Preemptive control of graft-versus-host disease in a murine allogeneic transplant model using retrovirally transduced murine suicidal lymphocytes.
Suicidal lymphocytes could greatly expand the role of allogeneic transplantation by reducing graft-versus-host disease (GVHD) as a barrier to transplantation, but optimization of their use is hindered by the lack of adequate animal models. To develop an animal model that used retrovirally transduced suicidal lymphocytes in a GVHD setting, a well-characterized MHC-matched murine transplant model (B10.BR-->AKR/J) was adapted. B10.BR splenic lymphocytes stimulated with concanavalin A and interleukin 2 were infected with a retrovirus containing the low-affinity nerve growth factor receptor (LNGFR) and the HSV-TK gene and immunomagnetically selected; these LNGFR+/TK+ allogeneic lymphocytes were then cotransplanted with 1 x 10(7) bone marrow cells into lethally irradiated AKR/J recipients. The LNGFR+/TK+ donor lymphocytes persisted in the peripheral circulation for 6 months in both syngeneic and allogeneic settings. Doses of 2 x 10(6) TK+ allogeneic lymphocytes produced GVHD with a severity and time course similar to that induced by naive lymphocytes. Survival of TK+ allogeneic lymphocyte-bearing mice was significantly improved (P = 0.01) when ganciclovir (GCV; 2 mg/day) was administered on days 7-13 post transplant by i.p. injection, demonstrating that GVHD could be prevented. Fluorescence-activated cell sorting analysis demonstrated 4-fold reduction but persistent circulation of LNGFR+ lymphocytes in mice treated with GCV at various time points 1-3 months after transplantation, demonstrating selective killing of GVHD-reactive cells. We conclude that retrovirally transduced LNGFR+/TK+ murine lymphocytes can be produced, persist after transplant, remain alloreactive, and can be killed by GCV administration, resulting in reduced GVHD.
Kornblau
S M
SM
Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. skornblau@mdacc.tmc.edu
Stiouf
I
I
Snell
V
V
Przepiorka
D
D
Stephens
L C
LC
Champlin
R
R
Marini
F C
FC
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D016923:Cell Death; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008806:Mice, Inbred AKR; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000637:transplantation*; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic; D018183:Transplantation Chimera
D020800:Receptor, Nerve Growth Factor; D013937:Thymidine Kinase; D015774:Ganciclovir