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Role of perforin, granzymes and the proliferative state of the target cells in apoptosis and necrosis mediated by bispecific-antibody-activated cytotoxic T cells.

Abstract
Bispecific monoclonal antibodies (bi-mAb), directed against a tumor-associated antigen and the CD3 or CD28 antigen on T lymphocytes, induce activation of resting T lymphocytes and target-specific tumor cell lysis. We now show that both necrosis and apoptosis contribute to T-cell-mediated tumor cell destruction. Even though T cells up-regulate FAS/APO-1 expression upon bi-mAb stimulation, FAS/APO-1-mediated apoptosis does not contribute to bi-mAb-mediated destruction of Hodgkin's cells. CD8+ lymphocytes were the most potent effectors of bi-mAb-mediated cytotoxicity and had the highest levels of mRNA coding for perforin and granzyme A and B. Ca2+-complexing agents, which abrogate perforin activity, led to decreased levels of necrosis, while inhibition of granzyme activity in effector or target cells had a similar effect on apoptosis. Granzyme-mediated apoptosis critically dependent on the proliferative state of the target cells, while perforin-induced necrosis was not cell-cycle-dependent. Our results underline the importance of the expression levels of perforin and granzymes in the effector T cells and of the proliferative state of the target cells in bi-mAb-mediated apoptosis and necrosis of tumor cells.
AuthorsC Renner, G Held, S Ohnesorge, S Bauer, K Gerlach, J P Pfitzenmeier, M Pfreundschuh
JournalCancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 44 Issue 2 Pg. 70-6 (Apr 1997) ISSN: 0340-7004 [Print] Germany
PMID9177467 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Bispecific
  • Antigens, CD
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • fas Receptor
  • Perforin
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • GZMA protein, human
Topics
  • Antibodies, Bispecific (immunology)
  • Antibody-Dependent Cell Cytotoxicity (immunology)
  • Antigens, CD (immunology)
  • Apoptosis
  • Blotting, Northern
  • Cytotoxicity, Immunologic (immunology)
  • DNA Fragmentation
  • Granzymes
  • Hodgkin Disease (pathology)
  • Humans
  • Lymphocyte Activation (physiology)
  • Membrane Glycoproteins (physiology)
  • Necrosis
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Serine Endopeptidases (physiology)
  • T-Lymphocytes, Cytotoxic (immunology)
  • fas Receptor (physiology)

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