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* Institute for Cellular Therapeutics and
Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202; and
Frankel Laboratory of Experimental Bone Marrow Transplantation, Department of Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petach Tikvah, Israel
The critical role played by Fas ligand (FasL) in immune homeostasis renders this molecule an attractive target for immunomodulation to achieve tolerance to auto- and transplantation Ags. Immunomodulation with genetically modified cells expressing FasL was shown to induce tolerance to alloantigens. However, genetic modification of primary cells in a rapid, efficient, and clinically applicable manner proved challenging. Therefore, we tested the efficacy of donor splenocytes rapidly and efficiently engineered to display on their surface a chimeric form of FasL protein (SA-FasL) for tolerance induction to cardiac allografts. The i.p. injection of ACI rats with Wistar-Furth rat splenocytes displaying SA-FasL on their surface resulted in tolerance to donor, but not F344 third-party cardiac allografts. Tolerance was associated with apoptosis of donor reactive T effector cells and induction/expansion of CD4+CD25+FoxP3+ T regulatory (Treg) cells. Treg cells played a critical role in the observed tolerance as adoptive transfer of sorted Treg cells from long-term graft recipients into naive unmanipulated ACI rats resulted in indefinite survival of secondary Wistar-Furth grafts. Immunomodulation with allogeneic cells rapidly and efficiently engineered to display on their surface SA-FasL protein provides an effective and clinically applicable means of cell-based therapy with potential application to regenerative medicine, transplantation, and autoimmunity.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in parts by grants from the National Institutes of Health (R21 DK61333, R01 AI47864, R21 AI057903, and R21 HL080108 to H.S. and E.S.Y.), the Juvenile Diabetes Research Foundation (1-2001-328 to H.S.), the American Diabetes Association (1-05-JF-56 to E.S.Y. and H.S.), and the Commonwealth of Kentucky Research Challenge Trust Fund.
2 E.S.Y. and X.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Esma Yolcu or Dr. Haval Shirwan, Institute for Cellular Therapeutics, 570 South Preston Street, Donald Baxter Biomedical Building, Suite 404E, University of Louisville, Louisville, KY 40202. E-mail addresses: e0yolc01{at}gwise.louisville.edu and haval.shirwan{at}louisville.edu
4 Abbreviations used in this paper: SA, streptavidin; FasL, Fas ligand; SA-FasL, chimeric molecule containing the extracellular functional domain of FasL lacking the metalloproteinase cleavage sites fused to streptavidin; WF, Wistar-Furth; Treg, T regulatory; MST, median survival time; SA-FasL LT, SA-FasL-engineered cells treated long-term graft recipients; SA Rej, SA-engineered cell-treated animals with acute graft rejection; Teff, T effector; BiP, Drosophila secretion signal.
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