title: Inhibition of complement component C5 protects porcine chondrocytes from xenogeneic rejection.
abstract: OBJECTIVE
  Tissue-based xenografts such as cartilage are rejected within weeks by humoral and cellular mechanisms that preclude its clinical application in regenerative medicine. The problem could be overcome by identifying key molecules triggering rejection and the development of genetic-engineering strategies to counteract them. Accordingly, high expression of α1,2-fucosyltransferase (HT) in xenogeneic cartilage reduces the galactose α1,3-galactose (Gal) antigen and delays rejection. Yet, the role of complement activation in this setting is unknown.
  
  
  METHODS
  To determine its contribution, we assessed the effect of inhibiting C5 complement component in α1,3-galactosyltransferase-knockout (Gal KO) mice transplanted with porcine cartilage and studied the effect of human complement on porcine articular chondrocytes (PAC).
  
  
  RESULTS
  Treatment with an anti-mouse C5 blocking antibody for 5 weeks enhanced graft survival by reducing cellular rejection. Moreover, PAC were highly resistant to complement-mediated lysis and primarily responded to human complement by releasing IL-6 and IL-8. This occurred even in the absence of anti-Gal antibody and was mediated by both C5a and C5b-9. Indeed, C5a directly triggered IL-6 and IL-8 secretion and up-regulated expression of swine leukocyte antigen I (SLA-I) and adhesion molecules on chondrocytes, all processes that enhance cellular rejection. Finally, the use of anti-human C5/C5a antibodies and/or recombinant expression of human complement regulatory molecule CD59 (hCD59) conferred protection in correspondence with their specific functions.
  
  
  CONCLUSIONS
  Our study demonstrates that complement activation contributes to rejection of xenogeneic cartilage and provides valuable information for selecting approaches for complement inhibition.
authors.affiliation: New Therapies of Genes and Transplants Group, Bellvitge Biomedical Research Institute (IDIBELL) and Bellvitge University Hospital-ICS, Barcelona, Spain. Electronic address: roberta.sommaggio@gmail.com.
authors.forename: R
authors.initials: R
authors.lastname: Sommaggio
authors.forename: M
authors.initials: M
authors.lastname: Pérez-Cruz
authors.forename: J L
authors.initials: JL
authors.lastname: Brokaw
authors.forename: R
authors.initials: R
authors.lastname: Máñez
authors.forename: C
authors.initials: C
authors.lastname: Costa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018957:CD59 Antigens / Q000276:immunology; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects*; D019902:Chondrocytes / Q000637:transplantation*; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology; D015936:Complement C5a / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D005700:Galactosyltransferases / Q000235:genetics; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D064593:Heterografts / Q000276:immunology*; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D018957:CD59 Antigens; D003182:Complement C5; D015938:Complement Membrane Attack Complex; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D016209:Interleukin-8; C047610:SC5b-9 protein complex; C438668:swine leukocyte antigen; D015936:Complement C5a; D005700:Galactosyltransferases
keywords: Chemokines; Chondrocytes; Complement; Cytokines; Xenotransplantation