Background

Strong immunological barriers to xeno-transplants from lower mammals into humans can destroy a transplanted solid organ within minutes, a process termed HyperAcute Rejection.  The principal technology being developed by NewLink Genetics is based on this phenomenon. HyperAcute rejection results from a high level of naturally acquired immunity against organisms or tissues incorporating a(1, 3)-Galactosyl (α-Gal) epitopes on the cell surface. The α-Galactosyl Transferase (α-GT) enzyme causes specific glycosylation patterns, directing the addition of α-Gal to N-acetyl glucosamine residues in the Trans Golgi apparatus in most mammalian species. A large number of glycoproteins and glycolipids possess multiple carbohydrate side chains and can contain multiple α-Gal epitopes. 

A unique property of the immune systems of Old World primates, including man, is the presence of a very potent innate immune response against α-Gal present on the surface of cells comprising the tissues of nearly all other organisms. One result is that humans can, and do, develop active immune responses against the epitope. The presence of this epitope on the surface of human intestinal flora provides a strong chronic stimulus for the development of antibodies against the α-Gal epitopes. These antibodies are typically acquired in the first six months of life in parallel with the transition to a more adult diet and/or colonization with adult colonic flora. The resulting antibody titers against the α-Gal epitope are among the highest recorded in humans and anti-α-Gal antibodies can comprise >1% of the entire circulating antibody repertoire.

The universal presence of high titer antibodies against this epitope is responsible for the well-documented immunologic phenomenon known as HyperAcute rejection, experimentally observed during attempts at xenotransplantation of organs from lower mammals to baboons.  In the minutes immediately following revascularization of donor organ transplants with the host circulation, the graft vasculature is effectively destroyed. An examination of the mechanism revealed that donor vascular endothelial cells have α-Gal epitopes on their surface that are rapidly bound by high-titer host circulating anti-α-Gal antibodies. These antibodies are complement fixing and the α-Gal (+) cells are rapidly lysed with high efficiency. The universality and thoroughness of the response creates an absolute block to transplantation.