Transduction of donor hematopoietic stem-progenitor cells with Fas ligand enhanced short-term engraftment in a murine model of allogeneic bone marrow transplantation.
Fas-mediated apoptosis is a major physiologic mechanism by which activated T cells are eliminated after antigen-stimulated clonal expansion generates a specific cellular immune response. Because activated T cells are the major effectors of allograft rejection, we hypothesized that genetically modifying allogeneic bone marrow (BM) cells prior to transplantation could provide some protection from host T-cell attack, thus enhancing donor cell engraftment in bone marrow transplantation (BMT). We undertook studies to determine the outcome of lentiviral vector-mediated transduction of Fas ligand (FasL) into lineage antigen-negative (lin(-)) mouse BM cells (lin(-) BMs), in an allogeneic BMT model. FasL-modified lin(-) BMs killed Fas-expressing T cells in vitro. Mice that received transplants of allogeneic FasL(+) lin(-) BMs had enhanced short-term engraftment, after nonmyeloablative conditioning, as compared to controls. We observed no major hepatic toxicity or hematopoietic or immune impairment in recipient mice at these time points. These results suggest potential therapeutic approaches by manipulating lymphohematopoietic stem-progenitor cells to express FasL or other immune-modulating genes in the context of BMT.
Whartenby
Katharine A
KA
Sidney Kimmel Comprehensive Cancer Center at JHU, School of Medicine, Johns Hopkins University, Bunting-Blaustein Cancer Research Building, Room 2M44, 1650 Orleans Street, Baltimore, MD 21231, USA. whartka@jhmi.edu
Straley
Erin E
EE
Kim
Heeje
H
Racke
Frederick
F
Tanavde
Vivek
V
Gorski
Kevin S
KS
Cheng
Linzhao
L
Pardoll
Drew M
DM
Civin
Curt I
CI
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D003713:Dendritic Cells / Q000276:immunology; D004198:Disease Susceptibility; D053222:Fas Ligand Protein; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D049452:Green Fluorescent Proteins; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008088:Listeriosis / Q000276:immunology; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology / Q000633:toxicity; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014019:Tissue Donors; D014162:Transfection; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins