The ability of soluble saccharides to prevent hyperacute rejection in xenotransplantation

Abstract

A consequence of the successful development in clinical transplantation is the increasing shortage of human organs. Xenotransplantation, transplantation of cells, tissues, and organs between individuals of different species has been proposed as a potential solution, and the pig is considered the most appropriate donor species. A disadvantage of using the pig is the hyperacute rejection (HAR), following revascularisation of pig organs with human blood, in which the graft is destroyed within minutes to hours. Human preformed anti-pig antibodies binding to specific antigens in the graft, mainly Gala1-3Gal terminating structures, followed by complement activation initiate the HAR.Different approaches to inhibit the initiation of HAR have been proposed, such as, reducing the Gala1-3Gal antigen expression, reducing the amount of preformed anti-pig antibodies and regulation of the complement cascade.The present study has focused on the ability of soluble saccharides to prevent the HAR process by blocking anti-pig xenoantibodies. The experimental models used were: (1) the interaction between pig aortic endothelial cells (PAEC) and human platelet rich plasma (h-PRP); (2) in vitro xenoperfusion of pig kidneys by human blood; and (3) a pig to baboon heart xenotransplantation. Preincubation of h-PRP with soluble Gala1-3Gal disaccharides reduced the platelet anti-aggregating response that follows the interaction of PAEC and untreated h- PRP most likely due to an increased release of PGI2 from the PAEC. Perfusion of pig kidneys with untreated human blood rapidly leads to an impaired kidney function and tissue damage. Addition of Gala1-3Gal (and Gala1-2Gal) disaccharides to the human perfusate resulted in an improved organ function. Immunohistochemistry revealed less deposition of immunoglobulin and complement factors in the pig kidneys perfused with Gala1-3Gal (and Gala1-2Gal) supplemented human blood compared to control kidneys. In a pig heart to baboon xenotransplantation model, i.v infusion of a Gala1-3Gal / Gala1-3Galb1-4GlcNAc saccharide mixture, prior to and continuously for 4 hours after transplantation, reduced the baboon serum cytotoxcicity to pig cells. The pig heart survived more than 8 hours, but was then rejected, indicating that the saccharide infusion delayed an early graft rejection but did not prevent graft rejection.