BACKGROUND: The current limitation to the clinical application of xenotransplantation using pig organs is a rejection process that has been termed delayed xenograft rejection or acute vascular rejection. It is thought that acute vascular rejection may be mediated at least in part by both the continued synthesis, of preexisting, and the induction, posttransplantation, of antibodies against the carbohydrate moiety galalpha1-3gal that is present on glycoproteins and glycolipids of the pig endothelium. The synthesis of these antibodies has proven difficult to control with currently available immunosuppressive agents. METHODS: We have synthesized galalpha1-3gal conjugated polyethylene glycol polymers that can bind to anti-galalpha1-3gal antibodies and tested their activity in non-human primates. RESULTS: These conjugates when administered to non-human primates can substantially reduce the levels of preexisting and control the induction of anti-galalpha1-3gal antibodies. The level of circulating antibody-secreting cells that make anti-galalpha1-3gal antibodies is also reduced. CONCLUSION: These alpha-gal polyethylene glycol conjugates may have the potential to control the anti-gal antibody response in a pig to primate organ transplant setting and may be a useful therapeutic agent in prolonging graft survival.
BACKGROUND: The current limitation to the clinical application of xenotransplantation using pig organs is a rejection process that has been termed delayed xenograft rejection or acute vascular rejection. It is thought that acute vascular rejection may be mediated at least in part by both the continued synthesis, of preexisting, and the induction, posttransplantation, of antibodies against the carbohydrate moiety galalpha1-3gal that is present on glycoproteins and glycolipids of the pig endothelium. The synthesis of these antibodies has proven difficult to control with currently available immunosuppressive agents. METHODS: We have synthesized galalpha1-3gal conjugated polyethylene glycol polymers that can bind to anti-galalpha1-3gal antibodies and tested their activity in non-human primates. RESULTS: These conjugates when administered to non-human primates can substantially reduce the levels of preexisting and control the induction of anti-galalpha1-3gal antibodies. The level of circulating antibody-secreting cells that make anti-galalpha1-3gal antibodies is also reduced. CONCLUSION: These alpha-galpolyethylene glycol conjugates may have the potential to control the anti-gal antibody response in a pig to primate organ transplant setting and may be a useful therapeutic agent in prolonging graft survival.
Authors: Andreas G Katopodis; Richard G Warner; Rudolf O Duthaler; Markus B Streiff; Armin Bruelisauer; Olivier Kretz; Birgit Dorobek; Elke Persohn; Hendrik Andres; Alain Schweitzer; Gebhard Thoma; Willy Kinzy; Valerie F J Quesniaux; Emanuele Cozzi; Hugh F S Davies; Rafael Mañez; David White Journal: J Clin Invest Date: 2002-12 Impact factor: 14.808
Authors: Guerard W Byrne; Paul G Stalboerger; Eduardo Davila; Carrie J Heppelmann; Mozammel H Gazi; Hugh C J McGregor; Peter T LaBreche; William R Davies; Vinay P Rao; Keiji Oi; Henry D Tazelaar; John S Logan; Christopher G A McGregor Journal: Xenotransplantation Date: 2008 Jul-Aug Impact factor: 3.907
Authors: Guerard W Byrne; Agnes M Azimzadeh; Mohamed Ezzelarab; Henry D Tazelaar; Burcin Ekser; Richard N Pierson; Simon C Robson; David K C Cooper; Christopher G A McGregor Journal: Xenotransplantation Date: 2013 Sep-Oct Impact factor: 3.907