title: Complement Alternative Pathway Deficiency in Recipients Protects Kidney Allograft From Ischemia/Reperfusion Injury and Alloreactive T Cell Response.
abstract: Despite the introduction of novel and more targeted immunosuppressive drugs, the long-term survival of kidney transplants has not improved satisfactorily. Early antigen-independent intragraft inflammation plays a critical role in the initiation of the alloimmune response and impacts long-term graft function. Complement activation is a key player both in ischemia/reperfusion injury (IRI) as well as in adaptive antigraft immune response after kidney transplantation. Since the alternative pathway (AP) amplifies complement activation regardless of the initiation pathways and renal IR injured cells undergo uncontrolled complement activation, we speculated whether selective blockade of AP could be a strategy for prolonging kidney graft survival. Here we showed that Balb/c kidneys transplanted in factor b deficient C57 mice underwent reduced IRI and diminished T cell-mediated rejection. In in vitro studies, we found that fb deficiency in T cells and dendritic cells conferred intrinsic impaired alloreactive/allostimulatory functions, respectively, both in direct and indirect pathways of alloantigen presentation. By administering anti-fB antibody to C57 wt recipients in the early post Balb/c kidney transplant phases, we documented that inhibition of AP during both ischemia/reperfusion and early adaptive immune response is necessary for prolonging graft survival. These findings may have implication for the use of AP inhibitors in clinical kidney transplantation.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Casiraghi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Azzollini
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Todeschini
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Fiori
authors.affiliation: Laboratory of Clinical and Experimental Immunology, Immunology Department, University of São Paulo, São Paulo, Brazil.
authors.forename: R A
authors.initials: RA
authors.lastname: Cavinato
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cassis
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Solini
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Pezzuto
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mister
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
authors.forename: J M
authors.initials: JM
authors.lastname: Thurman
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Benigni
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.|IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.|Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.|Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: G
authors.identifier: http://orcid.org/0000-0002-6194-3446
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Chiara Cucchi de Alessandri e Gilberto Crespi Transplant Research Center, Bergamo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Noris
mesh_terms: D064591:Allografts; D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D011415:Complement Factor B / Q000172:deficiency* / Q000235:genetics; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011415:Complement Factor B
keywords: animal models; basic (laboratory) research/science; complement biology; kidney transplantation/nephrology; translational research/science