title: Induction of tolerance to cardiac allografts using donor splenocytes engineered to display on their surface an exogenous fas ligand protein.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, USA. e0yolc01@gwise.louisville.edu
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Xiao
authors.initials: X
authors.lastname: Gu
authors.forename: Chantale
authors.initials: C
authors.lastname: Lacelle
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Laura
authors.initials: L
authors.lastname: Bandura-Morgan
authors.forename: Nadir
authors.initials: N
authors.lastname: Askenasy
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011916:Rats, Inbred F344; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D053222:Fas Ligand Protein; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma