD recipients. Moreover, PTCy-haplo recipients with LTV showed a significantly higher incidence of cGVHD, but not acute GVHD. Our observations suggest that an early increase in the levels of HLA-DR+ activated T-cells may be implicated in the development of cGVHD in patients treated with PTCy who received LTV. Further studies are warranted to validate our results and elucidate the detailed mechanisms of our new insights.

Transplant Donor KIR Genotype Influences the Rate of CMV Reactivation Following T-Replete Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 188-188 ◽  
Author(s):  
Mark Cook ◽  
David C. Briggs ◽  
Charles F. Craddock ◽  
Premini Mahendra ◽  
Donald Milligan ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloablative Conditioning ◽  
Kir Genes ◽  
Group A ◽  
Group B ◽  
Cmv Reactivation ◽  
Haplotype A

Abstract Background CMV reactivation is the commonest viral complication following allogeneic stem cell transplantation (SCT) and is a direct consequence of immunodeficiency. Natural killer (NK) and T-cells are the primary effector populations that suppress CMV replication. Killer immunoglobulin-like receptors (KIRs) are expressed on the surface of NK cells and T-cell subsets. Inhibitory KIRs have specificity for defined alleles of class I HLA and deliver an inhibitory signal to the cell. Activating KIRs bind weakly to HLA molecules and their true ligands remain unknown. KIR genes are polymorphic. Two broad haplotypes exist which differ in the number of activatory KIR genes that they contain. Haplotype A has 1 activatory KIR gene whereas haplotype B contains additional activatory genes. Methods We studied 107 patients undergoing allogeneic SCT at 3 UK Institutions to evaluate the effect of activating KIRs on CMV reactivation. Two thirds received standard myeloablative conditioning with TBI/Cy or Bu/Cy. One third received non-myeloablative conditioning. Recipient/donor CMV sero-status was determined by ELISA. Reactivation was defined as two successive PCR assays detecting >400 copies/ml. KIR genotyping was performed by PCR-SSP. Results In CMV seropositive recipients, the CMV reactivation rate was 50% in transplants from sibling donors and 64% in transplants from unrelated or HLA non-identical donors. In sibling transplants where both donor and recipient were CMV seropositive and the donor was homozygous for KIR Haplotype A (group A) the CMV reactivation rate was 65% .In contrast if the donor possessed at least one KIR haplotype B (group B) the reactivation rate was reduced to 27.5% (p=0.014). The protective effect of group B donors was seen only in patients who received a myeloablative non-T-depleted transplant. Here, the reactivation rate was 70.6% (12 from 17) when transplanted from a group A donor compared with 23.8% (5 from 21) when transplanted from a group B donor (p=0.0039). If a group B donor was used no reactivation was seen after 41 days, whereas in transplants from group A donors the risk of reactivation continued until day 100 (figure 1,p=0.018). The donor KIR genotype did not influence CMV reactivation rates in patients who received T-depleted grafts from sibling, unrelated or haploidentical donors. Conclusion In T-cell replete sibling donor transplants the use of a donor with multiple activating KIRs significantly reduces the risk of CMV reactivation when both donor and recipient are CMV seropositive. This is the first direct evidence of activating KIRs exerting a controlling effect on CMV in humans.

scholarly journals Clonal Dynamics and Publicness of CMV-Specific TCR Repertoire after Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4551-4551
Author(s):  
Takashi Toya ◽  
Ayumi Taguchi ◽  
Kazutaka Kitaura ◽  
Yuki Otsuka ◽  
Ryosuke Konuma ◽  
...  
Keyword(s):  
Stem Cell ◽  
Next Generation Sequencing ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Peripheral Blood ◽  
Tcr Repertoire ◽  
Cmv Reactivation ◽  
Generation Sequencing

[Background] Cytomegalovirus (CMV) disease is a major complication after allogeneic stem cell transplantation (SCT). However, mechanisms of adoptive immunity against CMV are not fully elucidated. Recently, high-throughput next-generation sequencing (NGS) technology made it possible to shed light on the detailed and comprehensive landscape of T-cell receptor (TCR) repertoire. In this study, we analyzed TCR repertoire of CMV-specific cytotoxic T-cells (CMV-CTLs) in patients who suffered from CMV reactivation after SCT to clarify the diversity and dynamics of CMV-specific T-cell immunity. [Methods] We sequentially collected peripheral blood mononuclear cells from patients with HLA-A*24:02 who received SCT in our institution. Samples were collected weekly or every two weeks from their neutrophil engraftment until approximately 100 days after SCT. CMV reactivation was evaluated weekly with CMV antigenemia test. CD8 and CMV pp65 tetramer positive cells were sorted and unbiased next-generation sequencing-based analyses of TRBV/TRBJ gene segments were performed at the timing of CMV reactivation in 16 patients, and TRA gene segments were also analyzed in 10 patients. In addition, TCR beta repertoires after 2-4 weeks were analyzed in 12 patients. In the 12 patients, the dynamics of TCR repertoire diversity and proportional changes of each clone were assessed. We evaluated the diversity by Shannon-Weber index, and we defined TCR beta clonotypes found in two or more patients using the same TRBV/TRBJ gene segments and CDR3 amino acid sequences as public. This study was approved by the ethics committee of Tokyo Metropolitan Komagome Hospital. [Results] Among 16 patients, 11 received bone marrow, 3 received peripheral blood stem cells, and 2 received cord blood transplant. Underlying diseases were acute myeloid leukemia in 7, acute lymphoblastic leukemia in 7, and myelodysplastic syndromes in 2 patients. Median age at SCT was 50 years old (range: 20-71). Median duration from SCT to first CMV reactivation was 39 days (range: 16-55) and 7 patients (43.8%) were administered systemic corticosteroid at the time of reactivation (prednisolone 10-30mg/day). Median peripheral blood CMV-CTLs count at that time was 29.47/uL (range: 4.65-229.6). In most patients TCR beta repertoire of CMV-specific CTLs when CMV reactivated was highly skewed (median Shannon-Weber index was 1.44 [range: 0.542-3.164]). TCR alpha and beta were analyzed together in 10 patients and their diversity correlated well (p<0.001). Interestingly, 12 of 16 patients (75.0%) had at least one public TCR and, in all 12 patients with public TCR, the most frequent TCRs were public. Diversity of TCR repertoire was significantly lower in patients with public TCR compared with those in patients without (p=0.039). There was no obvious association between presence of public TCR and multiple events of CMV reactivation (p=0.57). When we evaluated clonal transition in 12 patients whose TCR beta repertoires were analyzed sequentially, the public clonotypes were continuously detected in 10 of 11 patients with public TCR and remained dominant in 9, while in one patient frequency of the most frequent public clone declined massively (from 50.25% among assigned reads to 6.63%). In addition, there were two patterns of subsequent clonal behavior in TCR repertoire of CMV-CTLs. In 10 patients, prevailing clones persisted and TCR repertoires of CMV-CTLs remained oligoclonal (Figure A). However, in other two patients, TCR repertoires of CMV-CTLs became more diverse (Shannon-Weber index at the time of reactivation and a few weeks after was 0.558/2.958 in one patient and 1.471/3.86 in another), major clones lost, and new private clones appeared afterwards (Figure B). Polyclonal pattern (TCR repertoire of CMV-CTLs was diverse at the time of reactivation or after a few weeks) was detected in 3 patients out of 16 patients, and the pattern was exclusively seen in patients who were administered corticosteroid when CMV reactivated (42.9% vs 0.0%, p=0.063). [Conclusion] TCR repertoire of CMV-CTLs at the time of CMV reactivation after SCT is highly oligoclonal and frequently shared among different patients, but can dynamically change in a short period in some patients. Functional analyses of the dominant TCRs to understand their reactivity against CMV epitope and elucidation of the clinical significance and developmental mechanisms of clone shift are strongly warranted. Figure Disclosures Kitaura: Repertoire Genesis Inc.: Employment. Suzuki:Repertoire Genesis Inc.: Equity Ownership.

scholarly journals Prognostic Value of Lymphopenia and Lymphocytosis after Peripheral Blood Haplo-Identical Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3319-3319
Author(s):  
Yannick LE Bris ◽  
Thierry Guillaume ◽  
Camille Debord ◽  
Pierre Peterlin ◽  
Soraya Wuilleme ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation ◽  
Cmv Status

Introduction Chronic expansion of large granular lymphocytes (LGL) has been reported after classical matched allogeneic hematopoietic stem cell transplantation (SCT) with bone marrow, peripheral (PB) or cord blood (CB) as source of graft. This proliferation is indolent and carries a favorable prognosis. Little is known of the incidence and features of LGL expansions in haplo-SCT with post-transplant cyclophosphamide (PTCy), where the impact of the duration of lymphopenia is also ill-documented. Patients & methods This study included 85 adult patients (pts) who received a haplo-SCT between 11/2013 and 03/2019 for hematological diseases. The 3 conditioning regimen used were i) Baltimore (n=28, 11/2013-05/2017) i.e. fludarabine 30 mg/m²/day (d), d -6 to -2, cyclophosphamide 14.5 mg/kg d -6, low dose total body irradiation (LDTBI) 2 Grays d-1, ii) Clo-Baltimore (n=28, 03/2014-04/2017), i.e. Clofarabine 30 mg/m²/d, d -6 to -2, cyclophosphamide 14.5 mg/kg d -6, LDTBI 2 Grays d -1, iii) CloB2A1 (n=29, 05/2017-03/2019) with Clofarabine 30 mg/m²/d,d -6 to -2, busulfan 3,4 mg/kg d -3 and -2, ATG 2,5 mg/kg d-1. All pts received mobilized PB as SC source on d 0 and PTCY 50 mg/kg/d on d +3 and +4 with cyclosporine and mycophenolate mofetyl as graft versus host disease (GVHD) prophylaxis. All pts provided informed consent for data collection. The duration of lymphopenia (<1.5x109/L) as well as occurrence, duration and immunophenotype of LGL expansion (>4x109/L) were recorded. The patients with primary graft failure (n=6) or dead before 3 months (mo) post-SCT were excluded (n=7). Engraftment was monitored by qPCR on PB cells and sorted CD3+ T-cells. TCR-γ/β gene rearrangements of CD3+ collected during sustained lymphocytosis were assessed with the Biomed-2 PCR method (n=7). Data were analyzed considering viral reactivation episodes (CMV, EBV, HHV6 or BK virus), acute or chronic GVHD, relapse and survival. Results The study included 72 adults treated with haplo-SCT (43 males, median age: 59 yo (24-71)) with a median follow-up of 31 mo for alive patients. Most pts had a myeloid disease (64%) and 57% were in complete remission at the time of haplo-SCT. The median duration of lymphopenia was 6 mo (1-49), significantly shorter in pts with a CloB2A1 conditioning (151 d vs. Baltimore 293 d vs. Clo-Baltimore 387 d, p=0.003) or with CMV reactivation (138 d vs 361 d, p<0.0001). Brisk LGL expansion was characterized morphologically in 10 pts (14%), of donor origin in the 9 pts tested. It occurred at a median of 5 mo (2-8), whatever the GVHD prophylaxis. These pts had a shorter duration of lymphopenia (4 vs 10 mo, p=0.0002). The median duration of LGL expansion was 6 mo (0.1-22) with a median lymphocyte count of 5.8x109/L (4.3-19.4). Immunophenotyping disclosed expansions of NK-cells (n=2), CD8+ CD4- T-cells (n=6) or CD4- CD8- TCR gd T-cells (n=2). They were oligoclonal (n=4) or monoclonal (n=3). A recipient CMV+ status was strongly associated with the onset of LGL expansion (89% vs 20%, p=0.0001), and with CMV reactivation (35% vs 4%, p=0.001) but not with that of other viruses. Grade 2-4 acute and chronic GVHD were not correlated with LGL expansion. ROC curve analyses identified that pts with more than 216 d of lymphopenia (AUC=0.83, p<0.001) had a better 2y disease-free survival (DFS) (77% vs 38%, p=0.0008) and 2y overall survival (OS) (81% vs 45%, p =0.0006) (Fig. 1). LGL expansion was associated with a significantly lower incidence of relapse (10% vs 50%, p=0.03), better 2y-DFS (86% vs. 51%, p=0.05) and a trend towards a better 2y-OS (86% vs. 54%, p=0.1) (Fig. 2). Only 1 of these pts has relapsed and died of transplant-related mortality. Neither the recipient's CMV status nor CMV reactivation influenced DFS or OS. Multivariate analysis showed that the disease risk index score (Armand 2014), lymphopenia (>216 days) and LGL expansion, but not age (> 60yo), were independently associated with a better DFS and OS (p<0.0001). Conclusion A shorter duration of lymphopenia after haplo-SCT confers unexpectedly shorter survivals, suggesting the expansion of non-allo-reactive T-cells with a reduced graft versus leukemia effect. LGL expansion (14%) is not a rare event after haplo-SCT, mainly involves CD8+ T-cells, occurs preferably in CMV+ recipients or in pts with CMV reactivation. It is associated with a favorable outcome, similar to that observed in matched and CB SCT. Disclosures Peterlin: AbbVie Inc: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Chevallier:Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria.

Human Cytomegalovirus: Degranulation Is a Prominent Feature of Functionally Impaired pp65- and IE-1-Specific T-Cells in Patients after Allogeneic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2572-2572
Author(s):  
Stephan Fuhrmann ◽  
Susanne Ganepola ◽  
Lutz Uharek ◽  
Eckhard Thiel ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Human Cytomegalovirus ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Cmv Reactivation

Abstract Human cytomegalovirus (CMV) reactivation and disease is still a frequent complication after allogeneic stem cell transplantation (allo SCT). It is well accepted that T-cell immunity is mandatory to control CMV infection and disease and much effort has been put into the development of cell-based monitoring assays. Nevertheless, no reliable marker for protective immunity has been established to date. Most studies use one CMV model antigen (pp65) to compare the frequencies of cytokine producers (mainly IFNg) or multimer-specific T-cells. Methods: In total, we recruited 16 patients after allo SCT, (7 high risk, 9 standard risk pts.). We used 8-colour flow cytometry to detect degranulation (mobilized CD107a/b), intracellular IFNg, TNFa, IL-2 production and CD28-expression in peptide pool stimulated pp65 and IE-1 specific CD8 T-cells. Results were compared to 7 healthy CMV exposed donors. Results: Degranulation identifies the highest percentage of CMV-specific T-cells in allo-transplanted patients (pp65: 0,94% degranulation and 0,31% IFNg; IE-1: 1,44% degranulation and 0,87% IFNg, mean frequency). These T-cells are relatively cytokine deficient compared to those in healthy donors (cytokine-production/degranulation ratio: SCT=0,42, healthy=0,72 for pp65, p=0,048; SCT=0,61, healthy= 1,00 for IE-1, p=0,133, U-test). The cytokine expression pattern differs between antigens used for stimulation, for example more IL-2-producers could be detected in the pp65 specific compartment (12,5% for pp65 and 4,5% for IE-1 of all activated CD8 T-cells, p=0,015). Conclusion: This study demonstrates that degranulation is the most prominent marker of CMV-specific T-cells (pp65 and IE-1) in allo SCT patients. Looking at IFN-g producers only may underestimate the frequencies of CMV specific T-cells in this setting. Furthermore, these subsets have a divergent functionality in transplant recipients compared to healthy individuals. Our data challenge the concept of enumerating CMV specific T-cells to estimate immunity. We rather propose measuring functional differences in the T-cell response may help to identify patients with a high risk of CMV reactivation. A careful dissection of these differences is a prerequisite for the development of monitoring tools and adoptive T-cell transfer.

Functional Helper T Cell Response to CMV Predicts Probability of CMV Vireamia Following Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2224-2224
Author(s):  
Hubertus C. Buyck ◽  
Samantha J. Paston ◽  
Mark W. Lowdell ◽  
Stephen Mackinnon ◽  
Vincent C. Emery
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cell Response ◽  
T Cell Response ◽  
Reduced Intensity Conditioning ◽  
Cmv Reactivation ◽  
Reduced Intensity

Abstract CMV reactivation after allogeneic stem cell transplantation remains problematic and is increasing in frequency with the use of reduced intensity conditioning regimens. A functional immune response is critical to control viral replication and hence disease. In this study, 19 allogeneic stem cell transplant recipients at risk for CMV reactivation were followed for a median of 185 days. Six patients received myeloablative conditioning and thirteen patients received reduced intensity conditioning therapy. Functional CMV specific immune responses were monitored by flow cytometry, measuring CD4 and CD8 specific intracellular interferon gamma production in response to stimulation with peptide pools of 15 mer overlapping peptides spanning the entire length of the immunodominant PP65 and IE1 proteins. In addition the CD4 response to whole CMV antigen, which is capable of presenting multiple viral antigens, was also determined. 53% of patients experienced a CMV reactivation with a median time to 1st reactivation of 53.5 days (range 20–134). In comparison with the CMV reactivation group, the mean day 50 CD4 whole CMV antigen response was approximately 2 logs lower in the reactivated group (0.065X106/L) than the non-reactivated group (3.620X106/L) suggesting that CMV specific CD4 function is an important predictor of patients at risk of CMV reactivation. The incidence of CMV reactivation in patients receiving Campath-1H was 71% (10 out of 14 patients) while none of the 5 patients in the non-Campath-1H group reactivated. The use of Campath-1H as part of the conditioning regimen was associated with a significantly lower day 50 CD4 whole CMV antigen response (0.06X106/L) vs (4.53X106/L) for the non-Campath-1H group, suggesting a mechanism for the observed increased frequency of CMV reactivation with the use of this agent. The relative contribution of the CD4 and CD8 responses to IE1 and PP65 has also been determined in this patient group. In summary, the absolute functional helper T cell response to CMV was predictive of viral reactivation following transplant.

scholarly journals T-cell receptor repertoire of cytomegalovirus-specific cytotoxic T-cells after allogeneic stem cell transplantation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Takashi Toya ◽  
Ayumi Taguchi ◽  
Kazutaka Kitaura ◽  
Fumi Misumi ◽  
Yujiro Nakajima ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Cytotoxic T Cells ◽  
Major Complication ◽  
Cell Receptor ◽  
Receptor Repertoire ◽  
Cmv Reactivation

AbstractCytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8+/CMV pp65 tetramer+ cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson’s index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2–4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.

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