Inhibition of xenoreactive natural antibody production by retroviral gene therapy.
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 Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal) on donor tissues. This epitope is synthesized by the enzyme glucosyltransferase uridine 5'-diphosphate galactose:beta-D-galactosyl-1, 4-N-acetyl-D-glucosaminide alpha(1-3)galactosyltransferase (E.C. 2.4.1.151), or simply alphaGT. When a functional alphaGT gene was introduced by retroviral gene transfer into bone marrow cells, alphaGal 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.
Bracy
J L
JL
Cellular and Molecular Biology Program, Allegheny University of the Health Sciences, 2900 Queen Lane, Philadelphia, PA 19129, USA.
Sachs
D H
DH
Iacomini
J
J
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D001854:Bone Marrow Cells / Q000201:enzymology*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000096:biosynthesis / Q000276:immunology*; D005700:Galactosyltransferases / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection / Q000517:prevention & control*; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D012190:Retroviridae / Q000235:genetics; D013552:Swine; D014183:Transplantation, Heterologous
D000939:Epitopes; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase