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Basic Science Reports

Display of Fas Ligand Protein on Cardiac Vasculature as a Novel Means of Regulating Allograft Rejection

From The Leah and Edward M. Frankel Laboratory of Bone Marrow Transplantation, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel (N.A.); Institute for Cellular Therapeutics, University of Louisville, Louisville, Ky, (E.S.Y., H.S.); Starzl E. Thomas Transplantation Institute, University of Pittsburgh, Pittsburgh, Pa (Z.W.); and Department of Microbiology and Immunology, University of Louisville, Louisville, Ky (H.S.).

Correspondence to Nadir Askenasy, The Leah and Edward M. Frankel Laboratory of Bone Marrow Transplantation, Department of Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan St, Petach Tikva, Israel 49202 (e-mail anadir{at}012.net.il), or Haval Shirwan, Institute for Cellular Therapeutics, 570 S. Preston St, University of Louisville, Louisville, KY 40202 (e-mail haval.shirwan@louisville.edu).

Background— 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.

Methods and Results— 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<0.05) by intravenous treatment of graft recipients with 1 dose of SA-FasL–decorated donor splenocytes on days 2 and 6 after transplantation, respectively.

Conclusions— This study shows for the first time that exogenous proteins can be displayed on the endothelium of solid organs for therapeutic purposes. This approach provides a convenient and rapid means of displaying exogenous proteins on the surface of cells, tissues, and solid organs, with broad research and therapeutic implications.

Key Words: immunology • proteins • apoptosis • transplantation • gene therapy

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