title: Donor antioxidant strategy prolongs cardiac allograft survival by attenuating tissue dendritic cell immunogenicity(†).
abstract: Ischemic reperfusion injury (IRI) enhances allograft immunogenicity, worsens transplantation outcome, and is the primary cause of activation of the recipient innate immune response, resulting in subsequent amplification of the alloimmune adaptive response. Here, we aimed at demonstrating that the link between innate injury and alloimmunity occurs predominantly through activation of allograft-derived dendritic cells (ADDC). Perfusion of MCI-186, a free radical scavenger, into donor cardiac allografts prior to transplantation resulted in prolongation of complete MHC-mismatched allograft survival in the absence of immunosuppression (MST of 8 vs. 26 days). This prolongation was associated with a reduction in trafficking of ADDC to recipient lymphoid tissue as well as a reduction in T cell priming. Depleting ADDC with diphtheria toxin (using DTR-GFP-DC mice as donors) 24 h prior to transplant resulted in abrogation of the prolongation observed with MCI-186 treatment, demonstrating that the beneficial effect of MCI-186 is mediated by ADDC. This donor-specific anti-ischemic regimen was also shown to reduce chronic rejection, which represents the primary obstacle to long-term allograft acceptance. These data for the first time establish a basis for donor anti-ischemic strategies, which in the ever-expanding marginal donor pools, can be instituted to promote engraftment.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jurewicz
authors.forename: T
authors.initials: T
authors.lastname: Ueno
authors.forename: J
authors.initials: J
authors.lastname: Azzi
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Murayama
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: M
authors.initials: M
authors.lastname: Niimi
authors.forename: R
authors.initials: R
authors.lastname: Abdi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000008:administration & dosage; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000379:methods* / Q000473:pathology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000276:immunology; D013997:Time Factors; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D000077553:Edaravone; D000983:Antipyrine