Regulation of alloresponses after bone marrow transplantation using donor T cells expressing a thymidine kinase suicide gene.
Donor T cells have a critical role in promoting engraftment after allogeneic bone marrow transplantation (BMT), but also cause graft versus host disease (GVHD). Ex vivo T cell depletion has been an effective strategy to reduce GVHD but has been associated with impaired alloengraftment and host immunity. Using an MHC-mismatched murine model, we have examined an alternative approach to GVHD prevention whereby donor T cells are selectively eliminated in vivo after BMT using transgenic T cells in which a thymidine kinase (TK) suicide gene is targeted to the T cell. Lethally irradiated AKR/J (H-2k) mice transplanted with TCD C57BL/6 (B6)(H-2b) bone marrow (BM) plus B6 TK+ T cells and then treated with GCV post-BMT had significantly less GVHD severity and improved immune reconstitution compared to untreated mice, providing proof of principle that this strategy could mitigate GVHD. To assess the impact of GCV administration on alloengraftment, sublethally irradiated AKR mice were transplanted with TCD B6 BM alone or admixed with limiting numbers (5 x 10(5)) of B6 TK+ T cells. When tested 3-4 weeks post-transplant, control TCD BM mice all rejected their grafts. Conversely, > 80% of GCV-treated mice had sustained donor T cell engraftment comparable to what was observed in untreated animals. Notably, GCV-treated mice were more likely to have mixed T cell chimerism early post-BMT than untreated animals, however, nearly all GCV-treated mice progressed to complete donor T cell engraftment by 2-3 months post-transplant. Preservation of engraftment was critically dependent upon the GCV administration schedule and required that GCV be delayed for at least one week post-transplant. These studies demonstrate that specific incorporation of a suicide gene into donor T cells is a viable strategy that can be employed to reduce GVHD without compromising alloengraftment.
Drobyski
William R
WR
Bone Marrow Transplant Program, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
Gendelman
Maria
M
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007167:Immunotherapy / Q000379:methods*; D017710:Lymphocyte Transfusion / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000378:metabolism / Q000637:transplantation; D013937:Thymidine Kinase / Q000235:genetics*; D014184:Transplantation, Homologous
D013937:Thymidine Kinase; D015774:Ganciclovir