Preservation of graft-versus-infection effects after suicide gene therapy for prevention of graft-versus-host disease

The main complications following allogeneic hematopoietic stem cell transpl antation are graft-versus-host disease and poor immune reconstitution leadi ng to severe infections. Mature donor T cells present in the transplant fac ilitate T cell reconstitution in adults, but also induce graft-versus-host disease, which itself impairs immune reconstitution. Thus, infusing a large number of donor T cells with a diverse repertoire should accelerate functi onal immune reconstitution after transplantation, only if graft-versus-host disease can be controlled. We previously demonstrated that preventive trea tment with ganciclovir could control graft-versus-host disease in mice if d onor T cells are made to express viral thymidine kinase as a "suicide" gene . Here we evaluated the recovery of functional antiviral immune responses i n such mice. Irradiated mice received an allogeneic hematopoietic stem cell transplantation with thymidine kinase-expressing T cells and were protecte d from graft-versus-host disease by ganciclovir treatment, and then challen ged with lymphocytic choriomeningitis virus. Grafted mice could mount effic ient antilymphocytic choriomeningitis virus immune responses leading to vir al elimination. Furthermore, when transplanted cells were obtained from mic e previously immunized against lymphocytic choriomeningitis virus, grafted mice developed memory-type accelerated responses against the virus. We conc lude that efficient graft-versus-infection effects can be mediated by naive T cells and memory donor T cells that persist after suicide gene therapy f or prevention of graft-versus-host disease.