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.