scholarly journals Frequency and Phenotype of JC Virus-Specific CD8+ T Lymphocytes in the Peripheral Blood of Patients with Progressive Multifocal Leukoencephalopathy

2007 ◽  
Vol 81 (7) ◽  
pp. 3361-3368 ◽  
Author(s):  
Marco A. Lima ◽  
Angela Marzocchetti ◽  
Patrick Autissier ◽  
Troy Tompkins ◽  
Yiping Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Jc Virus ◽  
Study Groups ◽  
Bk Virus ◽  
Effector Memory ◽  
Color Flow ◽  
Significant Difference ◽  
Effector Memory Cells

ABSTRACT JC virus (JCV)-specific CD8+ cytotoxic T lymphocytes (CTL) are associated with a favorable outcome in patients with progressive multifocal leukoencephalopathy (PML) and cross-recognize the polyomavirus BK virus (BKV). We sought to determine the frequency and phenotype in fresh blood of CD8+ T cells specific for two A*0201-restricted JCV epitopes, VP1p36 and VP1p100, and assess their impact on JC and BK viremia and viruria in 15 healthy subjects, eight human immunodeficiency virus-positive (HIV+) individuals, and nine HIV+ patients with PML (HIV+ PML patients) classified as survivors. After magnetic preenrichment of CD8+ T cells, epitope-specific cells ranged from 0.001% to 0.22% by tetramer staining, with no significant difference among the three study groups. By use of seven-color flow cytometry, there was no predominant differentiation phenotype subset among JCV-specific CD8+ T cells in healthy individuals, HIV+ subjects, or HIV+ PML patients. However, in one HIV+ PML patient studied in the acute phase, there was a majority of activated effector memory cells. BKV DNA was undetectable in all blood samples by quantitative PCR, while a low JC viral load was found in the blood of only one HIV+ and two HIV+ PML patients. JCV and BKV DNA were detected in 33.3% and 13.3% of all urine samples, respectively, independent of the presence of JCV-specific CTL. The detection of JCV DNA in the urine was associated with the presence of a JCV VP1p100 CTL response. Immunotherapies aiming at increasing the cellular immune response against JCV may be valuable in the treatment of HIV+ individuals with PML.

The Humanized Anti PD-1 Antibody, CT-011, Increases Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1216-1216
Author(s):  
Rinat Rotem-Yehudar ◽  
Philippe Armand ◽  
Steve Devine ◽  
Joseph W. Fay ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
B Cell Lymphoma ◽  
Peripheral Tolerance ◽  
Effector Memory ◽  
Memory Cells ◽  
Antibody Treatment ◽  
Effector Memory Cells ◽  
Memory T Lymphocytes ◽  
Memory Lymphocytes

