Biomaterial Database

Soluble Galalpha(1,3)Gal conjugate combined with hDAF preserves morphology and improves function of cardiac xenografts. 2007

Ulrike Brandl, and Matthias Erhardt, and Sebastian Michel, and Hannah Jöckle, and Lars Burdorf, and Iris Bittmann, and Matthias Rössle, and Volker Mordstein, and Paolo Brenner, and Claus Hammer, and Bruno Reichart, and Michael Schmoeckel

Department of Cardiac Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. ubrandl@med.uni-muenchen.de

BACKGROUND Cytotoxic anti-Galalpha(1,3)Gal antibodies play a key role in the rejection of pig organs transplanted into primates. Regimens reducing anti-Galalpha(1,3)Gal antibodies were associated with severe side effects unable to prevent antibody rebound until soluble synthetic oligosaccharides with terminal Galalpha(1,3)Gal inhibiting antigen binding became available. We displayed kinetics of anti-pig and anti-Galalpha(1,3)Gal IgM and IgG antibody levels using GAS914, a Galalpha(1,3)Gal trisaccharide conjugated to poly-l-lysine, and investigated corresponding changes of parameters of heart function. METHODS Using a working heart model, hDAF pig hearts were perfused with human blood containing GAS914 (group 1). As controls hDAF pig hearts (group 2) and landrace pig hearts (group 3) were perfused with human blood only. Levels of anti-Galalpha(1,3)Gal (IgM, IgG) and anti-pig antibodies were assessed to prove the effectiveness of GAS914. As parameters of heart function, cardiac output (CO), stroke work index (SWI), coronary blood flow (CBF) and coronary resistance were measured. Creatine phosphokinases, lactate dehydrogenase and aspartate aminotransferase were evaluated as markers of myocardial damage. Histological and immunohistochemical investigations were performed at the end of perfusion. RESULTS In group 1 an immediate and extensive reduction in both IgM and IgG anti-Galalpha(1,3)Gal was found. Anti-pig antibodies were eliminated accordingly. Antibody binding to GAS914 was complete before the start of organ perfusion. Corresponding to rapid antibody elimination in group 1 GAS914 not only was able to significantly prolong the beating time of the heart in hDAF pigs, but also to clearly improve functional parameters. When switching to the working heart mode hDAF pig hearts perfused with human blood containing GAS914 (group 1) revealed a CO starting at a significantly higher level than hDAF (group 2) and non-transgenic pig hearts (group 3) perfused with human blood only. Similarly, in group 1 SWI was significantly increased at the beginning of perfusion compared to that of group 2 and group 3. The increase in CBF during perfusion and the corresponding fall of coronary resistance occurred without significant differences between the groups revealing the independence of hDAF and GAS914. CONCLUSIONS Due to an immediate and profound reduction in Galalpha(1,3)Gal-specific antibodies, soluble Galalpha(1,3)Gal conjugates not only prolong survival, but also improve the hemodynamic performance of the heart in DAF pigs.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D010477	Perfusion	Treatment process involving the injection of fluid into an organ or tissue.	Perfusions
D002302	Cardiac Output	The volume of BLOOD passing through the HEART per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with STROKE VOLUME (volume per beat).	Cardiac Outputs,Output, Cardiac,Outputs, Cardiac
D004187	Disaccharides	Oligosaccharides containing two monosaccharide units linked by a glycosidic bond.	Disaccharide
D006084	Graft Rejection	An immune response with both cellular and humoral components, directed against an allogeneic transplant, whose tissue antigens are not compatible with those of the recipient.	Transplant Rejection,Rejection, Transplant,Transplantation Rejection,Graft Rejections,Rejection, Graft,Rejection, Transplantation,Rejections, Graft,Rejections, Transplant,Rejections, Transplantation,Transplant Rejections,Transplantation Rejections
D006352	Heart Ventricles	The lower right and left chambers of the heart. The right ventricle pumps venous BLOOD into the LUNGS and the left ventricle pumps oxygenated blood into the systemic arterial circulation.	Cardiac Ventricle,Cardiac Ventricles,Heart Ventricle,Left Ventricle,Right Ventricle,Left Ventricles,Right Ventricles,Ventricle, Cardiac,Ventricle, Heart,Ventricle, Left,Ventricle, Right,Ventricles, Cardiac,Ventricles, Heart,Ventricles, Left,Ventricles, Right
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000910	Antibodies, Heterophile	Antibodies elicited in a different species from which the antigen originated. These antibodies are directed against a wide variety of interspecies-specific antigens, the best known of which are Forssman, Hanganutziu-Deicher (H-D), and Paul-Bunnell (P-B). Incidence of antibodies to these antigens--i.e., the phenomenon of heterophile antibody response--is useful in the serodiagnosis, pathogenesis, and prognosis of infection and latent infectious states as well as in cancer classification.	Antibodies, Heterogenetic,Antibodies, Heterotypic,Antibodies, Xenogeneic,H-D Antibodies,Hanganutziu-Deicher Antibodies,Heteroantibodies,Heterologous Antibodies,Heterophile Antibodies,P-B Antibodies,Paul-Bunnell Antibodies,Xenoantibodies,Antibodies, Heterologous,Antibodies, Heterophil,Antibodies, Xenogenic,Forssman Antibody,Heterogenetic Antibodies,Antibody, Forssman,Heterophil Antibodies,Heterotypic Antibodies,Xenogeneic Antibodies,Xenogenic Antibodies
D014183	Transplantation, Heterologous	Transplantation between animals of different species.	Xenotransplantation,Heterograft Transplantation,Heterografting,Heterologous Transplantation,Xenograft Transplantation,Xenografting,Transplantation, Heterograft,Transplantation, Xenograft