Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells

2000 ◽  
Vol 48 (12) ◽  
pp. 673-683 ◽  
Author(s):  
Daming Shan ◽  
Jeffrey A. Ledbetter ◽  
Oliver W. Press
Keyword(s):  
B Cells ◽  
Human B Cells ◽  
Signaling Events ◽  
Induced Apoptosis ◽  
Anti Cd20

scholarly journals Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5191-5201 ◽  
Author(s):  
Stephen A. Beers ◽  
Ruth R. French ◽  
H. T. Claude Chan ◽  
Sean H. Lim ◽  
Timothy C. Jarrett ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Type I ◽  
Type Ii ◽  
Antigenic Modulation ◽  
Lymphatic Leukemia ◽  
Human B Cells ◽  
Anti Cd20

Abstract Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

scholarly journals Effect of anti-CD20 monoclonal antibody, Rituxan, on cynomolgus monkey and human B cells in a whole blood matrix

Cytometry ◽  
2003 ◽  
Vol 52A (2) ◽  
pp. 101-109 ◽  
Author(s):  
Yulia Vugmeyster ◽  
Kathy Howell ◽  
Anahid Bakshl ◽  
Clarissa Flores ◽  
Eleanor Canova-Davis
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Whole Blood ◽  
Cynomolgus Monkey ◽  
Human B Cells ◽  
Anti Cd20

scholarly journals B cell receptor triggering sensitizes human B cells to TRAIL-induced apoptosis

2010 ◽  
Vol 88 (5) ◽  
pp. 937-945 ◽  
Author(s):  
Andre Ortlieb Guerreiro-Cacais ◽  
Jelena Levitskaya ◽  
Victor Levitsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Human B Cells ◽  
Induced Apoptosis

p53 and COX-2 Inhibitors Control the Replication and Viability of Non-Transformed and CLL B Lymphocytes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3146-3146
Author(s):  
Patricia Mongini ◽  
Matthew Kaufman ◽  
Jonathan E. Kolitz ◽  
Steven L. Allen ◽  
Joshua Trott ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Negative Regulator ◽  
P53 Expression ◽  
Activation Induced Cell Death ◽  
Human B Cells ◽  
Cox 2 ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Transcription Factor P53

Abstract Innate immune system-driven replication of antigen receptor-triggered, non-transformed human B2 cells depends upon BAFF-mediated survival signals. The latter promote a COX-2--PGE2--Mcl-1 pathway within the dividing subpopulation and significantly reduce activation-induced apoptosis within clonal progeny (J. Immunol. 176:6736, 2006). Mcl-1 is known to counter mitochondria-dependent apoptosis induced by Foxo-upregulated Bim and by p53-upregulated Bax, Bak, Bid and Bad. To gain insight into mechanism(s) responsible for this activation-induced apoptosis, levels of the above pro-apoptotic molecules, as well as the transcription factor p53, were monitored in cultures of CFSE-labeled, non-transformed human B cells stimulated by surrogate C3dg-bound antigen, IL-4 and BAFF. The latter typically undergo 5–6 divisions over a week of culture. Based on the preferentially upregulated expression of p53 and its downstream pro-apoptotic molecules, and the reversing effects of p53 siRNA, it was concluded that the activation-induced cell death involves a p53-mediated apoptosis program. The day 2 administration of Nutlin, a pharmacologic inhibitor of p53 interaction with its negative regulator, MdM2, resulted in further augmented p53 expression and activity. This was revealed by diminished cycling and increased apoptosis within the replicating population. To examine whether positive/negative modulation of the COX-2--PGE-2--Mcl-1 pathway can alter the sensitivity to Nutlin (10 mM), activated cultures were additionally supplemented with either exogenous PGE2 (10 nM) or the COX-2 inhibitor, CAY10404 (30 mM). While a pulse with PGE2 reversed the pro-apoptotic effects of Nutlin, a concurrent pulse with COX-2 inhibitor augmented the degree of apoptosis observed. For example, while absolute cell yield (viable + apoptotic) in cultures with DMSO vehicle control, Nutlin, Nutlin + COX-2 inhibitor, or Nutlin + PGE2 was 167 ×103, 72 ×103, 41 ×103, and 96 ×103, respectively, the percent viability within the divided fraction was 61%, 48%, 39%, and 71%, respectively. The data suggest that a COX-2--PGE2--Mcl-1 pathway may override the effects of an active p53 pathway in cycling, non-transformed human B lymphocytes. Ongoing studies are exploring whether proliferating CLL clones are likewise reciprocally regulated by p53 and COX-2 pathways. CFSE-labeled CLL B cells were stimulated for 8 days with TLR9 ligand, ODN-2006 (0.2 mM) + IL15 (15 ng/ml), yielding up to 7–8 divisions. A day 5 pulse with Nutlin resulted in significant day 8 apoptosis of both the cycling and few non-cycling cells within activated CLL cultures (e.g. undivided cells = 64% and 10% viability, and divided cells = 45% and 2%, within control and Nutlin cultures, respectively). Preliminary results indicate that COX-2 inhibitor significantly impairs CLL replication and viability in a manner dependent upon the timed addition of inhibitor. A day 2 pulse with CAY10404 reduced the day 8 yield of CLL cells with ≥ 4 divisions, as well as slightly reducing undivided cell viability. A day 5 pulse impaired the yield of cells with ≥ 5 divisions and the viability of both non-cycling and dividing CLL. Present studies are evaluating whether low concentrations of Nutlin and COX-2 inhibitor may exhibit synergy in blocking the growth/viability of CLL clones. A two-pronged therapeutic approach at augmenting p53 levels and diminishing COX-2 levels might be warranted in the treatment of CLL.

scholarly journals CD20 as a gatekeeper of the resting state of human B cells

2021 ◽  
Vol 118 (7) ◽  
pp. e2021342118
Author(s):  
Kathrin Kläsener ◽  
Julia Jellusova ◽  
Geoffroy Andrieux ◽  
Ulrich Salzer ◽  
Chiara Böhler ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Resting State ◽  
Cell Activation ◽  
Surface Proteins ◽  
Metabolic Reprogramming ◽  
Human B Cells ◽  
Anti Cd20

CD20 is a B cell-specific membrane protein and represents an attractive target for therapeutic antibodies. Despite widespread usage of anti-CD20 antibodies for B cell depletion therapies, the biological function of their target remains unclear. Here, we demonstrate that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. CRISPR/Cas9-mediated ablation of CD20 in resting B cells resulted in relocalization and interaction of the IgM-class B cell antigen receptor with the coreceptor CD19. This receptor rearrangement led to a transient activation of B cells, accompanied by the internalization of many B cell surface marker proteins. Reexpression of CD20 restored the expression of the B cell surface proteins and the resting state of Ramos B cells. Similarly, treatment of Ramos or naive human B cells with the anti-CD20 antibody rituximab induced nanoscale receptor rearrangements and transient B cell activation in vitro and in vivo. A departure from the resting B cell state followed by the loss of B cell identity of CD20-deficient Ramos B cells was accompanied by a PAX5 to BLIMP-1 transcriptional switch, metabolic reprogramming toward oxidative phosphorylation, and a shift toward plasma cell development. Thus, anti-CD20 engagement or the loss of CD20 disrupts membrane organization, profoundly altering the fate of human B cells.

Fas-induced apoptosis of human B cells can be inhibited by over-expression of Bcl-2

1997 ◽  
Vol 56 ◽  
pp. 74
Author(s):  
M.K. Alam ◽  
S. Davison ◽  
J.D. Norton ◽  
J.J. Murphy
Keyword(s):  
B Cells ◽  
Over Expression ◽  
Human B Cells ◽  
Induced Apoptosis

scholarly journals Ca2+-related signaling events influence TLR9-induced IL-10 secretion in human B cells

2014 ◽  
Vol 44 (5) ◽  
pp. 1285-1298 ◽  
Author(s):  
Saskia Ziegler ◽  
Katrin Gartner ◽  
Uwe Scheuermann ◽  
Tanja Zoeller ◽  
Julia Hantzschmann ◽  
...  
Keyword(s):  
B Cells ◽  
Human B Cells ◽  
Signaling Events
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