Abstract Abstract 1216 Poster Board I-238 Background: PD-1 (Program Death-1), an immune inhibitory receptor and its ligands PD-L1 and PD-L2, participate in peripheral tolerance and play a key role in immune suppression and evasion mechanisms in cancer and chronic infectious diseases. PD-1 inhibits activation signals and functions as a pro-apoptotic receptor in effector lymphocytes, and consequently regulates the extent and duration of specific adaptive and innate immune responses. CT-011, a humanized antibody, blocks the function of PD-1, resulting in increased activities of T and NK cells in vitro and in enhanced tumor immunity in experimental tumor models. At the molecular level, the antibody enhances PI3K-mediated survival and trafficking signals, attenuates cell death in effector/memory (CD4+CD45RO+) cells, and enhances trafficking in response to Stromal Cell-derived Factor-1 (SDF-1). We hypothesized that CT-011 would enhance effector/memory cells in patients with DLBCL after AuSCT and delay recurrence. Methods: We treated 41 patients (pts) with DLBCL from 30-90 days after AuSCT with CT-011 and now report data on effector/memory and memory lymphocytes in the first 30 pts. CT-011 was given at a dose of 1.5mg/kg for 3 doses, 6 weeks apart. The primary endpoint was to determine the proportion of patients who have not relapsed or died within 18 months following autologous PBSCT, and it is too early for that analysis. Our secondary endpoint was to measure the number of effector /memory and memory lymphocytes before and after treatment, and those data are the subject of this report. Results: Flow cytometry analyses (Table) on pre (baseline: BL) and post-treatment blood samples from the first 30 pts enrolled show elevated levels of specific effector/memory and memory CD4+ T lymphocytes following treatment with CT-011; the median absolute number (ABS) of effector/memory CD4+CD45RO+CD62L-CCR7- cells was increased by +49% from BL (p<0.05) 6 weeks following the first treatment with CT-011, reaching a 2 fold increase in the ABS levels from BL and a 45% increase in the median percentage of the total lymphocyte population (p<0.05) 4 weeks after the third antibody treatment (week 16). The percentage of peripheral memory CD4+ CD62L-CD127+ cells was also increased by 61% from BL (median, p<0.05) on week 16. The observed increase, particularly of the effector/memory CD4+CD45RO+CD62L-CCR7- lymphocytes, a subset directly linked to PD-1 activity and to tumor immune surveillance, likely indicates a specific cellular response to CT-011, since no significant changes were observed for other memory cell subsets including CD4+CD45RO+CD62L+CCR7+cells, CD4+ CD62L+CD127+ cells, CD8+ CD62L-CD127+, CD8+CD62L+CD127+ cells or CD4+CD25+ FOXP3+ suppressor T cells. Overall no changes were observed in the level of total lymphocytes or T cells throughout 16 weeks of follow up from the 1st antibody treatment. Transient reduction of 32% (median, p<0.05) and 25% (median, p<0.05) in the ABS levels of CD3+CD8+ and CD3+CD45RO+, respectively, was observed at week 12, which recovered to baseline or higher levels on week 16. These changes may be explained by trafficking or recycling of CD8+ effector/memory cells from the periphery to target organs. Conclusions: Consistent with its mechanism of action, CT-011 increases the levels of specific CD4+ effector/memory and memory T lymphocytes. This is the first demonstration of safe induction of effector memory and memory lymphocytes, essential components of tumor- immune control, in lymphoma patients following AuSCT. This antibody may have promise for the treatment of lymphoma. Disclosures: Rotem-Yehudar: Cure Tech: Employment. Gordon:Cure Tech: Membership on an entity's Board of Directors or advisory committees.

Predictive value of circulating B cells and T cell subsets in melanoma patients treated with neoadjuvant ipilimumab and interferon.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15036-e15036
Author(s):  
Arjun Khunger ◽  
Ghanashyam Sarikonda ◽  
Jenn Tsau ◽  
Zeni Alfonso ◽  
Jane Gao ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Peripheral Blood ◽  
Post Treatment ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Memory Cells ◽  
Color Flow ◽  
Time Points ◽  
Effector Memory Cells

e15036 Background: Patients with locally/regionally advanced melanoma were treated on a clinical trial with a neoadjuvant combination of ipilimumab (ipi) and high dose IFNα2b (HDI) (Tarhini et al, JITC 2018). In this study, immune cell composition in peripheral blood samples collected at various time points was measured to determine any correlation with clinical outcomes and investigate the immune modulating effect of the combination therapy. Methods: Patients were randomized to neoadjuvant ipi at 3 mg/kg or 10 mg/kg, both given in combination with HDI. Tumor radiologic responses were designated as complete (CR), partial (PR), stable disease (SD) or disease progression (PD). Pathologic complete response (pCR) was defined as absence of viable tumor on histologic assessment. Peripheral blood mononuclear cells (PBMC) from treated patients (N = 28) were tested at baseline (before initiating ipi-HDI), then at 6-weeks, 3-months and 12-months (following neoadjuvant ipi-HDI). High complexity (14-color) flow cytometry analysis was performed to detect key immunological biomarkers including myeloid derived suppressor cells (MDSCs), B cells, regulatory T cells (Tregs), PD-1 and TIM3 expression on T-cells, and differentiation of T-cells into Th1, Th2 or Th17 phenotype at different time points during systemic immunotherapy. Statistical significance was determined using R-package employing Kruskal’s test. Results: Lower levels of peripheral Tregs (p = 0.02), MDSCs (p = 0.05), and CD4 effector memory cells (p = 0.04) at 3-months post treatment correlated with radiologic response. In addition, lower change from baseline at 3 months in CD4/CD8 ratio (p = 0.04), levels of Tregs (p = 0.01) and CD4 effector memory cells (p = 0.02) was associated with radiologic response. Patients exhibiting pCR had significantly lower Tregs (p = 0.04) at 6-months post treatment and significantly higher CD8 central memory cells at both 3 months (p = 0.04) and 12 month time-points (p = 0.01) as compared to patients without pCR. Finally, patients without pCR had significantly lower change from baseline in CD19 B cells at 6 months (p = 0.01) and 12 months (p = 0.04) as compared to patients with pCR. Conclusions: Our data demonstrates that the levels of immunosuppressive cells including Tregs and MDSCs in periphery are negatively associated with response. Higher levels of CD8 memory cells and B cells on-treatment are associated with clinical benefit.

scholarly journals Immunization of Volunteers with Salmonella enterica Serovar Typhi Strain Ty21a Elicits the Oligoclonal Expansion of CD8+ T Cells with Predominant Vβ Repertoires

2005 ◽  
Vol 73 (6) ◽  
pp. 3521-3530 ◽  
Author(s):  
Rosângela Salerno-Gonçalves ◽  
Rezwanul Wahid ◽  
Marcelo B. Sztein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Salmonella Enterica ◽  
Flow Cytometric Analysis ◽  
Cell Receptor ◽  
Effector Memory ◽  
Color Flow ◽  
Cell Clones ◽  
Effector Memory Cells ◽  
Ifn Γ

ABSTRACT CD8+ T cells are likely to play an important role in host defense against Salmonella enterica serovar Typhi by several effector mechanisms, including lysis of infected cells (cytotoxicity) and gamma interferon (IFN-γ) secretion. In an effort to better understand these responses, we studied the T-cell receptor (TCR) repertoire of serovar Typhi-specific CD8+ T cells in humans. To this end, we determined the TCR beta chain (Vβ) usage of CD8+ T cells from three volunteers orally immunized with Ty21a typhoid vaccine by flow cytometry using a panel of monoclonal antibodies. Although TCR Vβ usage varied among volunteers, we identified oligoclonal Vβ subset expansions in individual volunteers (Vβ 2, 5.1, 8, 17, and 22 in volunteer 1; Vβ 1, 2, 5.1, 14, 17, and 22 in volunteer 2; and Vβ 3, 8, 14, and 16 in volunteer 3). These subsets were antigen specific, as shown by cytotoxicity and IFN-γ secretion assays on Vβ sorted cells and on T-cell clones derived from these volunteers. Moreover, eight-color flow cytometric analysis showed that these clones exhibited a T effector memory phenotype (i.e., CCR7− CD27− CD45RO+ CD62L−) and coexpressed gut homing molecules (e.g., high levels of integrin α4β7, intermediate levels of CCR9, and low levels of CD103). In conclusion, our results show that long-term T-cell responses to serovar Typhi in Ty21a vaccinees are oligoclonal, involving multiple TCR Vβ families. Moreover, these serovar Typhi-specific CD8+ T cells bearing defined Vβ specificities are phenotypically and functionally consistent with T effector memory cells with preferential gut homing potential.

scholarly journals CONTENTS OF CD4+ AND CD8+ EFFECTOR MEMORY CELLS AND PROLIFERATIVE ACTIVITY OF T LYMPHOCYTES IN BRONCHIAL ASTHMA

2019 ◽  
Vol 21 (3) ◽  
pp. 503-516
Author(s):  
M. Sh. Barkovskaya ◽  
E. A. Blinova ◽  
L. V. Grishina ◽  
M. I. Leonova ◽  
V. M. Nepomniashchikch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Bronchial Asthma ◽  
Proliferative Activity ◽  
Memory T Cells ◽  
Effector Memory ◽  
Memory Cells ◽  
Healthy Donors ◽  
Effector Memory Cells

Bronchial asthma is a chronic inflammatory disease of the respiratory tract. T-lymphocytes play a key role in pathogenesis of this allergic disease. The reduction in number of naïve T cells and the accumulation of memory T cells in bronchial asthma are accompanied by dysregulation of T lymphocyte function. In present study, we have investigated the contents of different T lymphocyte subpopulations in peripheral blood as well as in resting and PHA-stimulated cultures, along with their proliferative capacity in patients with bronchial asthma and healthy donors. The study included 10 patients with bronchial asthma (age 45.4±11.8 years). One-half of patients was in remission state, the others having been at the stage of clinical exacerbation. The group of donors was formed by healthy individuals matched by gender and age to the patients. Based on expression of cell surface markers CD45R0, CD62L and CD197 (CCR7), the CD4+ and CD8+T lymphocytes were divided into central (Tcm) and effector memory cells (Tem), naïve T lymphocytes (Tnaïve) and terminally differentiated effector cells (Temra) using flow cytometry technique. The proliferative activity of Tcm, Tem and Tnaïve was evaluated in response to PHA as a functional marker of T cells. We have found that the percentage of peripheral CD4+TemCD62L+ and CD8+TemCD62L+ cells in the patients with asthma exacerbation was significantly reduced, if compared to the donors. Following PHA stimulation, these differences in T cell subsets between the groups of patients and donors were not detectable. We performed a correlation analysis between the memory T cell contents and age of the subjects studied. It was shown that the relative amounts of CD4+ and CD8+ memory cells increased with age in asthmatics, but not in healthy donors. Analysis of mitogen-induced proliferation showed that Tcm and Tnaïve cells proliferated more actively than other subpopulations in both groups. Meanwhile, the proliferative activity of CD4+T lymphocytes and subsets of CD8+Tcm, CD4+Tcm and CD4+Tem62L was higher in the group of asthma patients in remission state than in the patients with exacerbating disease, and healthy donors. The revealed increase in the relative number of memory T cells with age suggests that these cells participate in development of bronchial asthma. Proliferative response of the studied subpopulations, which was comparable to the donor values, suggests a functional maintenance of memory T cells and naïve T lymphocytes in bronchial asthma. The increased proliferation of some T-cell subpopulations in asthmatics in remission suggests an activated state of memory T cells. The observed decrease in the number of CD4+TemCD62L+ and CD8+TemCD62L+ in patients with asthma exacerbation may be, by our opinion, associated with an active inflammatory process in the airways.

scholarly journals Combined Treatment With Pembrolizumab and Allogenic BK Virus-Specific T Cells in Progressive Multifocal Leukoencephalopathy

2021 ◽  
Vol 8 (5) ◽  
pp. e1042
Author(s):  
Rebecca Wicklein ◽  
Simon Heidegger ◽  
Mareike Verbeek ◽  
Britta Eiz-Vesper ◽  
Britta Maecker-Kolhoff ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progressive Multifocal Leukoencephalopathy ◽  
Treatment Option ◽  
Jc Virus ◽  
Brain Mri ◽  
Combined Treatment ◽  
Human Leukocyte ◽  
Bk Virus ◽  
Diffusion Restriction

