scholarly journals T-cell subpopulations in chronic lymphocytic leukemia: abnormalities in distribtuion and in in vitro receptor maturation

Blood ◽  
1979 ◽  
Vol 54 (2) ◽  
pp. 540-544 ◽  
Author(s):  
NE Kay ◽  
JD Johnson ◽  
R Stanek ◽  
SD Douglas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Healthy Controls ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
T Cell Membrane

Purified human thymus-derived (T) lymphocytes were analyzed by detection of Fc receptors for either IgG or IgM in healthy controls and in patients with chronic lymphocytic leukemia (CLL). There was a significant and persistent increase in the numbers of T cells bearing receptors for IgG (Fc gamma) in CLL patients in comparison to the controls. After an in vitro culture period, there was a significantly decreased appearance of cells with IgM receptors (Fcmu) in CLL patients in comparison to the control group. These results indicate an imbalance in circulating T-cell subpopulations for CLL patients. In addition, an in vitro defect in CLL T-cell membrane receptor appearance is present.

scholarly journals T-cell subpopulations in chronic lymphocytic leukemia: abnormalities in distribtuion and in in vitro receptor maturation

Blood ◽  
1979 ◽  
Vol 54 (2) ◽  
pp. 540-544 ◽  
Author(s):  
NE Kay ◽  
JD Johnson ◽  
R Stanek ◽  
SD Douglas
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Healthy Controls ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
T Cell Membrane

Abstract Purified human thymus-derived (T) lymphocytes were analyzed by detection of Fc receptors for either IgG or IgM in healthy controls and in patients with chronic lymphocytic leukemia (CLL). There was a significant and persistent increase in the numbers of T cells bearing receptors for IgG (Fc gamma) in CLL patients in comparison to the controls. After an in vitro culture period, there was a significantly decreased appearance of cells with IgM receptors (Fcmu) in CLL patients in comparison to the control group. These results indicate an imbalance in circulating T-cell subpopulations for CLL patients. In addition, an in vitro defect in CLL T-cell membrane receptor appearance is present.

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Billy Michael Chelliah Jebaraj ◽  
Annika Müller ◽  
Rashmi Priyadharshini Dheenadayalan ◽  
Sascha Endres ◽  
Philipp M. Roessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Treatment Benefit ◽  
Btk Inhibitors

Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop by a mutation in cysteine 481 of BTK (C481S), which prevents the irreversible binding of the drugs. In the present study we performed pre-clinical characterization of vecabrutinib, a next generation non-covalent BTK inhibitor, with ITK inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wildtype BTK. In the murine Eµ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, while the naïve populations were increased. Of importance, vecabrutinib treatment significantly reduced frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on activation and proliferation of isolated T-cells. Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

Platelets from Patients with Myocardial Infarction Can Activate T Cells in Vitro

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3448-3448 ◽  
Author(s):  
Elena E. Solomou ◽  
Vasilios Gizas ◽  
Theodora Babali ◽  
Angelos Perperis ◽  
Evgenia Verigou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
T Cells ◽  
T Cell ◽  
Unstable Angina ◽  
T Cell Activation ◽  
Healthy Subjects ◽  
Cell Activation ◽  
Control Group ◽  
Healthy Controls

Abstract Specific aim: Our aim was to examine whether T cells can be activated by the circulating activated platelets from patients with myocardial infarction (with ST elevation-STEMI) Methods: After written informed consent was obtained, peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood obtained from 20 patients with STEMI (18 men and 2 women) at the time of hospital admission at diagnosis, before receiving any treatment, as well as 5 days and 30 days later. We also analyzed 10 healthy subjects (8 men and 2 women), and 5 patients with unstable angina who served as the disease control group. PBMCs were analyzed by flow cytometry with the following markers and their isotypic controls: CD4, CD25, CD69, and FOXP3. We also isolated platelet rich plasma or plasma alone from the patients and the healthy subjects, and used in mixed cultures with PBMCs. Results: We first examined T cell activation by measuring CD69 expression on CD4 T cells following incubation with platelets obtained from patients with STEMI. T cells treated with platelets from patients with STEMI showed increased expression of CD69 (as an activation marker) compared with T cells treated with platelets from healthy subjects (p<0.05, Figure 1). There was no T cell activation following incubation with plasma alone from patients or healthy controls. We then examined the percentages of CD4+CD25+hi (regulatory T cells). There was no statistical difference in Tregs between patients at presentation and controls (healthy subjects and disease control group). Five days later, patients with STEMI displayed increased levels of Tregs compared with the 2 control groups; one month later, Treg numbers returned to the initial presentation levels (p<0.05, Figure 2) Conclusion: To our knowledge we describe for the first time that platelets from patients with STEMI can activate T cells in vitro. In patients with STEMI, an increase in Tregs possibly in an effort to suppress immune system activation secondary to platelet activation, appears shortly after the infarct and normalizes a month later. Figure 1. T cell activation after treatment with platelets from patients with STEMI compared with the platelets from healthy controls or plasma alone Figure 1. T cell activation after treatment with platelets from patients with STEMI compared with the platelets from healthy controls or plasma alone Figure 2. Increased T regs in patients with STEMI , 5 days after admission (STEMI EXIT) ( UA;unstable angina, STEMI 1mfup; STEMI after one month) Figure 2. Increased T regs in patients with STEMI , 5 days after admission (STEMI EXIT) ( UA;unstable angina, STEMI 1mfup; STEMI after one month) Disclosures No relevant conflicts of interest to declare.

