scholarly journals CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1375-1382 ◽  
Author(s):  
EJ Schattner ◽  
J Mascarenhas ◽  
J Bishop ◽  
DH Yoo ◽  
A Chadburn ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Fas Ligand ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Cd4 T Cell ◽  
Cd40 Ligation ◽  
Death Signals

Cytotoxic function of CD4+ Th1 cells is mediated by Fas (CD95, APO-1) and its ligand (Fas ligand). Recent studies using nontransformed B cells and the Ramos Burkitt's lymphoma (BL) B-cell line cells show that CD40 ligation at the B-cell surface by activated, CD40 ligand (CD40L)- bearing, CD4+ T cells upregulates Fas expression on B cells and primes B cells for Fas-mediated death signals. In this work, we examine whether this CD4+ T-cell-dependent molecular pathway for Fas upregulation and B-cell apoptosis reflects a peculiarity of the Ramos B- cell line or is applicable to other Burkitt's tumors as well. In 5 of the 6 Epstein-Barr virus-negative BL cell lines examined, the cells constitutively express undetectable or low levels of Fas and are resistant to Fas-mediated signals induced by monoclonal anti-Fas antibody. All 6 of the BL cell line B cells upregulate Fas in response to CD40 ligation, and in 4 of the cases they become sensitive to Fas- mediated death signals. In one BL cell line, the cells are constitutively sensitive to Fas-mediated cytolysis and are unaffected by CD40 signals. Next, we applied these immunologic manipulations to cells from a refractory clinical sample and observed that the tumor cells could be induced to express Fas and undergo apoptosis in our system. These results establish CD4+ T cells and the Fas-Fas ligand system as important immune regulators of Burkitt's lymphoma B cells and indicate that the susceptibility of tumor cells to Fas-mediated death signals can be modulated by specific activation events at the cell surface.

scholarly journals CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway.

1995 ◽  
Vol 182 (5) ◽  
pp. 1557-1565 ◽  
Author(s):  
E J Schattner ◽  
K B Elkon ◽  
D H Yoo ◽  
J Tumang ◽  
P H Krammer ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
B Cells ◽  
Programmed Cell Death ◽  
B Cell ◽  
B Lymphocytes ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Cd40 Ligation

The Apo-1/Fas antigen (CD95) mediates programmed cell death of lymphocytes when bound by Fas ligand or anti-Apo-1/Fas antibody. In contrast, the CD40 antigen provides a potent activation and survival signal to B lymphocytes when it is engaged by its T cell ligand (CD40L, gp39) or cross-linked by anti-CD40 antibody. In this study, we use human tonsillar B cells and the Ramos Burkitt's lymphoma B cell line, which serves as a model for human germinal center B lymphocytes, to study the effectors of Apo-1/Fas expression and apoptosis of human B cells. We found that Apo-1/Fas expression was upregulated on both malignant and normal human B lymphocytes after CD40 ligation induced by (a) cognate T helper-B cell interaction mediated by microbial superantigen (SAg); (b) contact-dependent interaction with CD40L+, but not CD40L- Jurkat mutant T cell clones; and (c) monoclonal anti-CD40, but not any of a panel of control antibodies. Enhanced B cell Fas/Apo-1 expression is functionally significant. Coculture of Ramos Burkitt's lymphoma line cells with irradiated SAg-reactive CD4+ T cells with SAg or CD40L+ Jurkat T cells results in B cell apoptosis, evidenced by reduced cell viability and DNA laddering. This process is augmented by the addition of anti-Apo-1/Fas monoclonal antibody, consistent with an acquired susceptibility to Apo-1/Fas-mediated apoptosis. These data support an immunoregulatory pathway in which seemingly contradictory signals involving the B cell proliferation/survival antigen CD40, as well as the Apo-1/Fas molecule, which mediates programmed cell death of lymphocytes, are linked in the process of human B cell activation.

scholarly journals DIFFERENTIAL EXPRESSION OF CD150/SLAMF1 IN NORMAL AND MALIGNANT B CELLS ON THE DIFFERENT STAGES OF MATURATION

2016 ◽  
Vol 38 (2) ◽  
pp. 101-107 ◽  
Author(s):  
I M Gordienko ◽  
L M Shlapatska ◽  
L M Kovalevska ◽  
S P Sidorenko
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Hodgkin’S Lymphoma ◽  
Burkitt’S Lymphoma ◽  
Lymphoma Cell ◽  
Burkitt's Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Mrna Levels

