Ganciclovir-sensitive acute graft-versus-host disease in mice receiving herpes simplex virus-thymidine kinase-expressing donor T cells in a bone marrow transplantation setting.
BACKGROUND
The use of donor T cells expressing the herpes simplex thymidine kinase (HSV-TK) gene followed by ganciclovir (GCV) treatment could allow for specific modulation of the alloreactivity occurring after bone marrow transplantation. We are presently exploring such an approach in a phase I clinical trial.


METHODS
To examine the beneficial effect of administrating HSV-TK-expressing donor T lymphocytes +/- GCV treatment on acute graft-versus-host disease (aGVHD) control, irradiated Balb/c or C57BL/6 mice underwent transplantation with allogeneic bone marrow cells in conjunction with CD3+ allogeneic splenocytes from transgenic mice expressing an HSV-TK transgene. GCV treatment was initiated upon the occurrence of severe aGVHD.


RESULTS
GCV treatment resulted in a 40-60% long-term survival rate of GVHD-free recipients having received HSV-TK-expressing T cells, whereas only 0-6% of mice survived without GCV treatment. Lethal aGVHD occurred in all the control animals having received non-HSV-TK-expressing T cells, irrespective of GCV treatment.


CONCLUSIONS
Our results demonstrate that the administration of donor HSV-TK-expressing T cells to hematopoietic stem cell graft recipients followed by GCV treatment at the onset of severe aGVHD significantly reduces aGVHD-induced mortality and results in GVHD-free surviving recipients.
Contassot
E
E
Laboratoire de Thérapeutique Immuno-moléculaire, Etablissement de Transfusion Sanguine, Besançon, France.
Ferrand
C
C
Angonin
R
R
Cohen
J L
JL
de Carvalho Bittencourt
M
M
Lorchel
F
F
Laithier
V
V
Cahn
J Y
JY
Klatzmann
D
D
Herve
P
P
Tiberghien
P
P
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D015774:Ganciclovir / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018139:Simplexvirus / Q000502:physiology*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000201:enzymology* / Q000821:virology*; D013937:Thymidine Kinase / Q000096:biosynthesis*
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir