alpha-Galactosyl oligosaccharides conjugated with polyethylene glycol as potential inhibitors of hyperacute rejection upon xenotransplantation.
Antibodies to an alpha-galactosyl saccharide structure are mainly responsible for hyperacute rejection after pig-to-primate xenotransplantation. The beneficial effect of alpha-galactosyl oligosaccharides has been shown on the inhibition of anti-pig natural antibodies. We synthesized polyethylene glycol (PEG)-conjugates of alpha-galactosyl disaccharide (Di) and trisaccharide (Tri) as potential inhibitors of the rejection reaction. The half lives of Di, Tri, PEG-conjugated Di (Di-PEG) and PEG-conjugated Tri (Tri-PEG) were 18.1 +/- 2.3 min, 20.2 +/- 0.9 min, 38.7 +/- 2.8 min and 35.8 +/- 1.6 min, respectively. Furthermore, Di-PEG and Tri-PEG showed biphasic clearance, and their half lives at the second phase were longer than 10 hours. PEG-conjugated oligosaccharides (Di-PEG, Tri-PEG) markedly inhibited cytotoxic action of human sera to pig kidney cell line (PK15) compared to unconjugated oligosaccharides (Di, Tri). The binding of IgM antibodies to PK15 cells, however, was more strongly blocked by unconjugated oligosaccharides than PEG-conjugated oligosaccharides. This phenomenon can be explained by the finding that PEG has anti-complement activity and masks antigenic sites of oligosaccharides. In conclusion, conjugation of PEG to oligosaccharides provided two beneficial effects; prolonged intravascular retention time and anti-complement activity, upon systemic application of the oligosaccharides. The present findings opened a new approach to treatment of hyperacute rejection after xenotransplantation.
Nagasaka
T
T
Department of Biochemistry I, Nagoya University School of Medicine, Japan.
Kobayashi
T
T
Muramatsu
H
H
Fujimoto
H
H
Matsuo
I
I
Ajisaka
K
K
Kadomatsu
K
K
Hayashi
S
S
Yokoyama
I
I
Hayakawa
A
A
Muramatsu
T
T
Takagi
H
H
D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control*; D006207:Half-Life; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D009844:Oligosaccharides / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013552:Swine; D014183:Transplantation, Heterologous
D019138:Antibodies, Blocking; D003169:Complement Inactivator Proteins; D007075:Immunoglobulin M; D009844:Oligosaccharides; D011092:Polyethylene Glycols