Superantigen-staphylococal-enterotoxin-A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells
| Autor: | Frauke Krull, Wolfgang Bethge, Johannes Ihle, Ursula Holzer, Mikael Dohlsten, Terje Kalland, Günther E. Dannecker, Ralph A. Reisfeld, Rupert Handgretinger, Dietrich Niethammer |
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| Rok vydání: | 1995 |
| Předmět: |
Cancer Research
Lymphoma B-Cell T-Lymphocytes T cell Immunology chemical and pharmacologic phenomena Major histocompatibility complex Enterotoxins Neuroblastoma Gangliosides Tumor Cells Cultured Superantigen medicine Humans Immunology and Allergy Cytotoxic T cell Staphylococcal Protein A MHC class II Superantigens biology T-cell receptor Histocompatibility Antigens Class II Antibodies Monoclonal Flow Cytometry Fusion protein Virology Molecular biology medicine.anatomical_structure Oncology biology.protein Antibody |
| Zdroj: | Cancer Immunology Immunotherapy. 41:129-136 |
| ISSN: | 1432-0851 0340-7004 |
| Popis: | Superantigens such as the staphylococcal enterotoxin A (SEA) are among the most potent T cell activators known. They bind to major histocompatibility complex (MHC) class II molecules and interact with T cells depending on their T cell receptor (TCR) V beta expression. Superantigens also induce a variety of cytokines and trigger a direct cytotoxic effect against MHC-class-II-positive target cells. In order to extend superantigen-dependent cell-mediated cytotoxicity (SDCC) to MHC-class-II-negative neuroblastoma cells, SEA was linked to the anti-ganglioside GD2 human/mouse chimeric monoclonal antibody (mAb) ch14.18. Ganglioside GD2 is expressed on most tumours of neuroectodermal origin but is expressed to a lesser extent on normal tissues. The linkage of ch14.18 to SEA was achieved either with a protein-A-SEA fusion protein or by chemical coupling. Both constructs induced T-cell-mediated cytotoxicity towards GD2-positive neuroblastoma cells in an effector-to-target(E:T)-ratio- and dose-dependent manner in vitro. To reduce the MHC class II affinity of SEA, a point mutation was introduced in the SEA gene (SEAm9) that resulted in 1000-fold less T cell killing of MHC-class-II-expressing cells as compared to native SEA. However, a protein-A-SEAm9 fusion protein mediated cytotoxicity similar to that of protein-A-SEA on ch14.18-coated, MHC-class-II-negative neuroblastoma cells. Taken together, these findings suggest that superantigen-dependent and monoclonal-antibody-targeted lysis may be a potent novel approach for neuroblastoma therapy. |
| Databáze: | OpenAIRE |
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