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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3087-3093.
Prepublished online as a Blood First Edition Paper on December 30, 2004; DOI 10.1182/blood-2004-09-3737.
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Submitted September 27, 2004
Accepted December 18, 2004
Redirected primary T-cells harboring a chimeric receptor require co-stimulation for their antigen-specific activation
Dinorah Friedmann-Morvinski, Alain Bendavid, Tova Waks, Daniel Schindler, and Zelig Eshhar*
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
* Corresponding author; email: zelig.eshhar{at}weizmann.ac.il.
Chimeric receptor (CR)-redirected lymphocytes (T-bodies) have great potential in the eradication of tumor cells. To extend this approach to target cells that do not express surface ligands to co-stimulatory receptors (e.g. cancer cells), we have generated an antibody-based tripartite chimeric receptor (TPCR) that contains scFv linked to the co-stimulatory molecule, CD28 without its ligand binding domain, and to the cytoplasmic moiety of the FcR gamma subunit. In this study, we tested the ability of TNP-specific TPCR to drive primary, naive T-cells derived from CR-transgenic (Tg) mice to undergo full activation. As a control, we used Tg mice expressing a similar transgene, but lacking the signaling region of CD28 (Tg-TPCR CD28). Only T-cells from the TPCR-Tg and not the CD28-truncated TPCR-Tg mice, could undergo activation following stimulation on hapten modified target cells not expressing B7. Moreover, when stimulated with TNP-protein displayed on plastic, the TPCR transgenic T-cells expressing the entire TPCR gene became fully activated for proliferation, IL-2 production, protection from apoptosis, and killing of TNP modified target cells. Finally, TPCR-Tg mice manifested a DTH response following skin challenge in the absence of priming. Taken together, our results suggest that the TPCR is the receptor configuration of choice for clinical applications employing primary T- or stem cells.
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