Inhibition of Xenoreactive Natural Antibody Production by Retroviral Gene Therapy

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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.