title: Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines.
abstract: In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.
authors.affiliation: Department of Medicine III, Hematology, and Oncology, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wehler
authors.forename: Marion
authors.initials: M
authors.lastname: Nonn
authors.forename: Britta
authors.initials: B
authors.lastname: Brandt
authors.forename: Cedrik M
authors.initials: CM
authors.lastname: Britten
authors.forename: Mark
authors.initials: M
authors.lastname: Gröne
authors.forename: Mariya
authors.initials: M
authors.lastname: Todorova
authors.forename: Irina
authors.initials: I
authors.lastname: Link
authors.forename: Shamsul A
authors.initials: SA
authors.lastname: Khan
authors.forename: Ralf G
authors.initials: RG
authors.lastname: Meyer
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Udo F
authors.initials: UF
authors.lastname: Hartwig
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000473:pathology; D002478:Cells, Cultured / Q000737:chemistry / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005347:Fibroblasts / Q000276:immunology; D006086:Graft vs Host Disease / Q000517:prevention & control; D006680:HLA Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006648:Histocompatibility; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods*; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D007519:Isoantigens / Q000276:immunology; D020014:K562 Cells / Q000276:immunology; D007680:Kidney Neoplasms / Q000473:pathology; D007951:Leukemia, Myeloid / Q000473:pathology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion / Q000379:methods*; D012867:Skin / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D014162:Transfection; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D007519:Isoantigens; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D023201:CD40 Ligand