ObjectiveWe report a combination of BK virus-specific T cells and pembrolizumab as a treatment option in progressive multifocal leukoencephalopathy (PML).ResultsA 57-year-old male patient diagnosed with PML presented a fast-progressing right hemiparesis, aphasia, and cognitive deficits. Brain MRI showed a severe leukoencephalopathy with diffusion restriction. The patient was treated with 10 doses of pembrolizumab (2 mg/kg body weight) in differing intervals and 2 partially human leukocyte antigen-matched allogenic BK virus-specific T cell transfusions after the fifth pembrolizumab treatment. Although pembrolizumab alone decreased the viral load but failed to control the virus, BK-specific T cell transfer further enhanced the decline of JC virus copies in the CSF. Moreover, the regression of leukoencephalopathy and disappearance of diffusion restriction in subsequent brain MRI were observed. The combined treatment resulted in a clinical stabilization with improvements of the cognitive and speech deficits.DiscussionThis case supports the hypothesis that pembrolizumab is more efficient in the presence of an appropriate number of functional antigen-specific T cells. Thus, the combined treatment of pembrolizumab and virus-specific T cells should be further evaluated as a treatment option for PML in future clinical trials.

scholarly journals Comparison of leucocyte profiles between healthy children and those with asymptomatic and symptomatic Plasmodium falciparum infections

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Diana Ahu Prah ◽  
Linda Eva Amoah ◽  
Matthew P. Gibbins ◽  
Yaw Bediako ◽  
Aubrey J. Cunnington ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
Peripheral Blood ◽  
Parasite Load ◽  
Study Groups ◽  
Healthy Children ◽  
Peripheral Cell ◽  
Peripheral Blood Leucocyte ◽  
Cell Counts ◽  
Significant Difference

Abstract Background The immune mechanisms that determine whether a Plasmodium falciparum infection would be symptomatic or asymptomatic are not fully understood. Several studies have been carried out to characterize the associations between disease outcomes and leucocyte numbers. However, the majority of these studies have been conducted in adults with acute uncomplicated malaria, despite children being the most vulnerable group. Methods Peripheral blood leucocyte subpopulations were characterized in children with acute uncomplicated (symptomatic; n = 25) or asymptomatic (n = 67) P. falciparum malaria, as well as malaria-free (uninfected) children (n = 16) from Obom, a sub-district of Accra, Ghana. Leucocyte subpopulations were enumerated by flow cytometry and correlated with two measures of parasite load: (a) plasma levels of P. falciparum histidine-rich protein 2 (PfHRP2) as a proxy for parasite biomass and (b) peripheral blood parasite densities determined by microscopy. Results In children with symptomatic P. falciparum infections, the proportions and absolute cell counts of total (CD3 +) T cells, CD4 + T cells, CD8 + T cells, CD19 + B cells and CD11c + dendritic cells (DCs) were significantly lower as compared to asymptomatic P. falciparum-infected and uninfected children. Notably, CD15 + neutrophil proportions and cell counts were significantly increased in symptomatic children. There was no significant difference in the proportions and absolute counts of CD14 + monocytes amongst the three study groups. As expected, measures of parasite load were significantly higher in symptomatic cases. Remarkably, PfHRP2 levels and parasite densities negatively correlated with both the proportions and absolute numbers of peripheral leucocyte subsets: CD3 + T, CD4 + T, CD8 + T, CD19 + B, CD56 + NK, γδ + T and CD11c + cells. In contrast, both PfHRP2 levels and parasite densities positively correlated with the proportions and absolute numbers of CD15 + cells. Conclusions Symptomatic P. falciparum infection is correlated with an increase in the levels of peripheral blood neutrophils, indicating a role for this cell type in disease pathogenesis. Parasite load is a key determinant of peripheral cell numbers during malaria infections.

scholarly journals CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

2004 ◽  
Vol 200 (11) ◽  
pp. 1407-1417 ◽  
Author(s):  
Adrian F. Ochsenbein ◽  
Stanley R. Riddell ◽  
Michele Brown ◽  
Lawrence Corey ◽  
Gabriela M. Baerlocher ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Effector Memory ◽  
Term Survival ◽  
Functional Consequences

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response.

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