Elimination of leukemia in the absence of lethal graft-versus-host disease after allogenic bone marrow transplantation. J Immunol 2003 Mar 15;170(6):3046-53
Date
03/11/2003Pubmed ID
12626559DOI
10.4049/jimmunol.170.6.3046Scopus ID
2-s2.0-0037443557 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
Donor T cells are able to effect a graft-vs-leukemia (GVL) response but also induce graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation. We used an AKR leukemia murine transplant model, analogous to human acute lymphoblastic leukemia, in which donor T cells expressed a thymidine kinase suicide gene, to test whether separation of GVL and graft-vs-host (GVH) responses was feasible by selectively eliminating alloactivated donor T cells at defined time points posttransplant. Under experimental conditions where untreated mice could not be cured of disease without dying from GVHD, mice transplanted with thymidine kinase-positive T cells and subsequently administered ganciclovir (GCV) could eliminate leukemia without lethal GVHD. Timing of GCV administration, donor T cell dose, and preexisting leukemia burden were observed to be critical variables. Eradication of leukemia without lethal GVHD in GCV-treated mice implied that the kinetics of GVL and GVH responses were asynchronous and could therefore be temporally dissociated by timely GCV administration. That this strategy was feasible in a murine leukemia model in which GVHD and GVL reactivity are tightly linked suggests that this approach may be relevant to the treatment of selected human leukemias where similar constraints exist. This strategy represents an alternative approach to separating GVL and GVH reactivity and challenges the current paradigm that separation of these responses is dependent upon the administration of donor T cells with restricted specificity for leukemia as opposed to host Ags.
Author List
Drobyski WR, Gendelman M, Vodanovic-Jankovic S, Gorski JAuthor
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Marrow Transplantation
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Dose-Response Relationship, Immunologic
Drug Administration Schedule
Ganciclovir
Graft vs Host Disease
Graft vs Leukemia Effect
Injections, Intraperitoneal
Mice
Mice, Inbred AKR
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Transplantation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
T-Lymphocyte Subsets
Thymidine Kinase
Transplantation, Homologous
Tumor Cells, Cultured
