Document Detail


The role of B cell-mediated T cell costimulation in the efficacy of the T cell retargeting bispecific antibody BIS20x3.
MedLine Citation:
PMID:  15528335     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this study, we investigated the role of the naturally occurring B cell-mediated T cell costimulation in the antitumor efficacy of the bispecific Ab BIS20x3. BIS20x3 has a dual specificity for both CD20 and CD3 and has previously been shown to effectively direct the lytic potential of cytolytic T cells toward malignant, CD20(+) B cells. BIS20x3 instigated T cell-B cell interaction caused a dose-dependent activation of T cells that was 30 times stronger when compared with T cell activation induced by monovalent anti-CD3 Abs. The activation of T cells by BIS20x3 and B cells appeared functional and resulted in the rapid induction of high lytic potential in freshly isolated peripheral T cells. BIS20x3-mediated T cell-B cell interaction resulted in a significant up-regulation of ICAM-1 on B cells and the activation of T cells was found to be dependent on the interaction of ICAM-1 with LFA-1 and trans-activation by the NF-kappaB pathway. Also, the lytic potential of freshly isolated T cells activated via BIS20x3 appeared to be dependent on NF-kappaB signaling in the target B cells. Interestingly, the costimulatory signaling effects described in this study appeared specifically related to the targeting against CD20 because targeting against CD19, by a CD3xCD19-directed bispecific Ab, was significantly less effective in inducing T cell activation and T cell-mediated B cell lysis. Together these results demonstrate that the malignant B cells actively contribute to their own demise upon CD20-directed bispecific Ab-mediated T cell targeting.
Authors:
Alja J Stel; Bart-Jan Kroesen; Susan Jacobs; Herman Groen; Lou F M H de Leij; Hanneke C Kluin-Nelemans; Sebo Withoff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  173     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-11-05     Completed Date:  2004-12-17     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6009-16     Citation Subset:  AIM; IM    
Affiliation:
Department of Pathology and Laboratory Medicine, Section Medical Biology-Laboratory Tumor Immunology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. A.J.Stel@med.rug.nl
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Bispecific / metabolism,  therapeutic use*
Antibodies, Monoclonal / metabolism,  therapeutic use*
Antigens, CD20 / immunology,  physiology
Antigens, CD3 / immunology,  metabolism,  physiology
Antineoplastic Agents / metabolism,  therapeutic use
B-Lymphocytes / immunology*,  metabolism,  pathology*
Cell Death / immunology
Cell Line, Transformed
Cell Line, Tumor
Cross-Linking Reagents / metabolism,  therapeutic use
G0 Phase / immunology
Humans
Intercellular Adhesion Molecule-1 / metabolism,  physiology
Jurkat Cells
Lymphocyte Activation / immunology*
Lymphocyte Cooperation / immunology
Lymphocyte Function-Associated Antigen-1 / metabolism,  physiology
NF-kappa B / genetics,  metabolism
Signal Transduction / immunology
T-Lymphocytes / cytology,  immunology*,  metabolism
Transcription, Genetic / immunology
Chemical
Reg. No./Substance:
0/Antibodies, Bispecific; 0/Antibodies, Monoclonal; 0/Antigens, CD20; 0/Antigens, CD3; 0/Antineoplastic Agents; 0/Cross-Linking Reagents; 0/Lymphocyte Function-Associated Antigen-1; 0/NF-kappa B; 126547-89-5/Intercellular Adhesion Molecule-1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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