Intravenous synthetic αgal saccharides delay hyperacute rejection following pig-to-baboon heart transplantation

Academic Article

Abstract

  • Several oligosaccharides containing the terminal structure Galα1-3Gal (αGal) and different side chains were tested in vitro for their ability to block natural antiαGal antibodies. A di-and a trisaccharide (diαGal and triαGal) were selected. A blood group B baboon, having IgG and IgM natural antipig titers of 1 : 256 and 1 : 1024 and a hemolytic titer (to pig red blood cells, RBCs) of 1 : 8, was chosen to measure pharmacokinetic parameters of the saccharides and to assess the extent of in vivo neutralization of the antibodies. Three grams each of the diαGal and the triαGal dissolved in saline were administered by bolus intravenous (i.v.) injection. Blood samples were collected at various times and urine was collected at 8 and 24 h. Plasma and urine concentrations of the αGal saccharides were estimated by an ELISA specially developed for this study. A fast distribution phase followed by equilibrium and excretion phases were observed, indicating a T1/2 in the order of 1 h. Fifty-eight per cent of the saccharides were recovered in the urine within 24 h. Determination of antipig antibody binding by FACS analysis and of serum cytotoxicity titers for pig endothelial cells demonstrated that a 70% reduction in binding and cytotoxicity could be achieved with plasma saccharide levels of 300-400 μg/ml. Six months later, a pig heart was transplanted heterotopically into the baboon. A 3-g bolus of the saccharide mixture (1.5 g of each saccharide) was given i.v. before allowing blood reperfusion of the transplanted heart, followed by an i.v. infusion of 1 g/hr for 1 hr and 0.5 g/hr for the 3 succeeding hours. Blood concentrations of the saccharides, CH50, hematology and cytotoxicity for PK15 cells were estimated in blood samples taken at various times. Heart function was observed to be satisfactory for 8 h, but was found to have ceased at 18 h. Myocardial biopsies taken at 3 and 5 h showed congestion only, suggestive of minimal vascular rejection, but by 18 h demonstrated severe vascular rejection. In conclusion, αGal saccharide therapy given for a period of 4 h delayed, but did not totally prevent, the development of vascular rejection in the pig- to-baboon heart transplant model. αGal saccharide therapy may be one of several useful approaches for the prevention of hyperacute rejection in pig- to-primate organ transplantation.
  • Authors

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    Author List

  • Romano E; Neethling FA; Nilsson K; Kosanke S; Shimizu A; Magnusson S; Svensson L; Samuelsson B; Cooper DKC
  • Start Page

  • 36
  • End Page

  • 42
  • Volume

  • 6
  • Issue

  • 1