Immunotherapy in multiple myeloma: Id-specific strategies suggested by studies in animal models.
Multiple myeloma (MM) cells produce monoclonal immunoglobulin (Ig) which serves as a truly tumor-specific antigen. The tumor-specific antigenic determinants are localized in the variable (V)-regions of the monoclonal Ig and are called idiotopes (Id). We review here the evidence obtained in a T-cell receptor (TCR) transgenic mouse model that Id-specific, MHC class II-restricted CD4+ T cells play a pivotal role in immunosurveillance and eradication of MHC class II-negative MM cells. In brief, monoclonal Ig secreted by MM cells is endocytosed and processed by antigen-presenting cells (APCs) in the tumor. Such tumor-resident dendritic cell APCs in turn present Id peptide on their class II molecules to Id-specific CD4+ T cells which become activated and indirectly kill the MHC class II-negative myeloma cells. However, if the Id-specific CD4+ cells fail to eliminate the MM cells during their initial encounter, the increasing number of tumor cells secretes so much monoclonal Ig that T-cell tolerance to Id is induced. Extending these findings to MM patients, Id-specific immunotherapy should be applied at a time of minimal residual disease and when new Id-specific T cells have been educated in the thymus, like after high-dose chemotherapy and autologous stem cell transplantation.
Corthay
Alexandre
A
University of Oslo, Institute of Immunology, Rikshospitalet University Hospital, N-0027 Oslo, Norway. Alexandre.Corthay@labmed.uio.no
Lundin
Katrin U
KU
Munthe
Ludvig A
LA
Frøyland
Marianne
M
Gedde-Dahl
Tobias
T
Dembic
Zlatko
Z
Bogen
Bjarne
B
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007114:Immunization; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*
D000951:Antigens, Neoplasm; D000949:Histocompatibility Antigens Class II; D007130:Immunoglobulin Idiotypes