Pharmacotherapy versus T lymphocytes for CMV.
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ABSTRACT:
SUBMITTER: Heslop HE
PROVIDER: S-EPMC3643755 | biostudies-literature | 2013 May
REPOSITORIES: biostudies-literature
Publications
In this issue of Blood, Blyth et al report a phase 2 study in 50 allogeneic hematopoietic stem cell transplant (HSCT) recipients who received donorderived cytomegalovirus (CMV)-specific cytotoxic T cells (CTLs) and compare outcomes with a group of concomitant controls who were transplanted at the trial centers but who did not receive CTLs. ...[more]
Similar Datasets
Project description:Poor immune reconstitution following haematopoietic stem cell transplantation (HSCT) can cause unwanted and harmful sequelae in recipients with chronic cytomegalovirus (CMV) infection. To understand the molecular mechanisms underlying poor reconstitution, we profiled the transcriptome-chromatin accessibility landscape of CMV-specific CD8+ memory lymphocytes from HCST recipients with different reconstitution efficiencies. Although the transcriptional and epigenomic signatures in non-reactive lymphocytes were not naïve or classic ‘exhaustion’ profiles, some gene expression was common to lymphocytes from other non-resolving infections. Reactive lymphocytes expressed higher levels of interferon/defence response and cell cycle genes in an interconnected network involving PI3KCG, STAT5B, NFAT, RBPJ, and NR3C1, increasing chromatin accessibility at the enhancer regions of immune and T cell receptor signalling pathway genes. We propose that increased HDAC6 expression in non-reactive lymphocytes decreases accessibility at particular enhancers including PI3KCG. Non-reactive cells also expressed higher levels of EGR and KLF factors that, along with lower expression of JARID2, maintained higher accessibility at promoter and CpG-rich regions of genes associated with apoptosis. Together, transcription factors and chromatin modulators create a different chromatin accessibility landscape in reactive and non-reactive cells that not only affects immediate gene expression but differentially primes the cells for responses to additional signals.
2018-04-09 | GSE104750 | GEO
Project description:The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1beta, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1beta, TNF-alpha, and IFN-gamma in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.
| S-EPMC2118179 | biostudies-literature
Project description:Targeted antiviral immune responses to the widespread human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) play a pivotal role in determining immune fitness. We show here for the first time that tumor-infiltrating B cell (TIB)- derived immunoglobulin G (IgG) from patients with pancreatic cancer or glioblastoma have unique anti-CMV/EBV immune recognition patterns compared to serum IgG. There is also great heterogeneity between patients, as well as between serum and TIB-IgG, while some viral targets elicited strongly both T-cell and IgG reactivity in tumor infiltrating T- and B-cells. These observations suggest that the anti-CMV/EBV humoral immune response in situ is highly unique and can be instrumental in developing next-generation immuno-biomarkers in addition to supplementing cellular therapy strategies for personalized cancer therapy targeting CMV or EBV in the tumor microenvironment.
| S-EPMC6244284 | biostudies-literature
Project description:Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant. Despite the predicted limited engraftment of CMV-CTLs derived from third-party donors, partially matched third-party donor-derived CMV-CTLs have demonstrated similar response rates to those derived from primary hematopoietic cell transplantation donors. Little is known about the mechanisms through which adoptive cellular therapies mediate durable responses. We performed a retrospective analysis of patients receiving CMV-CTLs for treatment of CMV viremia and/or disease after allogeneic transplant between September of 2009 and January of 2018. We evaluated whether response to adoptively transferred CMV-CTLs correlated with immune reconstitution (IR), using validated CD4+ IR milestones of 50 × 106/L and 200 × 106/L. In this analysis, a cohort of 104 patients received CMV-CTLs derived from a primary transplant donor (n = 25), a third-party donor (n = 76), or both (n = 3). Response to therapy did not increase the likelihood of achieving CD4+ IR milestones at 1 (P = .53 and P > .99) or 2 months (P = .12 and P = .33). The origin of CMV-CTLs did not impact subsequent CD4+ IR. CMV-CTLs appeared to interact with host immunity in mediating responses. Recipients with a baseline CD4 >50 × 106/L had higher response to therapy (P = .02), improved overall survival (P < .001), and protection from CMV-related death (P = .002). Baseline endogenous immunity appears to improve CMV-related and overall survival in this cohort and can be an important marker at the initiation of therapy.
