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rdf:type |
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lifeskim:mentions |
umls-concept:C0008109,
umls-concept:C0037083,
umls-concept:C0205171,
umls-concept:C0337112,
umls-concept:C0439828,
umls-concept:C0597357,
umls-concept:C1155065,
umls-concept:C1337056,
umls-concept:C1514562,
umls-concept:C1524075,
umls-concept:C1707689,
umls-concept:C1710082,
umls-concept:C1880389,
umls-concept:C1883204,
umls-concept:C1883221,
umls-concept:C2698651
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pubmed:issue |
1
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pubmed:dateCreated |
1998-5-7
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pubmed:abstractText |
T cells of tumor bearers often show defective TCR-mediated signaling events and, therefore, exhibit impaired immune responses. As such, patients with heavy tumor burden are often not amenable to adoptive T cell therapy. To overcome this limitation, we have developed a chimeric receptor that joins an extracellular single chain Fv (scFv) of a specific Ab for Ag recognition to an intracellular protein tyrosine kinase (PTK) for signal propagation. Stimulation through the scFv-PTK receptor should bypass defective TCR-proximal events and directly access the T cell's effector mechanisms. In this study we describe the optimization of a scFv-PTK configuration, leading to complete T cell activation. The cytosolic PTK Syk is superior to its family member, Zap-70, for intracellular signaling. As a transmembrane (TM) domain, CD4 performs better than CD8 when plastic-immobilized Ag serves as a stimulator. However, when APC are used to trigger chimeric receptors, the need for a flexible spacer between the scFv and TM domains becomes apparent. The CD8alpha-derived hinge successfully performs this task in chimeric scFv-Syk receptors regardless of its cysteine content. A cytotoxic T cell hybridoma expressing chimeric receptor genes composed of scFv-CD8(hinge)-CD8(TM)-Syk or scFv-CD8(hinge)-CD4(TM)-Syk is efficiently stimulated to produce IL-2 upon interaction with APC and specifically lyses appropriate target cells in a non-MHC-restricted manner.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD4,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD8,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Precursors,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Antigen, T-Cell,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Syk kinase,
http://linkedlifedata.com/resource/pubmed/chemical/ZAP-70 Protein-Tyrosine Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Zap70 protein, mouse
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0022-1767
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
160
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
145-54
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pubmed:dateRevised |
2011-11-2
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pubmed:meshHeading |
pubmed-meshheading:9551966-Animals,
pubmed-meshheading:9551966-Antigens, CD4,
pubmed-meshheading:9551966-Antigens, CD8,
pubmed-meshheading:9551966-Cells, Cultured,
pubmed-meshheading:9551966-Cysteine,
pubmed-meshheading:9551966-Cytotoxicity, Immunologic,
pubmed-meshheading:9551966-Dimerization,
pubmed-meshheading:9551966-Enzyme Precursors,
pubmed-meshheading:9551966-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:9551966-Lymphocyte Activation,
pubmed-meshheading:9551966-Mice,
pubmed-meshheading:9551966-Protein-Tyrosine Kinases,
pubmed-meshheading:9551966-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:9551966-Receptors, Antigen, T-Cell,
pubmed-meshheading:9551966-Recombinant Fusion Proteins,
pubmed-meshheading:9551966-Structure-Activity Relationship,
pubmed-meshheading:9551966-ZAP-70 Protein-Tyrosine Kinase
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pubmed:year |
1998
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pubmed:articleTitle |
Harnessing Syk family tyrosine kinases as signaling domains for chimeric single chain of the variable domain receptors: optimal design for T cell activation.
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pubmed:affiliation |
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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