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Tolerization of Galα1,3Gal‐reactive B cells in pre‐sensitized α1,3‐galactosyltransferase‐deficient mice by nonmyeloablative induction of mixed chimerism
Author(s) -
Ohdan Hideki,
Swenson Kirsten G.,
Kitamura Hiroshi,
Yang YongGuang,
Sykes Megan
Publication year - 2001
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1034/j.1399-3089.2001.00006.x
Subject(s) - bone marrow , immunology , medicine , galactosyltransferase , transplantation , antibody , cd8 , immune system , biology , biochemistry , enzyme
Using a α1,3‐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‐Galα1,3Gal (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 × 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.