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Prevention of graft-versus-host disease in mice using a suicide gene
expressed in T lymphocytes
JL Cohen, O Boyer, B Salomon, R Onclercq, F Charlotte, S Bruel, G Boisserie and D Klatzmann
CNRS ERS 107 Laboratoire de Biologie et Therapeutique des Pathologies
Immunitaires, Groupe Hospitalier Pitie-Salpetriere, Paris France.
Alloreactive T cells present in a bone marrow transplant are responsible
for graft-versus-host disease (GVHD), but their depletion is associated
with impaired engraftment, immunosuppression, and loss of the
graft-versus-leukemia effect. We developed a therapeutic strategy against
GVHD based on the selective destruction of these alloreactive T cells,
while preserving a competent T-cell pool of donor origin. We generated
transgenic mice expressing in their T lymphocytes the Herpes simplex type 1
thymidine kinase (TK) suicide gene that allows the destruction of dividing
T cells by a ganciclovir treatment. T cells expressing the TK transgene
were used to generate GVHD in irradiated bone marrow grafted mice. We show
that a short 7-day ganciclovir treatment, initiated at the time of bone
marrow transplantation, efficiently prevented GVHD in mice receiving
TK-expressing T cells. These mice were healthy and had a normal survival.
They maintained a T- cell pool of donor origin that responded normally to
in vitro stimulation with mitogens or third party alloantigens, but were
tolerant to recipient alloantigens. Our experimental system provides the
proof of concept for a therapeutic strategy of GVHD prevention using
genetically engineered T cells.
Volume 89,
Issue 12,
pp. 4636-4645,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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