Tolerization of anti-Galalpha1-3Gal natural antibody-forming B cells by induction of mixed chimerism.
Xenotransplantation could overcome the severe shortage of allogeneic organs, a major factor limiting organ transplantation. Unfortunately, transplantation of organs from pigs, the most suitable potential donor species, results in hyperacute rejection in primate recipients, due to the presence of anti-Galalpha1-3Gal (Gal) natural antibodies (NAbs) in their sera. We evaluated the ability to tolerize anti-Gal NAb-producing B cells in alpha1,3-galactosyltransferase knockout (GalT KO) mice using bone marrow transplantation (BMT) from GalT+/+ wild-type (WT) mice. Lasting mixed chimerism was achieved in KO mice by cotransplantation of GalT KO and WT marrow after lethal irradiation. The levels of anti-Gal NAb in sera of mixed chimeras were reduced markedly 2 wk after BMT, and became undetectable at later time points. Immunization with Gal+/+ xenogeneic cells failed to stimulate anti-Gal antibody production in mixed chimeras, whereas the production of non-Gal-specific antixenoantigen antibodies was stimulated. An absence of anti-Gal-producing B cells was demonstrated by enzyme-linked immunospot assays in mixed KO + WT --> KO chimeras. Thus, mixed chimerism efficiently induces anti-Gal-specific B cell tolerance in addition to T cell tolerance, providing a single approach to overcoming both the humoral and the cellular immune barriers to discordant xenotransplantation.
Yang
Y G
YG
Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129, USA.
deGoma
E
E
Ohdan
H
H
Bracy
J L
JL
Xu
Y
Y
Iacomini
J
J
Thall
A D
AD
Sykes
M
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016026:Bone Marrow Transplantation; D004187:Disaccharides / Q000276:immunology*; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D007108:Immune Tolerance; D007075:Immunoglobulin M; D051379:Mice; D008817:Mice, Mutant Strains; D011828:Radiation Chimera; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D004187:Disaccharides; D007075:Immunoglobulin M; C055075:galactosyl-(1-3)galactose; D005700:Galactosyltransferases; C037959:beta-D-galactosyl-N-acetylglucosaminylglycopeptide alpha-1,3-galactosyltransferase