Rapid generation of antiplasma cell activity in the bone marrow of myeloma patients by CD3-activated T cells.
We have recently shown that peripheral blood T cells of multiple myeloma (MM) patients are very susceptible to stimulation of the T-cell receptor/CD3 complex with anti-CD3 monoclonal antibodies (MoAbs). CD3 stimulation is currently under clinical investigation as a nonspecific approach to boost antitumor effector mechanisms. The aim of this study was to determine whether the hyperreactivity of MM T cells to CD3 stimulation could be exploited to generate antitumor activity. Bone marrow mononuclear cells (BMMCs) from 65 MM patients were stimulated with the anti-CD3 MoAb OKT3 and the effect of this stimulation on autologous T cells and plasma cells was evaluated. The number of CD3+ CD25+ cells on day 6 was significantly higher in MM than the controls (30 normal individuals) (P = .001). Kinetic studies showed that 3H-thymidine incorporation peaked on day 3 and that the T-cell expansion peaked on days 5 and 6. In MM, T-cell activation markedly affected the survival of autologous plasma cells; their number in OKT3-treated cultures was significantly lower than in unstimulated cultures (P < .0001). T-cell activation and plasma cell decrease were not observed when T cells were removed from BMMC preparations. MM produced significantly higher levels of interferon-gamma (P = .005) and tumor necrosis factor-beta (P = .001), but lower levels of tumor necrosis factor-alpha (P < .001) than normal individuals. Interferon-gamma only was partially involved in CD3-induced plasma cell killing. Transwell cultures showed that the main mechanism by which CD3+ CD25+ cells affected plasma cells was direct cell-to-cell contact rather than cytokines. In conclusion, T cells in MM BMMCs possess distinct features in terms of susceptibility to CD3 stimulation and cytokine production compared with normal bone marrow T cells that can be exploited to generate antiplasma cell activity.
Massaia
M
M
Divisione Universitaria di Ematologia, Ospedale Maggiore S. Giovanni Battista, Università di Torino, Italy.
Attisano
C
C
Peola
S
S
Montacchini
L
L
Omedé
P
P
Corradini
P
P
Ferrero
D
D
Boccadoro
M
M
Bianchi
A
A
Pileri
A
A
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008233:Lymphotoxin-alpha / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009101:Multiple Myeloma / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D016853:Muromonab-CD3 / Q000276:immunology / Q000494:pharmacology; D009367:Neoplasm Staging; D010950:Plasma Cells / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017252:CD3 Complex; D008233:Lymphotoxin-alpha; D016853:Muromonab-CD3; D011994:Recombinant Proteins; D007371:Interferon-gamma