Display of fas ligand protein on cardiac vasculature as a novel means of regulating allograft rejection

Fas ligand (FasL) is a potent death-inducing molecule with important functions in immune homeostasis and tolerance to self-antigens. The complex biological activities of FasL and its inefficient expression using conventional gene transfer approaches limit its use for immunomodulation to prevent allo...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2003-03, Vol.107 (11), p.1525-1531
Main Authors: ASKENASY, Nadir, YOLCU, Esma S, ZHILIANG WANG, SHIRWAN, Haval
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Biotinylation
Cell Movement
Cell Transplantation
Coronary Vessels - cytology
Endothelium, Vascular - chemistry
Fas Ligand Protein
Graft Rejection - immunology
Graft Rejection - pathology
Graft Rejection - therapy
Graft Survival
Heart Transplantation - immunology
Heart Transplantation - pathology
Kinetics
Medical sciences
Membrane Glycoproteins - genetics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microscopy, Fluorescence
Neutrophils - immunology
Recombinant Fusion Proteins - analysis
Spleen - cytology
Streptavidin - genetics
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
Surgery of the heart
Transplantation Tolerance
Transplantation, Homologous
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Summary:Fas ligand (FasL) is a potent death-inducing molecule with important functions in immune homeostasis and tolerance to self-antigens. The complex biological activities of FasL and its inefficient expression using conventional gene transfer approaches limit its use for immunomodulation to prevent allograft rejection. We have recently generated a chimeric FasL with core streptavidin (SA-FasL) with potent apoptotic activity and designed a novel approach to display it on the surface of several cell types via biotinylation. We herein tested whether SA-FasL can also be displayed on vascular endothelial cells in the heart and examined its effect on graft survival after transplantation into syngeneic and allogeneic hosts. SA-FasL was efficiently displayed on the vasculature of BALB/c hearts with a half-life of 9 days in vivo. Transplantation of hearts displaying SA-FasL into syngeneic hosts resulted in indefinite graft survival without detectable toxicity to the grafts and hosts. In contrast, transplantation of allogeneic C57BL/10 hearts displaying SA-FasL into BALB/c recipients resulted in graft rejection, but in a delayed fashion as compared with control hearts (mean survival time=17.4+/-5 versus 9.6+/-1 days). Allograft survival was further extended to 21+/-2.6 and 24+/-3 days (P
ISSN:0009-7322
1524-4539
DOI:10.1161/01.CIR.0000064893.96179.7E