title: Myeloma-reactive allospecific cytotoxic T lymphocytes lyse target cells via the granule exocytosis pathway.
abstract: Accumulating evidence indicates that a graft-vs.-myeloma effect (GVM) and its associated clinical remission of the disease can be induced by donor lymphocyte infusion in myeloma patients who have relapsed after allogeneic bone marrow transplantation. Although it is believed that GVM is induced by allospecific T cells, T-cell subsets and the mechanisms involved in the killing of myeloma cells by donor T cells have not been studied. In this study, we generated allospecific cytotoxic T lymphocyte (CTL) lines against three different myeloma cell lines, ARK, ARP-1 and U266, from unmatched healthy donors and examined their cytotoxicity against the target cells. Our results demonstrate that the allospecific CTLs efficiently lysed myeloma cells. The observed cytotoxicity was mediated mainly by CD8+ T cells and inhibited by MHC class I-blocking antibody. Furthermore, the CTLs lysed the target cells via the perforin-mediated pathway, as concanamycin A, but not brefeldin A (the selective inhibitors for perforin- or Fas-mediated pathways respectively) or tumour necrosis factor-alpha (TNF-alpha)-blocking antibody, abrogated the cytolytic activity of the cells. These CTLs expressed and produced predominantly TNF-alpha and interferon-gamma (IFN-gamma), indicating that they belong to the type 1 T-cell subsets. Taken together, these results indicate that CD8+ allospecific T cells may be responsible for mediating GVM and that the granule-mediated lysis of target cells is the major pathway in the CD8+ T-cell response against myeloma cells.
authors.affiliation: Myeloma and Transplantation Research Center, Arkansas Cancer Research Center, and Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chiriva-Internati
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.forename: M
authors.initials: M
authors.lastname: Cannon
authors.forename: B
authors.initials: B
authors.lastname: Barlogie
authors.forename: Q
authors.initials: Q
authors.lastname: Yi
mesh_terms: D019264:Adoptive Transfer; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D020126:Brefeldin A; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015550:Cell Degranulation; D003601:Cytotoxicity Tests, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D020350:Graft vs Tumor Effect; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D018942:Macrolides; D009101:Multiple Myeloma / Q000276:immunology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018942:Macrolides; D011500:Protein Synthesis Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020126:Brefeldin A; C036978:concanamycin A; D006180:Proton-Translocating ATPases