PMID- 12626559
OWN - NLM
STAT- MEDLINE
DCOM- 20030625
LR  - 20190516
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 170
IP  - 6
DP  - 2003 Mar 15
TI  - Elimination of leukemia in the absence of lethal graft-versus-host disease after 
      allogenic bone marrow transplantation.
PG  - 3046-53
AB  - 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.
FAU - Drobyski, William R
AU  - Drobyski WR
AD  - Bone Marrow Transplant Program, Department of Medicine, Medical College of 
      Wisconsin, Milwaukee, WI 53226, USA. bill@bmt.mcw.edu
FAU - Gendelman, Maria
AU  - Gendelman M
FAU - Vodanovic-Jankovic, Sanja
AU  - Vodanovic-Jankovic S
FAU - Gorski, Jack
AU  - Gorski J
LA  - eng
GR  - HL 55388/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - EC 2.7.1.21 (Thymidine Kinase)
RN  - P9G3CKZ4P5 (Ganciclovir)
SB  - IM
MH  - Animals
MH  - Bone Marrow Transplantation/*immunology/mortality
MH  - CD4-Positive T-Lymphocytes/enzymology/immunology
MH  - CD8-Positive T-Lymphocytes/enzymology/immunology
MH  - Dose-Response Relationship, Immunologic
MH  - Drug Administration Schedule
MH  - Ganciclovir/administration & dosage
MH  - Graft vs Host Disease/drug therapy/*immunology/*mortality
MH  - Graft vs Leukemia Effect/drug effects/immunology
MH  - Injections, Intraperitoneal
MH  - Mice
MH  - Mice, Inbred AKR
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neoplasm Transplantation
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug 
      therapy/*immunology/pathology
MH  - T-Lymphocyte Subsets/enzymology/immunology/transplantation
MH  - Thymidine Kinase/biosynthesis
MH  - Transplantation, Homologous
MH  - Tumor Cells, Cultured
EDAT- 2003/03/11 04:00
MHDA- 2003/06/26 05:00
CRDT- 2003/03/11 04:00
PHST- 2003/03/11 04:00 [pubmed]
PHST- 2003/06/26 05:00 [medline]
PHST- 2003/03/11 04:00 [entrez]
AID - 10.4049/jimmunol.170.6.3046 [doi]
PST - ppublish
SO  - J Immunol. 2003 Mar 15;170(6):3046-53. doi: 10.4049/jimmunol.170.6.3046.