Leukemia-associated monoclonal and oligoclonal TCR-BV use in patients with B-cell chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 1063-1070 ◽  
Author(s):  
Mohammad-Reza Rezvany ◽  
Mahmood Jeddi-Tehrani ◽  
Hans Wigzell ◽  
Anders Österborg ◽  
Håkan Mellstedt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cd8 T Cells ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

Abstract T-cell receptor–B-variable (TCR-BV) gene usage and the CDR3 size distribution pattern were analyzed by reverse transcription–polymerase chain reaction (RT-PCR) in patients with B-cell chronic lymphocytic leukemia (B-CLL) to assess the T-cell repertoire. The use of TCR-BV families in CD4 and CD8 T cells stimulated with autologous activated leukemic cells was compared with that of freshly obtained blood T cells. Overexpression of individual TCR-BV families was found in freshly isolated CD4 and CD8 T cells. Polyclonal, oligoclonal, and monoclonal TCR-CDR3 patterns were seen within such overexpressed native CD4 and CD8 TCR-BV families. In nonoverexpressed TCR-BV families, monoclonal and oligoclonal populations were noted only within the CD8 subset. After in vitro stimulation of T cells with autologous leukemic B cells, analyses of the CDR3 length patterns showed that in expanded TCR-BV populations, polyclonal patterns frequently shifted toward a monoclonal/oligoclonal profile, whereas largely monoclonal patterns in native overexpressed TCR-BV subsets remained monoclonal. Seventy-five percent of CD8 expansions found in freshly obtained CD8 T cells further expanded on in vitro stimulation with autologous leukemic B cells. This suggests a memory status of such cells. In contrast, the unusually high frequency of CD4 T-cell expansions found in freshly isolated peripheral blood cells did not correlate positively to in vitro stimulation as only 1 of 9 expansions continued to expand. Our data suggest that leukemia cell–specific memory CD4 and CD8 T cells are present in vivo of patients with CLL and that several leukemia cell–associated antigens/epitopes are recognized by the patients' immune system, indicating that whole leukemia cells might be of preference for vaccine development.

scholarly journals Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia

2020 ◽  
Vol 8 (1) ◽  
pp. e000471 ◽  
Author(s):  
Veronika Mancikova ◽  
Helena Peschelova ◽  
Veronika Kozlova ◽  
Aneta Ledererova ◽  
Adriana Ladungova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Car T Cells ◽  
Cell Engraftment ◽  
Car T

BackgroundWhile achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy.MethodsFirst, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9ATM-mutated, 8TP53-mutated, and 9 without mutations inATM,TP53,NOTCH1orSF3B1) and 6IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by ‘2S stimulation’ through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generatedATM-knockout andTP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT),ATM-knockout orTP53-knockout cells was also performed.ResultsPrimary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. ‘2S’ stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells’ in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-γ when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells’ survival. In vivo, CAR T cells prolonged the survival of mice injected with WT,TP53-knockout andATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared withATM-knockout,TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012).ConclusionsWhile in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated withTP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.

scholarly journals Expression of interleukin-2 receptor on T cell chronic lymphocytic leukemia cells and their response to interleukin-2

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 316-321
Author(s):  
M Tsudo ◽  
T Uchiyama ◽  
H Umadome ◽  
Y Wano ◽  
T Hori ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Activated T Cells ◽  
Cell Chronic Lymphocytic Leukemia

We analyzed peripheral blood leukemic cells from six patients with T cell chronic lymphocytic leukemia (T-CLL) with monoclonal antibodies including the anti-Tac antibody, which recognizes the receptor for interleukin 2 (IL 2). The patients were divided into two groups according to the reactivity of the monoclonal antibodies. Leukemic cells from three patients with T-CLL reacted with OKT3 and T4 but not T8, whereas those from the remaining three patients reacted with OKT3 and T8 but not T4. IL 2 receptor, which is expressed on activated T cells but not on resting T cells, was preferentially expressed on T4+ T- CLL cells. The IL 2 receptor on T4+ T-CLL cells was indistinguishable from that on normal activated T cells with respect to molecular weight and downregulation by the anti-Tac antibody. Moreover, fresh T4+ T-CLL cells, but not T8+ T-CLL cells, proliferated in response to exogenous IL 2 without prior activation, and this proliferation was inhibited by the anti-Tac antibody. These results suggest that malignant growth of T4+ T-CLL cells can be regulated by IL 2 not only in vitro but also in vivo.

scholarly journals Defective T cell responsiveness in chronic lymphocytic leukemia: analysis of activation events

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 578-581
Author(s):  
NE Kay ◽  
ME Kaplan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Proliferative Response ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Proliferative Potential ◽  
Hla Dr ◽  
Activation Antigens ◽  
T Cell Membrane

Chronic lymphocytic leukemia (CLL) is a B cell disorder in which major T cell proliferative defects are present. We investigated the nature of this deficit by studying several parameters known to be crucial in normal T cell proliferative response to mitogen. Purified peripheral blood T cells from B-CLL patients were analyzed for the presence of T3 antigen. We observed that CLL T cells have a direct correlation between levels of T3 membrane antigen and proliferative response to mitogen. The appearance of activation antigens (transferrin, HLA-DR, and interleukin 2 [IL 2] receptor) was normal in CLL T cells post-mitogen exposure. Despite the normal presentation of IL 2 receptor on CLL T cell membrane, there was decreased production of IL 2 by CLL patients (v controls) (39.6 +/- 10.2 cells per milliliter v 64.6 +/- 11.0 cells per milliliter). Finally, we were able partially, but not fully, to reconstitute CLL T proliferative response to mitogen by adding purified exogenous IL 2. These findings suggest that CLL T cells have multiple defects that may impact on their proliferative potential. Further insight into these deficits may result in strategies that will facilitate immunologic restoration in T cells of these patients.

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