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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2071-2076
GENE THERAPY
Suicide gene therapy of graft-versus-host disease: immune
reconstitution with transplanted mature T cells
José L. Cohen,
Olivier Boyer, and
David Klatzmann
From the Laboratoire de Biologie et Thérapeutique
des Pathologies Immunitaires CNRS/UPMC ESA 7087, Groupe Hospitalier
Pitié-Salpêtrière, Paris, France.
After allogeneic hematopoietic stem cell transplantation
(HSCT), mature transplanted T cells play a major role in restoration of
the immune system. However, they can also induce a life-threatening complication: graft-versus-host disease (GVHD). Suicide gene therapy of
GVHD aims to selectively eliminate alloreactive T cells mediating GVHD
while sparing nonalloreactive T cells that should contribute to immune
reconstitution. It was demonstrated previously that treatment with
ganciclovir (GCV) can control GVHD in mice by killing donor T cells
engineered to express the thymidine kinase (TK) suicide gene. TK allows phosphorylation of nontoxic GCV
into triphosphate GCV, which is selectively toxic for dividing cells.
Thus, in the TK-GCV system, the specificity of cell killing depends on
the cycling status of TK T cells rather than allogeneic
recognition. This is a potential drawback because in recipients of
lymphopenic allogeneic HSCT, alloreactive and homeostatic signals drive
the proliferation of donor T cells. It is shown here that the onset of
alloreactive T-cell division occurs earlier than that of
nonalloreactive T cells, thus establishing a time frame for GCV
administration. A 7-day GCV treatment initiated at the time of HSCT
allowed efficient prevention of GVHD, while sparing a pool of
nondividing donor TK T cells. These cells later expanded
and contributed to the replenishment of the recipient immune system
with a diversified T-cell receptor repertoire. These results provide a
rationale for designing the therapeutic scheme when using TK-GCV
suicide gene therapy in allogeneic HSCT.
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