A novel cytotoxicity of CD4+ Th1 clones on heat-shocked tumor targets. I. Implications for internal disintegration model for target death and hyperthermia treatment of cancers.
A novel cytotoxicity, which is normally hidden but unveiled upon interacting with heat-shocked tumor target, has been identified in CD4+ Th1 cells. When TNF-resistant, Ag-presenting tumor targets were heat shocked, the cytotoxicity by specific Th1 clones was significantly enhanced. Interestingly, the DNA of heat-shocked, unpulsed targets including Ia- tumor cells were also fragmented by Th1 clones. In contrast to the Ag-dependent, MHC-restricted cytotoxicity, the heat-shock-induced sensitivity to Th1 clones was a) Ag independent and MHC unrestricted, b) insensitive to CD4-mAb, c) resistant to actinomycin D and cycloheximide, and d) greatly enhanced by cholera toxin, PGE1, PGE2, and dibutyryl cAMP. This novel cytotoxicity was inhibited by mAb specific to lymphocyte function-associated Ag-1 and intercellular adhesion molecule-1. Upon culturing at 37 degrees C, mildly heat-shocked target cells gradually recovered, indicating that the heat-shock-induced sensitivity was transient and reversible. The implication of this study for a signal-induced internal disintegration mechanism for target death is discussed. The novel cytotoxicity of CD4+ Th1 cells may be an important mechanism of immune regulation under febrile conditions and an underlying mechanism for the hyperthermia treatment of cancers.
Department of Pathology, Boston University School of Medicine, MA 02118.
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Ozdemirli
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Akdeniz
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el-Khatib
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D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology; D002999:Clone Cells; D000242:Cyclic AMP / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D004249:DNA Damage; D004734:Energy Metabolism; D006358:Hot Temperature; D007111:Immunity, Cellular; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014407:Tumor Cells, Cultured / Q000276:immunology*
D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP