CD8(+) minor histocompatibility antigen-specific cytotoxic T lymphocyte clones eliminate human acute myeloid leukemia stem cells.
Effective immunotherapy for human leukemia based on infusions of T lymphocytes requires the identification of effector T cells that target the leukemic stem cell. The transplantation of human acute myeloid leukemia into nonobese diabetic/severe combined immune deficient (SCID) mice has identified a rare leukemic progenitor termed the SCID leukemia-initiating cell, which is present in low frequency in the leukemic population and is essential for establishing leukemic hematopoiesis. Thus, this transplant model may be ideally suited to identify effector T cells with antileukemic activity. We report that CD8(+) cytotoxic T lymphocyte (CTL) clones specific for minor histocompatibility antigens inhibit the engraftment of human acute myeloid leukemia cells in nonobese diabetic/SCID mice and demonstrate that this inhibition is mediated by direct CTL recognition of SCID leukemia-initiating cells. These results indicate that CD8(+) minor histocompatibility antigen-specific CTL may be mediators of the graft-versus-leukemia effect associated with allogeneic hematopoietic cell transplantation and provide an experimental model to identify and select T cell clones for immunotherapy to prevent or treat relapse after allogeneic hematopoietic cell transplantation.
Programs in Cancer/Blood Research and Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto M5G 1X8, Ontario, Canada.
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D
Bonnet
E H
EH
Warren
P D
PD
Greenberg
J E
JE
Dick
S R
SR
Riddell
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017690:Cell Transplantation; D002999:Clone Cells / Q000276:immunology; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007951:Leukemia, Myeloid / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D013234:Stem Cells / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015778:Minor Histocompatibility Antigens