A time to live, a time to die

T cells contained in marrow or mobilized peripheral blood apheresis products used for hematopoietic stem cell transplantation have both beneficial and detrimental effects in allogeneic recipients. Donor T cells that recognize recipient alloantigens prevent rejection and recurrent malignancy but also cause graft-versus-host disease (GVHD). Donor T cells that do not recognize recipient alloantigens contribute to immune reconstitution after the transplantation. The “surgical” approach of removing all T cells in the graft prevents GVHD but also prevents the beneficial effects of these cells. Drobyski and colleagues (page 2506) have identified a way to retain some of the benefits of donor T cells while preventing GVHD.

Previous studies have shown that GVHD can easily be prevented when donor T cells are transfected to express the H simplex virus enzyme thymidine kinase. Proliferating cells that express this enzyme are susceptible to ganciclovir, an antiviral drug. When ganciclovir is given at the right time after transplantation, TK⁺ donor T cells that proliferate rapidly in response to recipient alloantigens are induced to commit suicide, while some of the more slowly proliferating cells that do not recognize recipient alloantigens are spared. Drobyski and colleagues now show for the first time that, by delaying the administration of ganciclovir until 8-12 days after the transplantation, donor T cells that recognize recipient alloantigens have enough time to prevent rejection but not enough time to cause severe GVHD. These results offer proof of principle that strategies can be developed for controlling the detrimental effects of donor T cells while retaining some of their benefits. Precise balance in the conditioning regimen, number of T cells, and timing of ganciclovir administration was needed for success with this approach, emphasizing the formidable complexity likely to be encountered when attempts are made to translate these results in hematopoietic stem cell transplantation for humans.