title: Tissue-restricted T cell alloresponses across HLA barriers: selection and identification of leukemia-restricted CTL in HLA-mismatched stimulator-responder pairs.
abstract: Exploiting the graft-versus-leukemia (GVL) effect in mismatched transplants requires its separation from graft-versus-host disease (GVHD). We generated leukemia-specific cytotoxic T lymphocytes (CTL) in three haplotype-mismatched, two class I-mismatched and two single HLA-A locus-matched stimulator-responder pairs. Six patients with chronic myelogenous leukemia and one patient with acute myeloid leukemia transformed from MDS were studied. CTL generated after 10 days stimulation with unselected leukemic peripheral blood mononuclear cells inhibited leukemic CFU-GM colony growth (>85% at 10:1 effector:target ratio) with no third-party colony inhibition. In five pairs, responders were cultured separately with leukemia cells, PHA-B or LCL from the stimulator. After 2-4 restimulations, the T cell repertoire was examined by flow analysis using Vbeta-specific antibodies. Test cultures (but not controls) showed preferential expansion of 1-4 Vbeta families either common to two or more stimulators or unique to a particular stimulator. Notably, we elicited leukemia-specific TCR Vbeta expansions on four out of five occasions. In two pairs, responder cells selected for the appropriate leukemia-specific Vbeta family were shown to have leukemia-specific cytotoxicity. These leukemia-restricted T-cells were CD8+ or CD4+ and CD25+ or CD57+. The results support the development of strategies to selectively deplete GVHD and conserve GVL reactivity in mismatched transplants.
authors.affiliation: Allogeneic Stem Cell Transplant Section, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
authors.forename: G
authors.initials: G
authors.lastname: Sconocchia
authors.forename: J
authors.initials: J
authors.lastname: Melenhorst
authors.forename: R
authors.initials: R
authors.lastname: Eniafe
authors.forename: R
authors.initials: R
authors.lastname: Nakamura
authors.forename: N
authors.initials: N
authors.lastname: Hensel
authors.forename: A J
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018959:CD57 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000175:diagnosis*; D020544:Graft vs Leukemia Effect; D006680:HLA Antigens / Q000737:chemistry*; D006239:Haplotypes; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D010641:Phenotype; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors
chemical_list: D018959:CD57 Antigens; D006680:HLA Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2