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Polymorphism in the human anti-pig natural antibody repertoire: implications for antigen-specific immunoadsorption. 1998

W McKane, and J Lee, and R Preston, and A Hacking, and P Simpson, and S Lynds, and L Goldberg, and T Cairns, and D Taube
The Brent Laboratory, St. Mary's Hospital, London, United Kingdom.

BACKGROUND Anti-Galalpha1-3Gal antibodies cause hyperacute rejection (HAR) in pig-to-primate xenotransplantation. Long-term graft survival has not been achieved despite abrogation of HAR using transgenic pigs. IgG and IgM anti-Galalpha1-3Gal also play a role in the events following abrogation of HAR. Characterizing these antibodies and developing a system for their removal is therefore crucial to future success in xenotransplantation. RESULTS We have developed a neoglycoprotein enzyme-linked immunosorbent assay to probe the precise antigenic requirements for the binding of anti-Galalpha1-3Gal and have analyzed 77 normal sera. Sixty-six percent of individuals have IgG that recognizes the Galalpha1-3Gal di-, tri-, and pentasaccharides (D, T, and P, respectively), termed DTP phenotype. The frequency of other phenotypes was - -P, 13%; -TP, 12%; D-P, 8%; and DT-, 1%. The IgG subclasses found were IgG2 (95%), IgG3 (34%), IgG1 (31%), and IgG4 (17%). IgM in 91% of individuals recognized all three antigens. Further antibody heterogeneity was demonstrated when immunoadsorbents derived from Galalpha1-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc (PENTA) were tested. Galalpha1-3Galbeta1-4Glc (TRI 6) or PENTA agarose were effective for IgG removal in all individuals. For IgM removal, two deoxy derivatives were completely successful in 73% of individuals. Combining the Galalpha1-3Gal (DI) and TRI 6 agarose produced an adsorbent that completely removed anti-Galalpha1-3Gal IgG and IgM in all individuals tested. CONCLUSIONS Although the polymorphism in the anti-Galalpha1-3Gal repertoire, which we have demonstrated, represents a major obstacle to the development of an effective immunoadsorbent, the combination of DI and TRI 6 agarose appears sufficient for pig-to-human xenotransplantation.

UI MeSH Term Description Entries
D007074 Immunoglobulin G The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of IgG, for example, IgG1, IgG2A, and IgG2B. Gamma Globulin, 7S,IgG,IgG Antibody,Allerglobuline,IgG(T),IgG1,IgG2,IgG2A,IgG2B,IgG3,IgG4,Immunoglobulin GT,Polyglobin,7S Gamma Globulin,Antibody, IgG,GT, Immunoglobulin
D007164 Immunosorbents An insoluble support for an ANTIGEN or ANTIBODIES that is used in AFFINITY CHROMATOGRAPHY to adsorb the homologous antibody or antigen from a mixture. Many different substances are used, among them SEPHAROSE; GLUTARALDEHYDE; copolymers of ANHYDRIDES; polyacrylamides, etc. Immunoadsorbent,Immunoadsorbents,Immunosorbent
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D011110 Polymorphism, Genetic The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level. Gene Polymorphism,Genetic Polymorphism,Polymorphism (Genetics),Genetic Polymorphisms,Gene Polymorphisms,Polymorphism, Gene,Polymorphisms (Genetics),Polymorphisms, Gene,Polymorphisms, Genetic
D004187 Disaccharides Oligosaccharides containing two monosaccharide units linked by a glycosidic bond. Disaccharide
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
D000916 Antibody Diversity The phenomenon of immense variability characteristic of ANTIBODIES. It enables the IMMUNE SYSTEM to react specifically against the essentially unlimited kinds of ANTIGENS it encounters. Antibody diversity is accounted for by three main theories: (1) the Germ Line Theory, which holds that each antibody-producing cell has genes coding for all possible antibody specificities, but expresses only the one stimulated by antigen; (2) the Somatic Mutation Theory, which holds that antibody-producing cells contain only a few genes, which produce antibody diversity by mutation; and (3) the Gene Rearrangement Theory, which holds that antibody diversity is generated by the rearrangement of IMMUNOGLOBULIN VARIABLE REGION gene segments during the differentiation of the ANTIBODY-PRODUCING CELLS. Germ Line Theory,Antibody Diversities,Diversities, Antibody,Diversity, Antibody,Germ Line Theories,Theories, Germ Line,Theory, Germ Line
D000939 Epitopes Sites on an antigen that interact with specific antibodies. Antigenic Determinant,Antigenic Determinants,Antigenic Specificity,Epitope,Determinant, Antigenic,Determinants, Antigenic,Specificity, Antigenic

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