Tolerization of Gal alpha 1,3Gal-reactive B cells in pre-sensitized alpha 1,3-galactosyltransferase-deficient mice by nonmyeloablative induction of mixed chimerism.
Using a alpha 1,3-galactosyltransferase wild-type (GalT(+/+)) to deficient (GalT(-/-)) mouse bone marrow transplantation model, we have previously demonstrated that a non-myeloablative conditioning regimen is capable of permitting induction of allogeneic and xenogeneic mixed chimerism. Chimerism is associated with the rapid and lasting tolerization of anti-Gal alpha 1,3Gal (Gal) natural antibody (Ab)-producing B cells. However, one limitation of this model is that anti-Gal natural Ab levels are lower in GalT(-/-) mice than in humans and other primates. To overcome this limitation, we have now investigated the possibility of inducing such tolerance in GalT(-/-) mice that produce much higher levels of anti-Gal Abs due to presensitization with Gal-bearing xenogeneic cells. B6 GalT(-/-) mice that were pre-sensitized with rabbit red blood cells received non-myeloablative conditioning with depleting anti-CD4 and CD8 mAbs, 3Gy whole body and 7Gy thymic irradiation, and infusion of BALB/c GalT(+/+) bone marrow cells (BMC). Although engraftment of standard marrow doses was inhibited by the presensitization, long-lasting mixed chimerism could be induced in recipients of a high dose [160 x 10(6)] of allogeneic wild-type BMC. Achievement of persistent chimerism was associated with high levels of anti-Gal IgG(1) pretransplant, suggesting an inhibitory effect of non-complement-fixing IgG(1) Ab on anti-Gal-mediated marrow rejection. Induction of mixed chimerism was associated with a rapid disappearance of serum anti-Gal and tolerization of anti-Gal Ab-producing cells. B cells with anti-Gal receptors became undetectable in mixed chimeras. Mixed chimeras accepted subsequently transplanted donor-type GalT(+/+) hearts (> 140 days), whereas rapid (within 2 days) rejection of GalT(+/+) hearts occurred in conditioned control GalT(-/-) mice. In conclusion, when a high dose of GalT(+/+) BMC was administered to pre-sensitized GalT(-/-) mice, chimerism and tolerance were achieved. The absence of B cells with receptors recognizing Gal in mixed chimeras suggests a role for clonal deletion/receptor editing in the maintenance of B cell tolerance.
Ohdan
H
H
Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA.
Swenson
K G
KG
Kitamura
H
H
Yang
Y G
YG
Sykes
M
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation; D002240:Carbohydrate Sequence; D019070:Cell Lineage; D002678:Chimera / Q000276:immunology*; D017637:Clonal Deletion; D004187:Disaccharides / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival; D016027:Heart Transplantation; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011817:Rabbits; D013047:Specific Pathogen-Free Organisms; D013950:Thymus Gland / Q000528:radiation effects; D019172:Transplantation Conditioning / Q000379:methods*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014312:Trisaccharides / Q000276:immunology; D014916:Whole-Body Irradiation
D004187:Disaccharides; D000939:Epitopes; D007074:Immunoglobulin G; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; C055075:galactosyl-(1-3)galactose; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase