Inhibition of Xenoreactive Natural Antibody Production by Retroviral Gene Therapy

Abstract

The major barrier to transplantation across discordant species, such as from pig to human, is rejection mediated by xenoreactive natural antibodies (XNA) that bind the carbohydrate epitope Galα1-3Galβ1-4GlcNAc-R (αGal) on donor tissues. This epitope is synthesized by the enzyme glucosyltransferase uridine 5′-diphosphate galactose:β- d -galactosyl-1,4- N -acetyl- d -glucosaminide α(1-3)galactosyltransferase (E.C. 2.4.1.151), or simply αGT. When a functional αGT gene was introduced by retroviral gene transfer into bone marrow cells, αGal XNA production in a murine model ceased. Thus, genetic engineering of bone marrow may overcome humoral rejection of discordant xenografts and may be useful for inducing B cell tolerance.