Protection from lethal murine graft-versus-host disease without compromise of alloengraftment using transgenic donor T cells expressing a thymidine kinase suicide gene.
Donor T cells play a pivotal role in facilitating alloengraftment but also cause graft-versus-host disease (GVHD). Ex vivo T-cell depletion (TCD) of donor marrow is the most effective strategy for reducing GVHD but can compromise engraftment. This study examined an approach whereby donor T cells are selectively eliminated in vivo after transplantation using transgenic mice in which a thymidine kinase (TK) suicide gene is targeted to the T cell using a CD3 promoter/enhancer construct. Lethally irradiated B10.BR mice transplanted with major histocompatibility complex (MHC)-incompatible TCD C57BL/6 (B6) bone marrow (BM) plus TK(+) T cells were protected from GVHD after treatment with ganciclovir (GCV) in a schedule-dependent fashion. To examine the effect of GCV treatment on alloengraftment, sublethally irradiated AKR mice underwent transplantation with TCD B6 BM plus limiting numbers (5 x 10(5)) of B6 TK(+) T cells. Animals treated with GCV had comparable donor engraftment but significantly reduced GVHD when compared with untreated mice. These mice also had a significantly increased number of donor splenic T cells when assessed 4 weeks after bone marrow transplantation. Thus, the administration of GCV did not render recipients T-cell deficient, but rather enhanced lymphocyte recovery. Adoptive transfer of spleen cells from GCV-treated chimeric mice into secondary AKR recipients failed to cause GVHD indicating that donor T cells were tolerant of recipient alloantigens. These studies demonstrate that administration of TK gene-modified donor T cells can be used as an approach to mitigate GVHD without compromising alloengraftment.
Drobyski
W R
WR
Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. bill@bmt.mcw.edu
Morse
H C
HC
Burns
W H
WH
Casper
J T
JT
Sandford
G
G
D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D017252:CD3 Complex / Q000235:genetics; D004742:Enhancer Elements, Genetic; D015774:Ganciclovir / Q000494:pharmacology* / Q000627:therapeutic use; D005813:Genes, Synthetic; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011828:Radiation Chimera; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000201:enzymology / Q000637:transplantation; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D014184:Transplantation, Homologous / Q000009:adverse effects; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
D017252:CD3 Complex; D007519:Isoantigens; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir