title: An unanticipated role for survivin in organ transplant damage.
abstract: Ischemia/reperfusion (I/R) injury is a major determinant of graft survival in kidney transplantation. Survivin, an inhibitor of apoptosis that participates in the control of mitosis and cell cycle progression, has been implicated in renal protection and repair after I/R injury; however, no study has been performed in the transplant setting. We investigated the role of survivin in modulating posttransplant I/R injury in syngeneic and allogeneic kidney grafts, and studied whether protection from I/R injury impacted on the recipient immune system, on chronic allograft nephropathy and rejection. We used genetically engineered mice with survivin haploinsufficiency and WT mice in which survivin over-expression was induced by gene-delivery. Survivin haploinsufficiency in syngeneic grafts was associated with exuberant I/R tissue injury, which triggered inflammation eventually resulting in graft loss. Conversely, survivin over-expression in the grafts minimized I/R injury and dysfunction in syngeneic grafts and in a clinically relevant fully MHC-mismatched allogeneic combination. In the latter, survivin over-expression translated into limited anti-donor adaptive immune response and less long-term allograft injury with protection from renal parenchymal damage. Our data support survivin over-expression in the graft as a novel target for protocols aimed at limiting tissue damage at the time of transplant ultimately modulating the recipient immune system.
authors.affiliation: Centro Ricerche Trapianti, "Chiara Cucchi de Alessandri e Gilberto Crespi", IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Bergamo, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cassis
authors.forename: S
authors.initials: S
authors.lastname: Solini
authors.forename: N
authors.initials: N
authors.lastname: Azzollini
authors.forename: S
authors.initials: S
authors.lastname: Aiello
authors.forename: F
authors.initials: F
authors.lastname: Rocchetta
authors.forename: S
authors.initials: S
authors.lastname: Conti
authors.forename: R
authors.initials: R
authors.lastname: Novelli
authors.forename: E
authors.initials: E
authors.lastname: Gagliardini
authors.forename: M
authors.initials: M
authors.lastname: Mister
authors.forename: F
authors.initials: F
authors.lastname: Rapezzi
authors.forename: S
authors.initials: S
authors.lastname: Rapezzi
authors.forename: A
authors.initials: A
authors.lastname: Benigni
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
authors.forename: E M
authors.initials: EM
authors.lastname: Conway
authors.forename: M
authors.initials: M
authors.lastname: Noris
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D005260:Female; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000502:physiology*; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012097:Repressor Proteins / Q000502:physiology*; D000077022:Survivin; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D000077022:Survivin
keywords: Chronic allograft injury; gene therapy; ischemia/reperfusion injury; kidney transplantation; survivin