| S-EPMC7839363 | biostudies-literature
Project description:BACKGROUND:The landscape of smoking cessation may have changed in Europe recently. OBJECTIVES:To identify changes in use of smoking cessation assistance in the European Union (EU) and factors associated with use of cessation assistance. METHODS:Data from the 2012 (n=9921) and 2017 (n=9489) waves of the Eurobarometer survey were used. Self-reported use of smoking cessation assistance was assessed among smokers who had ever tried to quit and former smokers. Changes in use of each type of assistance were assessed using logistic regression. RESULTS:Among current and former smokers, those who had ever attempted to quit without assistance increased from 70.3% (2012) to 74.8% (2017). Current smokers were more likely to have used any assistance compared with former smokers (P<0.001). Use of e-cigarettes for smoking cessation assistance increased (3.7% to 9.7%)%), while use of pharmacotherapy (14.6% to 11.1%)%) and smoking cessation services (7.5% to 5.0%)%) declined. Younger people were more likely to have reported e-cigarette use for smoking cessation but less likely to have used a cessation service. Individuals living in countries with comprehensive smoking cessation policies were more likely to have used any cessation assistance (adjusted OR (aOR)=1.78; 95%?CI 1.15 to 2.76), pharmacotherapy (aOR=3.44; 95%?CI 1.78 to 6.66) and smoking cessation services (aOR=2.27; 95%?CI 1.27 to 4.06) compared with those living in countries with weak smoking cessation policies. CONCLUSIONS:These findings highlight the need for approaches that ensure that smokers get support to quit smoking across the EU. The question of whether the availability of e-cigarettes will displace other methods, and the impact of such a displacement, should be closely evaluated.
| S-EPMC6317445 | biostudies-literature
Project description:BackgroundThe rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown.MethodsUsing stored serial serum specimens from renal (n = 59) and liver (n = 35) transplant recipients (D+R-; CMV-seropositive donors, CMV-seronegative recipients) from 2 prospective, randomized, controlled, interventional prophylaxis trials of CMV immune globulin (CMVIG), CMV viral load was measured using the COBAS quantitative polymerase chain reaction assay and the World Health Organization CMV standard. Patients with severe CMV-associated disease were classified according to trial definitions. Pairwise comparisons of mean viral load among deceased, surviving diseased, and nondiseased patients were analyzed by 2-way analysis of variance. To determine if viral load could predict mortality, receiver operating characteristic (ROC) curves were constructed using area under the curve (AUC) of the viral load and peak viral concentration (Vmax).ResultsViral load (mean log10 [AUC], peak viral load [Vmax]) for patients with severe CMV disease was significantly higher compared with nondiseased patients (P < .001). Similarly, higher viral burden was significantly associated with mortality (P < .001). Viral load AUC and Vmax AUROCs for predicting mortality were 0.796 and 0.824, respectively, for renal patients, and 0.769 and 0.807, respectively, for liver patients.ConclusionsUsing specimens from studies preceding the antiviral prophylaxis era, CMV viral load was associated with severe CMV disease and death, supporting CMV viral load quantification as a proxy for CMV disease severity and disease-associated mortality end points in solid organ transplantation.
| S-EPMC6366655 | biostudies-literature
Project description:Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human in vitro expanded and flow-sorted human CD4+ and CD4- iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4- but not CD4+ iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment. Human CD4- iNKT cells reduced the activation of human T cells and their Th1 and Th17 differentiation in vivo. CD4- and CD4+ iNKT cells had distinct effects upon DC maturation and survival. Compared to their CD4+ counterparts, in co-culture experiments in vitro, human CD4- iNKT cells had a higher ability to make contacts and degranulate in the presence of mouse bone marrow-derived DCs, inducing their apoptosis. In vivo we observed that infusion of PBMC and CD4- iNKT cells was associated with decreased numbers of splenic mouse CD11c+ DCs. Similar differential effects of the iNKT cell subsets were observed on the maturation and in the induction of apoptosis of human monocyte-derived dendritic cells in vitro. These results highlight the increased immunosuppressive functions of CD4- versus CD4+ human iNKT cells in the context of alloreactivity, and provide a rationale for CD4- iNKT selective expansion or transfer to prevent GVHD in clinical trials.
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Project description:Comparison of the transcriptome of naive (CD45RA+ CD27+) and differentiated (CD27-CD28-) CD4+ lymphocytes from newborns with congenital human cytomegalovirus infection (cord blood samples) and pregnant women diagnosed with primary CMV infection. Naive cells from HCMV uninfected newborns were used as a control.
2015-01-18 | E-MEXP-3473 | biostudies-arrayexpress
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