Human HLA-specific T-cell clones with stable expression of a suicide gene: a possible tool to drive and control a graft-versus-host- graft-versus-leukemia reaction?
Allogeneic bone marrow transplantation is still limited by the morbidity and mortality caused by graft-versus-host disease (GVHD), resulting from host recognition by donor T lymphocytes. It is possible to drastically reduce the T-cell content of the graft. However, transplanted T cells can also have a beneficial effect by graft enhancement and the graft-versus-leukemia effect. How can we keep the beneficial GVL effect while protecting the patient from possible GVHD? A recent report proposed the ex vivo transfer of the herpes simplex thymidine kinase (HSv-tk) gene into donor T cells before their infusion with hematopoietic stem cells. This procedure is expected to allow selective donor T-cell depletion with ganciclovir should GVHD occur, but it has two major drawbacks: reinjection of a fraction of untransfected T cells cannot be avoided and heterogeneity of the transfected population results in increased risks such as HSv-tk gene instability or dysfunction of some of the transfected T cell. Alternative approaches must be considered. We demonstrate here the feasibility of generating HSv-tk transfected HLA-specific CD4+ cytotoxic T-cell clonal populations, in which 100% of the cells have the HSv-tk gene inserted at a single site within their genome. These clones retained their specificity, their function, and their sensitivity to ganciclovir treatment. Our approach is not limited to bone marrow transplantation. Indeed, this procedure represents a useful alternative to retroviral gene transduction and is applicable to every circumstance where clinical use of gene modified T-cell clones is to be considered.
Gallot
G
G
Institut National de la Santé et de la recherche Médicale (INSERM Unité 211), Nantes, France.
Hallet
M M
MM
Gaschet
J
J
Moreau
J F
JF
Vivien
R
R
Bonneville
M
M
Milpied
N
N
Vié
H
H
D000998:Antiviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D016923:Cell Death; D018274:Electroporation; D005240:Feasibility Studies; D015774:Ganciclovir / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006087:Graft vs Host Reaction; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D008212:Lymphocyte Depletion / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D013937:Thymidine Kinase / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
D000998:Antiviral Agents; D006680:HLA Antigens; D007519:Isoantigens; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir