Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)

Porakishvili, Nino; Roschupkina, Teona; Kalber, Tammy L.; Jewell, Andrew P.; Patterson, Kelli N.; Yong, Kwee; Lydyard, Peter M.

doi:10.1046/j.1365-2249.2001.01639.x

Cited by 56 publications

(50 citation statements)

References 33 publications

(35 reference statements)

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“…29,30 Our results obtained with intracytoplasmic staining confirmed that CD4 + T lymphocytes from CLL patients (n=12) produce significantly more IL-4 than those obtained from appropriate controls when activated in the presence of mitogenic anti-CD3/CD28 mAbs, (Figure 6A and B). On the contrary, CD8 + T lymphocytes from CLL patients produced significantly lower amounts of IFN-γ as compared to controls ( Figure 6A and B).…”

Section: Pd-1/pd-l1 Crosstalk Contributes To Suppressing Ifn-γ Producsupporting

confidence: 70%

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

et al. 2013

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Section: Pd-1/pd-l1 Crosstalk Contributes To Suppressing Ifn-γ Producsupporting

confidence: 70%

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

et al. 2013

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“…16,19,[22][23][24][25] The precise role that different T-cell subsets play in the immunodeficiency of CLL remains undetermined but functional studies have identified defects in immune synapse formation, costimulatory/accessory molecule expression and cytokine release. [15][16][17] Despite these problems, several T-cell-based therapeutic strategies have been tried in CLL including adoptive transfer of anti-CD3/anti-CD28 activated T cells, 26 T cells expressing chimeric antigen receptors, and vaccine therapy with dendritic cells pulsed with CLL-cell lysates. [27][28][29] The potential power of T cells to mediate therapeutic responses in CLL was demonstrated in a recent study using adoptive transfer of gene-modified (CD19 chimeric antigen receptor and 4-1BB) T cells.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 However, given the well-known T-cell dysfunction seen in CLL, blinatumomab may be less effective in this disease. [15][16][17] In the current study, we provide a detailed analysis of the mechanism of action of blinatumomab-induced cytotoxicity in CLL. Our findings are consistent with a model that relies upon the sequential activation of T cells and CLL cells and demonstrate that blinatumomab retains efficacy even in the presence ©2013 Ferrata Storti Foundation.…”

Section: Cd23mentioning

confidence: 99%

Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o n 2 0 1 3of CLL activation and pro-survival signals. Given these data, this approach represents a novel and promising therapeutic strategy for the treatment of CLL and, potentially, other lymphoid malignancies. Methods Blood samples from patients with chronic lymphocytic leukemiaTwenty-eight CLL patients (aged 53-83 years) were studied with full ethical approval. All blood samples from patients were obtained with informed consent (see Online Supplementary Methods). The majority of the assays were performed on fresh samples from treatment-naïve patients, except those for which the results are shown in Figure 1: in these assays, samples from patients who had received standard chemotherapy treatment were also tested. Antibodies and flow cytometryA full list of the antibodies used can be found in the Online Supplementary Methods. Blinatumomab (MT103, AMG103) was provided by Amgen Inc. (Munich, Germany). T cells were identified using CD4 and CD8 markers, while CLL cells were CD5 + CD4-CD8 -(>99% CD19 + ). Cell culturesPeripheral blood mononuclear cells (PBMC) were incubated in RPMI 1640 supplemented with 5% AB serum (AB media) for 3-7 days. Blinatumomab was added to PBMC cultures at a concentration of 10 or 100 ng/mL. Human T-cell activator CD3/CD28 dynabeads (Invitrogen) were added at 1x10 5 beads/1x10 6 PBMC as a positive control for T-cell activation. For absolute counts of T cells and CLL cells, an anti-CD3 antibody (Invitrogen) at a dose of 27.7 or 277 ng/mL was used as a positive control (same molar concentration as 10 or 100 ng/mL blinatumomab). Intracellular Ki67 stainingPBMC were labeled with antibodies against CD4, CD8, CCR7 and CD45RA, fixed and permeabilized (Fix and Perm with 1% NP40, Caltag-Medsystems, Buckingham, UK) before staining with a Ki67-FITC antibody for flow cytometric analysis. Cytokine secretion assayCytokines in tissue culture supernatants were measured using a Human Th1/Th2 11plex RTU Flowcytomix kit (eBioscience) for simultaneous detection of 11 cytokines. Intracellular cytokine staining and the determination of CD107 and granzyme B expressionPBMC were cultured (3 days) with 10 ng/mL blinatumomab, before treatment with Golgi plug and Golgi stop (BD biosciences), and incubation with an anti-CD107 antibody (5 h at 37°C). Intracellular expression of granzyme B or interferon (IFN)-g and tumor necrosis factor (TNF)-α in CD4 or CD8 T cells was measured by flow cytometry. Absolute counts of T cells and chronic lymphocytic leukemia cellsPBMC samples that had or had not been treated with blinatumomab (7 days) were surface-stained with antibodies against annexin V, CD5, CD8 and CD4. Absolute counts were determined by flow cytometry using Cytocount beads (Dako, Stockport, UK). Flow cytometry-based cytotoxicity assayMouse fibroblast cells transfected with CD40L [TL(CD40L)] and non-transfected cells (NTL) were cultured as previously described. 21 For co-cultures, irradiated (80 Gy) NTL or TL(CD40L) cells were seeded into a 48-well plate, and allow...

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“…Considered that tumorreactive Cytotoxic CD4+ T cells have been a bright point in immunotherapy of tumor (Porakishvili et al, 2001;Quezada et al, 2010;Akhmetzyanova et al, 2013), so we also measured perforin production of CD8+ T cells as well as CD4+ T cells. Unfortunately, CPT showed marginal effect on CD8+ cytotoxic T cells, even though that CD8+ cytotoxic T cells are classic tumor killing cells (Ohmura et al, 2008), but enhanced perforin production of CD4+ T cells.…”

Section: Discussionmentioning

confidence: 99%

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

Zhou

Xu²,

Hu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibit tumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Using a mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo with polarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation, and also increased IFN-γ and perforin production of CD4+ T cells in response to tumor-activated splenocytes. Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogated by concanamycin A(CMA), a perforin inhibitor, but not IFN-γ Ab. On the other hand, after depletion of CD4+ T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumor growth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggested that CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin. We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, and demonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells.

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Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL)

Cited by 56 publications

References 33 publications

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

Blinatumomab induces autologous T-cell killing of chronic lymphocytic leukemia cells

Cryptotanshinone Induces Inhibition of Breast Tumor Growth by Cytotoxic CD4+ T Cells through the JAK2/STAT4/ Perforin Pathway

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