title: In Contrast to Anti-C5 Therapy, Cobra Venom Factor Does Not Prevent Rejection of Xenogeneic Cartilage in Mice.
abstract: BACKGROUND
  The use of xenogeneic chondrocytes may benefit the development of clinical tissue-engineering applications for cartilage repair. However, cartilage xenografts are slowly rejected by humoral and cellular mechanisms to which galactose α1,3-galactose (Gal) antigen and complement contribute. Accordingly, transgenic expression of human α1,2-fucosyltransferase (HT) in porcine cartilage helps to protect from the Gal-mediated immune response. Here, we aimed to assess the effect of the broadly used complement inhibitor cobra venom factor (CVF) in comparison with anti-C5 therapy in α1,3-galactosyltransferase knockout (Gal KO) mice transplanted with porcine cartilage.
  
  
  METHODS
  Gal KO mice grafted with control or HT-transgenic cartilage were left untreated or treated systemically with either anti-C5 antibody or CVF for 5 weeks. The degree of rejection was evaluated by use of histopathological analysis, and serum anti-Gal antibodies were measured in all cohorts.
  
  
  RESULTS
  The rejection process of control cartilage was well advanced by 5 weeks after transplantation in untreated Gal KO mice, whereas enhanced graft survival characterized by reduced cellular immune infiltrate was found in mice grafted with HT cartilage and/or treated with anti-C5. In contrast, CVF administration led to inconsistent results, with some grafts showing no improvement or even increased amounts of granulocytes. Regarding antibody titers, the anti-Gal immunoglobulin (Ig)M increased in the control transplant cohort and remained unchanged in the HT-graft recipients at 5 weeks after transplantation. Notably, a strong anti-Gal IgM response was readily detected in CVF-treated mice of both transplanted cohorts.
  
  
  CONCLUSIONS
  CVF does not present advantages over anti-C5 therapy for preventing rejection of xenogeneic porcine cartilage.
authors.affiliation: Department of Molecular Sciences, Alexion Pharmaceuticals Inc, Cheshire, Connecticut; Global Pharmacovigilance and Epidemiology, Bristol-Myers Squibb, Wallingford, Connecticut.
authors.forename: J L
authors.initials: JL
authors.lastname: Brokaw
authors.affiliation: Department of Molecular Sciences, Alexion Pharmaceuticals Inc, Cheshire, Connecticut; New Therapies of Genes and Transplants Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. Electronic address: ccosta@idibell.cat.
authors.forename: C
authors.initials: C
authors.lastname: Costa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000187:drug effects* / Q000276:immunology; D002356:Cartilage / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D051056:Complement Inactivating Agents / Q000494:pharmacology*; D004187:Disaccharides / Q000276:immunology; D004546:Elapid Venoms / Q000494:pharmacology*; D005647:Fucosyltransferases / Q000235:genetics; D005700:Galactosyltransferases / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013552:Swine; D014183:Transplantation, Heterologous; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D000906:Antibodies; D003182:Complement C5; D051056:Complement Inactivating Agents; D004187:Disaccharides; D004546:Elapid Venoms; D005647:Fucosyltransferases; D005700:Galactosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C016310:cobra venom factor; C055075:galactosyl-(1-3)galactose; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase