Regulation of alloresponses after bone marrow transplantation using donor T cells expressing a XXXX kinase suicide gene.

@entity19 @entity2132 @entity1014 @entity12705
Donor T cells have a critical role in promoting engraftment after allogeneic bone marrow transplantation (BMT), but also cause @entity2132 ( @entity2132 ). Ex vivo T cell depletion has been an effective strategy to reduce @entity2132 but has been associated with impaired alloengraftment and host immunity. Using an MHC-mismatched @entity19 model, we have examined an alternative approach to @entity2132 prevention whereby donor T cells are selectively eliminated in vivo after BMT using transgenic T cells in which a @entity1014 kinase (TK) suicide gene is targeted to the T cell. Lethally irradiated AKR/J (H-2k) @entity19 transplanted with @entity12705 C57BL/6 (B6)(H-2b) bone marrow (BM) plus B6 TK+ T cells and then treated with GCV post-BMT had significantly less @entity2132 severity and improved immune reconstitution compared to untreated @entity19 , providing proof of principle that this strategy could mitigate @entity2132 . To assess the impact of GCV administration on alloengraftment, sublethally irradiated AKR @entity19 were transplanted with @entity12705 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 @entity12705 BM @entity19 all rejected their grafts. Conversely, > 80% of GCV-treated @entity19 had sustained donor T cell engraftment comparable to what was observed in untreated animals. Notably, GCV-treated @entity19 were more likely to have mixed T cell chimerism early post-BMT than untreated animals, however, nearly all GCV-treated @entity19 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 @entity2132 without compromising alloengraftment.
