Faculty Collaboration Database

Protection from lethal murine graft-versus-host disease without compromise of alloengraftment using transgenic donor T cells expressing a thymidine kinase suicide gene. Blood 2001 Apr 15;97(8):2506-13

Date

04/06/2001

Pubmed ID

11290616

DOI

10.1182/blood.v97.8.2506

Scopus ID

2-s2.0-0035871695 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

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.

Author List

Drobyski WR, Morse HC 3rd, Burns WH, Casper JT, Sandford G

Authors

James Casper MD Emeritus Professor in the Pediatrics department at Medical College of Wisconsin
William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Animals
Bone Marrow Transplantation
CD3 Complex
Enhancer Elements, Genetic
Ganciclovir
Genes, Synthetic
Graft Survival
Graft vs Host Disease
Immune Tolerance
Isoantigens
Mice
Mice, Inbred AKR
Mice, Inbred C57BL
Mice, Transgenic
Promoter Regions, Genetic
Radiation Chimera
Simplexvirus
Spleen
T-Lymphocytes, Cytotoxic
Thymidine Kinase
Transplantation, Homologous
Viral Proteins