Idiotype-specific cytotoxic T lymphocytes in multiple myeloma: evidence for their capacity to lyse autologous primary tumor cells

Multiple myeloma (MM) is a B-cell malignancy. The monoclonal immunoglobulin , secreted by myeloma plasma cells, carries unique antigenic determinants ( idiotype [Id]) that can be regarded as a tumor-specific antigen. Id-based i mmunotherapy has been explored in myeloma patients for the purpose of enhan cing or inducing Id-specific immune responses that might lead to tumor dest ruction. However, despite some evidence obtained from mouse plasmacytoma mo dels, it is still unclear whether Id-specific immunity may play a role in t he regulation of tumor cells in MM, In the current study, using dendritic c ells (DCs) as antigen-presenting cells, autologous Id-specific cytotoxic T lymphocyte (CTL) lines containing both CD4(+) and CD8(+) T cells were gener ated from myeloma patients. The results show that Id-specific CTLs not only recognized and lysed autologous Id-pulsed DCs but also significantly kille d the autologous primary myeloma cells, The cytotoxicity against the primar y tumor cells was major histocompatibility complex (MHC) class I- and, to a lesser extent, class Ii-restricted, indicating that myeloma cells could pr ocess Id protein and present Id peptides in the context of their surface MH C molecules, Furthermore, the CTLs lysed the target cells mainly through th e perforin-mediated pathway because Concanamycin A, but not Brefeldin A-the selective inhibitors for perforin- or Fas-mediated pathways-abrogated the cytolytic activity of the cells, These CTLs secreted predominantly interfer on-gamma and tumor necrosis factor-at on antigen stimulation, indicating th at they belong to the type-1 T-cell subsets. Taken together, these findings represent the first demonstration that Id-specific CTLs are able to lyse a utologous tumor cells in MM and, thus, provide a rationale for Id-based imm unotherapy in the disease. (Blood, 2001;97:1750-1755) (C) 2001 by The Ameri can Society of Hematology.