Characteristics of alpha-Gal epitope, anti-Gal antibody, alpha 1,3 galactosyltransferase and its clinical exploitation (Review)

摘要

The alpha-Gal epitope (Gal alpha 1,3Gal alpha 1,4GlcNAc-R) is ubiquitously presented in non-primate mammals, marsupials and New World Monkeys, but it is absent in humans, apes and Old World monkeys. However, the anti-Gal antibody (similar to 1% of immunoglobulins) is naturally generated in human, and is found as the immunoglobulin G (IgG), IgM and IgA isotypes. Owing to the specific binding of the anti-Gal antibody with the a-Gal epitope, humans have a distinct anti-alpha-gal reactivity, which is responsible for hyperacute rejection of organs transplanted from a-gal donors. In addition, the alpha 1,3 galactosyltransferases (alpha 1,3GT) can catalyze the synthesis of the alpha-Gal epitope. Therefore, the alpha 1,3GT gene, which encodes the alpha 1,3GT, is developed profoundly. The distributions of the alpha-Gal epitope and anti-Gal antibody, and the activation of alpha 1,3GT, reveal that the enzyme of alpha 1,3GT in ancestral primates is ineffective. Comparison of the nucleotide sequence of the human alpha 1,3-GT pseudogene to the corresponding different species sequence, and according to the evolutionary tree of different species, the results of evolutionary inactivation of the alpha 1,3GT gene in ancestral primates attribute to the mutations under a stronger selective pressure. However, on the basis of the structure, the mechanism and the specificity of the a-Gal epitope and anti-Gal antibody, they can be applied to clinical exploitation. Knocking out the alpha 1,3GT gene will eliminate the xenoantigen, Gal(alpha 1,3)Gal, so that the transplantation of alpha 1,3GT gene knockout pig organ into human becomes a potential clinically acceptable treatment for solving the problem of organ shortage. By contrast, the alpha-Gal epitope expressed through the application of chemical, biochemical and genetic engineering can be exploited for the clinical use. Targeting anti-Gal-mediated autologous tumor vaccines, which express alpha-Gal epitope to antigen-presenting cells, would increase their immunogenicity and elicit an immune response, which will be potent enough to eradicate the residual tumor cells. For tumor vaccines, the way of increasing immunogenicity of certain viral vaccines, including flu vaccines and human immunodeficiency virus vaccines, can also be used in the elderly. Recently, alpha-Gal epitope nanoparticles have been applied to accelerate wound healing and further directions on regeneration of internally injured tissues.