Graft rejection and fatal graft versus host disease (GVHD) prohibit the clinical use of allogeneic marrow or peripheral blood stem cell (PBSC) transplantation in those patients who otherwise could benefit from this potentially curative treatment but lack a major histocompatibility complex (MHC) matched donor. Using the dog model of MHC haploidentical mismatched PBSC transplantation, we propose a strategy to overcome resistance to engraftment across MHC barriers and decrease the severity of GVHD. The hypothesis to be tested is that addback and transient activity of in vitro expanded, donor-derived, recipient-specific cytotoxic T lymphocytes (CTL) genetically modified with the herpes simplex thymidine kinase (HS- tk) gene can enhance engraftment of highly purified, lineage depleted CD34+ PBSC without severe GVHD. We will generate and in vitro expand HS-tk transduced CTL, purify donor CD34+ PBSC, and study the effect of transduced recipient-specific CTL on engraftment. We will then establish an optimal schedule for ganciclovir dosing in recipient dogs that eliminates HS-tk transduced T cells and diminishes GVHD while sustaining engraftment
| Georges, G E; Storb, R; Brunvand, M W et al. (1998) Canine T cells transduced with a herpes simplex virus thymidine kinase gene: a model to study effects on engraftment and control of graft-versus-host disease. Transplantation 66:540-4 |
