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Graft-Versus-Leukemia

Tissue-restricted T cell alloresponses across HLA barriers: selection and identification of leukemia-restricted CTL in HLA-mismatched stimulator–responder pairs

Bone Marrow Transplantation volume 32, pages 371–378 (2003)Cite this article

Summary:

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 Vβ-specific antibodies. Test cultures (but not controls) showed preferential expansion of 1–4 Vβ families either common to two or more stimulators or unique to a particular stimulator. Notably, we elicited leukemia-specific TCR Vβ expansions on four out of five occasions. In two pairs, responder cells selected for the appropriate leukemia-specific Vβ 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.

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Authors and Affiliations

  1. Allogeneic Stem Cell Transplant Section, National Heart, Lung and Blood Institute, Bethesda, MD, USA

    H Fujiwara, G Sconocchia, J Melenhorst, R Eniafe, R Nakamura, N Hensel & A J Barrett

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  1. H Fujiwara
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  2. G Sconocchia
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  3. J Melenhorst
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Fujiwara, H., Sconocchia, G., Melenhorst, J. et al. Tissue-restricted T cell alloresponses across HLA barriers: selection and identification of leukemia-restricted CTL in HLA-mismatched stimulator–responder pairs. Bone Marrow Transplant 32, 371–378 (2003). https://doi.org/10.1038/sj.bmt.1704142

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