title: Posttransplantation systemic immunomodulation with SA-FasL-engineered donor splenocytes has robust efficacy in preventing cardiac allograft rejection in mice.
abstract: Apoptosis induced by the engagement of FasL with Fas receptor on the surface of lymphocytes is an important immune homeostatic mechanism that ensures tolerance to self-antigens under normal physiologic conditions. As such, FasL has been extensively tested as a tolerogenic molecule with the use of gene therapy in settings of autoimmunity and transplantation with conflicting outcomes. Although the mechanistic basis of these contradictory observations is largely unknown, the use of wild-type FasL and the means by which the gene was expressed may provide an explanation. To overcome these complications, we generated a chimeric FasL protein with streptavidin (SA-FasL) having potent apoptotic activity and displayed this molecule effectively and rapidly on biotinylated biologic membranes for immunomodulation. In the present study, we displayed SA-FasL on the surface of BALB/c splenocytes and injected 5 × 10(6) cells intraperitoneally into C57BL/6 recipients of BALB/c heart grafts on days 1, 3, and 5 after-transplantation. To control initial graft-reactive immune responses and facilitate FasL-mediated apoptosis, rapamycin was used as an immunosuppressant at 0.2 mg/kg daily for a total of 15 doses immediately after heart transplantation. All mice injected with SA-FasL-engineered donor splenocytes accepted their grafts during the 100-day observation period. In marked contrast, immunomodulation with control streptavidin protein-engineered BALB/c splenocytes had minimal effect on graft survival (mean survival, 21.4 ± 1.5 d). Taken together, these results establish posttransplantation systemic immunomodulation with SA-FasL-engineered donor splenocytes under transient cover of rapamycin as an effective regimen in preventing cardiac allograft rejection in rodents with important clinical implications.
authors.affiliation: Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: K B
authors.initials: KB
authors.lastname: Woodward
authors.forename: H
authors.initials: H
authors.lastname: Shirwan
authors.forename: O
authors.initials: O
authors.lastname: Grimany-Nuno
authors.forename: E S
authors.initials: ES
authors.lastname: Yolcu
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D053222:Fas Ligand Protein / Q000276:immunology*; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology* / Q000276:immunology; D019809:Streptavidin
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D019809:Streptavidin