Background: Within B-cell lineage cell surface receptor CD150/SLAMF1 is broadly expressed starting from pre-B cells with upregulation toward plasma cells. However, expression of CD150 is rather limited on the surface of malignant B cells with the block of differentiation at the different stages of maturation. The aim of our work was to explore CD150 expression both on protein and mRNA levels with the emphasis on CD150 isoforms in malignant B-cell lines at the different stages of maturation in comparison with their normal B cell counterparts. Materials and Methods: Studies were performed on normal tonsillar B-cell subpopulations, Blymphoblastoid cell lines, malignant B-cell lines of different origin, including pre-B acute lymphoblastic leukemia, Burkitt’s lymphoma, Hodgkin’s lymphoma, and multiple myeloma. Protein CD150 expression was assessed by western blot analysis and the expression level of CD150 isoforms was evaluated using qRT-PCR. Results: Despite the similar CD150 expression both on mRNA and protein levels in normal B-cell subsets and B-lymphoblastoid cell lines, malignant B-cell lines demonstrated substantial heterogeneity in CD150 expression. Only Hodgkin’s lymphoma cell lines, Burkitt’s lymphoma cell lines BJAB and Raji, and also pre-B cell line BLIN-1 expressed CD150 protein. At the same time total CD150 and mCD150 mRNA was detected in all studied cell lines excluding pre-B cell line REH. The minor sCD150 isoform was found only in Hodgkin’s lymphoma cell lines and Burkitt’s lymphoma cell line Raji. The nCD150 isoform was broadly expressed in tested B cell lines with exception of REH and Daudi. Conclusion: Malignant Bcell lines at the different stages of maturation only partially resemble their normal counterparts by CD150 expression. In malignant B-cell lines, CD150 expression on mRNA level is much broader than on protein level. CD150 isoforms are differentially expressed in normal and malignant B cells with predominant expression of mCD150 isoform.

scholarly journals Activated CD4+CD25+ T cells selectively kill B lymphocytes

Blood ◽  
2006 ◽  
Vol 107 (10) ◽  
pp. 3925-3932 ◽  
Author(s):  
Dong-Mei Zhao ◽  
Angela M. Thornton ◽  
Richard J. DiPaolo ◽  
Ethan M. Shevach
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Death ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Fas Ligand ◽  
Cell Function ◽  
Cell Contact ◽  
Dependent Manner

The suppressive capacity of naturally occurring mouse CD4+CD25+ T cells on T-cell activation has been well documented. The present study is focused on the interaction of CD4+CD25+ T cells and B cells. By coculturing preactivated CD4+CD25+ T cells with B cells in the presence of polyclonal B-cell activators, we found that B-cell proliferation was significantly suppressed. The suppression of B-cell proliferation was due to increased cell death caused by the CD4+CD25+ T cells in a cell-contact–dependent manner. The induction of B-cell death is not mediated by Fas–Fas ligand pathway, but surprisingly, depends on the up-regulation of perforin and granzymes in the CD4+CD25+ T cells. Furthermore, activated CD4+CD25+ T cells preferentially killed antigen-presenting but not bystander B cells. Our results demonstrate that CD4+CD25+ T cells can act directly on B cells and suggest that the prevention of autoimmunity by CD4+CD25+ T cells can be explained, at least in part, by the direct regulation of B-cell function.

scholarly journals Induction of human IgE synthesis by CD4+ T cell clones. Requirement for interleukin 4 and low molecular weight B cell growth factor.

1989 ◽  
Vol 170 (5) ◽  
pp. 1477-1493 ◽  
Author(s):  
R H DeKruyff ◽  
T Turner ◽  
J S Abrams ◽  
M A Palladino ◽  
D T Umetsu
Keyword(s):  
Molecular Weight ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cell ◽  
Low Molecular Weight ◽  
Cell Clones ◽  
B Cell Growth Factor ◽  
Ige Synthesis

We have analyzed in detail the precise requirements for the induction of human IgE synthesis using several experimental approaches with purified B cells and well-characterized alloantigen-specific CD4+ T cell clones expressing different profiles of lymphokine secretion. Using these clones under cognate conditions in which the B cells expressed alloantigens recognized by the cloned T cells, we have confirmed that IL-4 is required for the induction of IgE synthesis, but we have clearly demonstrated that IL-4 by itself is not sufficient. With several cloned CD4+ T cell lines, including an IL-4-producing clone that could not induce IgE synthesis, and cloned T cells pretreated with cyclosporin A to inhibit lymphokine synthesis, we showed that Th cell-B cell interactions are necessary for IgE synthesis, and that low molecular weight B cell growth factor (LMW-BCGF) and IL-4, in combination, are lymphokines of major importance in the induction of IgE synthesis. Together our results indicate that optimal induction of an IgE-specific response requires the exposure of B cells to a particular complex of signals that include (a) a signal(s) involving Th-B cell interaction that primes B cells to receive additional signals from soluble lymphokines, (b) a specific B cell proliferative signal provided by LMW-BCGF, and (c) a specific B cell differentiation signal provided by IL-4.

scholarly journals Interleukin 2 induces antigen-reactive T cell lines to secrete BCGF-I.

1983 ◽  
Vol 158 (6) ◽  
pp. 2024-2039 ◽  
Author(s):  
M Howard ◽  
L Matis ◽  
T R Malek ◽  
E Shevach ◽  
W Kell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Interleukin 2 ◽  
Activated T Lymphocytes ◽  
T Cell Lines ◽  
Activated B Cells

Antigen-activated T lymphocytes produce within 24 h of stimulation a factor that is indistinguishable biochemically and functionally from the B cell co-stimulating growth factor, BCGF-I, originally identified in induced EL4 supernatants: Supernatants from antigen-stimulated T cell lines are not directly mitogenic for resting B cells, but synergize in an H-2-unrestricted manner with anti-Ig activated B cells to produce polyclonal proliferation but not antibody-forming-cell development; biochemical studies reveal the B cell co-stimulating factor present in antigen-stimulated T cell line supernatants is identical by phenyl Sepharose chromatography and isoelectric focusing (IEF) to EL4 supernatant BCGF-I. We thus conclude that normal T cells produce BCGF-I in response to antigenic stimulation. Analysis of the mechanism of BCGF-I production by antigen-stimulated T cells showed that optimum amounts of BCGF-I were obtained as quickly as 24 h post-stimulation, and that the factor producing cells in the T cell line investigated bore the Lyt-1+2- phenotype. As few as 10(4) T cells produced sufficient BCGF-I to support the proliferation of 5 X 10(4) purified anti-Ig activated B cells. Finally, the activation of normal T cell lines to produce BCGF-I required either antigen presented in the context of syngeneic antigen-presenting cells (APC) or interleukin 2 (IL-2).

Resistance to the Novel Translation Inhibitor Silvestrol Is Mediated by Elevated Mcl-1 Expression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1737-1737
Author(s):  
David M. Lucas ◽  
Ellen J. Sass ◽  
Ryan B. Edwards ◽  
Li Pan ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Multi Drug Resistance ◽  
Parental Line

Abstract Abstract 1737 Poster Board I-763 We previously reported the efficacy and B-cell selectivity of the natural product silvestrol in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), using both primary cells and B-cell lines. We also showed that silvestrol inhibits translation, resulting in rapid depletion of the short half-life protein Mcl-1 followed by mitochondrial damage and apoptosis. Cencic et al. reported that silvestrol directly blocks translation initiation by aberrantly promoting interaction of eIF4A with capped mRNA (PLoS One 2009; 4(4):e5223). However, the loss of Mcl-1 in breast and prostate cancer cell lines is delayed relative to what we observe in B-leukemias (48 hr vs. 4-6 hr in CLL and ALL cells). Additionally, silvestrol does not reduce Mcl-1 expression in normal T-cells to the same extent that it does in B-cells, potentially explaining in part the relative resistance of T-cells to this agent. We therefore investigated cell-type differences, as well as the importance of Mcl-1, in silvestrol-mediated cytotoxicity. We incubated the ALL cell line 697 with gradually increasing concentrations of silvestrol to generate a cell line (697-R) with resistance to 30 nM silvestrol (IC50 of parental 697 < 5 nM). No differences between 697-R and the parental line were detected upon detailed immunophenotyping. However, cytogenetic analysis revealed a balanced 7q;9p translocation in 697-R not present in the parental 697 cell line that may be related to the emergence of a resistant clone. We also detected no difference in expression of multi-drug resistance proteins MDR-1 and MRP, which can contribute to resistance to complex amphipathic molecules such as silvestrol. In contrast, we found that baseline Mcl-1 protein expression is strikingly increased in 697-R cells relative to the parental line, although these cells still show similar percent-wise reduction in Mcl-1 upon re-exposure to 80 nM silvestrol. To investigate whether this resistance to silvestrol is reversible, 697-R cells were maintained without silvestrol for 6 weeks (∼18 passages). During this time, viability remained near 99%. Cells were then treated with 30 nM silvestrol. Viability was 94% at 48 hr post-treatment and returned to 99% within a week, while parental 697 cells with the same treatment were completely dead. Baseline Mcl-1 levels remained elevated in 697-R even with prolonged silvestrol-free incubation. These results indicate that the resistance phenotype is not rapidly reversible, as is seen with transient upregulation of multi-drug resistance or stress-response proteins. Additionally, silvestrol moderately induces the transcription of several pro-apoptotic Bcl-2 family members and results in elevated levels of these proteins despite its translation inhibitory activity. Interestingly, no such activity is detected in silvestrol-treated normal T-cells. Together, these results support the hypothesis that in B-cells, silvestrol induces cell death by altering the balance of pro- and anti-apoptotic factors, and that increased Mcl-1 protein can force the balance back toward survival. This work further underscores the importance of Mcl-1 in silvestrol-mediated cytotoxicity. We are now investigating the mechanism of Mcl-1 upregulation in 697-R cells to identify a factor or pathway that can be targeted therapeutically to circumvent resistance. Silvestrol is currently undergoing preclinical pharmacology and toxicology investigation by the U.S. National Cancer Institute Drug Development Group at the Stage IIA level to facilitate its progression to Phase I clinical testing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rituximab Synergizes with Hydroxyurea or Vincristine in the Killing of Ramos Burkitt's Lymphoma B Cell Line

2014 ◽  
Vol 29 (2) ◽  
pp. 87-90 ◽  
Author(s):  
Mohamed Deyab ◽  
Abdulrhman Elbanani ◽  
Salah Tabal ◽  
Hajer Geriani ◽  
Yosra Lamami ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma

Rituximab during Pregnancy: Serum Levels, B Cell Counts and Immunoglobulin Levels in Mother and Child.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1508-1508
Author(s):  
Birte Friedrichs ◽  
Markus Tiemann ◽  
Michael K. Wenger ◽  
Karl Verpoort ◽  
Norbert Schmitz
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Serum Levels ◽  
Burkitt’S Lymphoma ◽  
Cell Counts ◽  
Mother And Child ◽  
Newborn Child ◽  
Immunoglobulin Levels

Abstract Recently the first cases of lymphoma patients treated with rituximab and combination chemotherapy during pregnancy were reported. We report on a patient with Burkitt’s lymphoma who was treated with rituximab and CHOP therapy early during pregnancy. We were able to monitor rituximab concentrations, B-/T- cell counts and immunoglobulin levels. After delivery these parameters were also measured in the newborn child. A 35-year-old female was diagnosed with CD20+ Burkitt’s lymphoma of the left breast in week 15 of pregnancy. The minimum stage was IIEA; however, the patient also had hepatosplenomegaly. We started treatment with four weekly infusions of rituximab (375mg/m2)(week 16,17,18,19). Treatment was well tolerated with minimal side effects; a minor response was documented by MRI of the breast and ultrasound of previously enlarged axillary lymph nodes. At that time, a decision was made to continue treatment with 6 courses of Cyclophosphamid, Doxorubicin, Vincristin and Prednison (CHOP) at 3 week intervals (week 21, 24, 27, 30, 33, 36). The first 4 courses were preceded by rituximab (375mg/m2). Immunotherapy was tolerated without significant problems. At the end of therapy (week 37) a complete remission was achieved, again documented by MRI and ultrasound. During therapy the child’s growth and intrauterine development were closely monitored by the attending gynecologist. No deviation from normal development were registered. In week 41 of pregnancy the patient delivered a healthy girl (3780g, 55cm, APGAR score 9/10/10) via caesarean section. The girl is now 19 month old, has repeatedly been seen by her pediatrician who reported completely normal growth and developmental status. The mother received high-dose therapy (BEAM) followed by autologous peripheral blood stem cell transplantion 2 months after delivery and has remained in CR with a normal performance status. As the mother has been extremely compliant we were able to repeatedly measure B cell counts, immunoglobulin levels and rituximab concentrations not only in the patient but also in the baby (table 1). Interestingly, at the time of birth very high serum levels of rituximab were measured in the child. Nonetheless a normal B cell recovery was seen during the following weeks, immunological status reached normal values 4 month after delivery and no overt infectious complications have been reported. As to our knowledge, for the first time data of rituximab serum concentrations are available from mother and child. To conclude, in this case combination of immuno- and chemotherapy could be safely administered, achieving a CR in the patient without causing any mental or developmental retardation in the newborn child. In accordance with other reports, this case supports the safety and efficacy of Rituximab administration during pregnancy. Table 1: B/T cell counts and Rituximab concentrations in mother and child during and after treatment with R-CHOP Time Mother Child *values within normal range week of pregnancy/ B-cells T-cells Rituximab B-cells T-cells Rituximab week after delivery CD 19+ CD 3+ CD 19+ CD 3+ cells/μl cells/μl ng/mL cells/μl cells/μl ng/mL 20 0 946 27 0 640 34 4 337 at birth 0 779 9750 0 93 32095 +4 0 759 70 6616* 5399 +18 37 504 &lt;500 1460* 5475* 700

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