Transplantation and Carbohydrate Antigen

 As antigens in allogenic transplantation, major histocompatibility class I antigens (HLA in man and H-2 in mouse) and ABH blood group antigens are known to be important. Although HLA antigenicity is determined by protein structure, the determinants of the ABH blood group antigens are carbohydrate in nature. Thus, carbohydrate antigens are important also in allogenic transplantation.

Carbohydrate antigens in xenotransplantation have recently become the focus of much interest . Since the number of donor organs is limited, xenotransplantation, especially pig-to-human transplantation, is now being considered. The first obstacle in xenotransplantation is hyperacute rejection. Antigens which are absent in the human are present in the porcine tissues, especially in the blood vessels, and antibodies against them are present in human blood. Thus, after xenotransplantation, complement-dependent cytotoxic reaction occurs immediately, and transplanted tissues including blood vessels are destroyed. For successful xenotransplantation, we must first suppress the hyperacute rejection reaction. The xenoantigen responsible for the hyperacute reaction was investigated, and the most important one was clarified to have the Gal alpha1-3Gal beta1-4GlcNAc structure. The alpha-galactosyl structure is broadly distributed in mammals, while it is absent in old world monkeys and humans. In the human blood, antibodies reacting to it are present probably due to infection of bacteria with alpha-galactosyl terminal residues.

There are several ways to suppress immunological reaction to the alpha-galactosyl antigen. Inhibition by Gal alpha1-3Gal, Gal alpha1-3Gal beta1-4GlcNAc or their conjugates with high molecular weight substances is an obvious approach. However, the necessity of a large amount of inhibitors is a problem. Attempts have also been made to enzymatically destroy the antigenic epitope. However, many alpha-galactosidases do not work at neutral pHs. We are planning to apply endo-beta-galactosidase C, which is active at neutral pH and acts on the antigenic structure to release Gal alpha1-3Gal. One of the most promising approaches is to genetically manipulate the pig so that it does not express Gal alpha1-3Gal structure. Gal alpha1-3Gal structure is synthesized by alpha-1, 2-galacosyltransferase using the Gal beta1-4GlcNAc terminus as the sugar acceptor. Therefore, this glycosyltransferase gene should preferably be removed. However, the gene knockout method available in the mouse is difficult to reproduce in pig due to the absence of pig embryonic stem cells. If the nuclear transplantation method works in the pig, this application might be an easier way to produce the antigen-less pig. It is also possible to reduce the alpha-galactosyl antigenicity by overexpressing other glycosyltransferases and reduce the availability of the sugar acceptor by competition. alpha1,2-Fucosyltransferase, sialyltransferase and N-acetylglucosaminyltransferase III gave good results.
Fig: A Project form xenotransplantable pigs based on a carbohydrate antigen

Takashi Muramatsu
(Department of Biochemistry, Nagoya University School of Medicine)
References (1) Sandrin MS, Vaughan HA, Dabkowski PL, McKenzie IFC : Anti-pig IgM antibodies in human serum react predominantly with Gal(alpha1-3)Gal epitopes. Proc. Natl. Acad. Sci. USA 90, 11391-11395, 1993
(2) Galili U, Clark MR, Shohet SB, Buehler J, Macher BA : Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha1 -3Gal epitope in primates. Proc. Natl. Acad. Sci. USA 84, 1369-1373, 1987
Jul. 15, 1999

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