Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes.
B-cell chronic lymphocytic leukaemia (B-CLL) is a slowly progressing malignancy of CD5(+) B cells, for which at present no curative treatment is available. In our current study, we apply a novel bridging reagent to redirect cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTL) to target B-CLL. A streptavidin-fused anti-CD20 single-chain variable fragment (scFv) is used in combination with biotinylated MHC class I molecules containing CMV pp65 peptide (HLA/CMV). We demonstrate that B-CLL cells coated with this CD20-HLA/CMV complex can be lysed by autologous CMV-specific CTL with similar efficiency as B-CLL cells directly loaded with CMV peptide. Killing is HLA restricted and occurs at scFv CD20 concentrations of >/=100 ng ml(-1) and HLA/CMV concentrations of >/=20 ng ml(-1). Furthermore, complex-coated B-CLL cells induce both proliferation and cytokine production (interferon gamma, tumour necrosis factor alpha and macrophage inflammatory protein-1 beta) in CMV-specific CD8(+) T cells. Hereby, a necessary step towards possible application of CD20-HLA/CMV complexes for immunotherapy of B-cell malignancies is constituted.
Mous
R
R
Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands. r.mous@amc.uva.nl
Savage
P
P
Remmerswaal
E B M
EB
van Lier
R A W
RA
Eldering
E
E
van Oers
M H J
MH
D018951:Antigens, CD20 / Q000096:biosynthesis / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000276:immunology*; D046912:Multiprotein Complexes / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018951:Antigens, CD20; D016207:Cytokines; D006680:HLA Antigens; D046912:Multiprotein Complexes; D010455:Peptides