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 thymidin e kinase (HSV-TK) gene followed by ganciclovir (GCV) treatment could allow for specific modulation of the alloreactivity occurring after bone marrow t ransplantation. We are presently exploring such an approach in a phase I cl inical trial. Methods, To examine the beneficial effect of administrating HSV-TK-expressi ng donor T lymphocytes +/- GCV treatment on-acute graft-versus-host disease (aGVHD) control, irradiated Balb/c or C57BL/6 mice underwent transplantati on with allogeneic bone marrow cells in conjunction with CD3(+) allogeneic splenocytes from transgenic mice expressing an HSV-TK transgene. GCV treatm ent was initiated upon the occurrence of severe aGVHD. Results. GCV treatment resulted in a 40-60% longterm 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. Conclusion. 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-ind uced mortality and results in GVHD-free surviving recipients.