title: Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy.
abstract: Allogeneic stem cell transplantation following reduced-intensity conditioning is being evaluated in patients with advanced B-cell chronic lymphocytic leukemia (B-CLL). The curative potential of this procedure is mediated by donor-derived alloreactive T cells, resulting in a graft-versus-leukemia effect. However, B-CLL may escape T-cell-mediated immune reactivity since these cells lack expression of costimulatory molecules. We examined the most optimal method to transform B-CLL cells into efficient antigen-presenting cells (APC) using activating cytokines, by triggering toll-like receptors (TLRs) using microbial pathogens and by CD40 stimulation with CD40L-transfected fibroblasts. CD40 activation in the presence of IL-4 induced strongest upregulation of costimulatory and adhesion molecules on B-CLL cells and induced the production of high amounts of IL-12 by the leukemic cells. In contrast to primary B-CLL cells as stimulator cells, these malignant APCs were capable of inducing the generation of B-CLL-reactive CD8(+) CTL lines and clones from HLA class I-matched donors. These CTL lines and clones recognized and killed primary B-CLL as well as patient-derived lymphoblasts, but not donor cells. These results show the feasibility of ex vivo generation of B-CLL-reactive CD8(+) CTLs. This opens new perspectives for adoptive immunotherapy, following allogeneic stem cell transplantation in patients with advanced B-CLL.
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands. M.Hoogendoorn@lumc.nl
authors.forename: M
authors.initials: M
authors.lastname: Hoogendoorn
authors.forename: J Olde
authors.initials: JO
authors.lastname: Wolbers
authors.forename: W M
authors.initials: WM
authors.lastname: Smit
authors.forename: M R
authors.initials: MR
authors.lastname: Schaafsma
authors.forename: R M Y
authors.initials: RM
authors.lastname: Barge
authors.forename: R
authors.initials: R
authors.lastname: Willemze
authors.forename: J H F
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism; D002999:Clone Cells / Q000166:cytology / Q000276:immunology; D018920:Coculture Techniques / Q000379:methods; D020544:Graft vs Leukemia Effect / Q000276:immunology; D006648:Histocompatibility; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D014019:Tissue Donors
chemical_list: D019013:CD40 Antigens; D015395:Histocompatibility Antigens Class I; D015847:Interleukin-4