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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

Tolerization of Galα1,3Gal‐reactive B cells in pre‐sensitized... Abstract: 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 × 106) of allogeneic wild‐type BMC. Achievement of persistent chimerism was associated with high levels of anti‐Gal IgG1 pretransplant, suggesting an inhibitory effect of non‐complement‐fixing IgG1 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

Tolerization of Galα1,3Gal‐reactive B cells in pre‐sensitized α1,3‐galactosyltransferase‐deficient mice by nonmyeloablative induction of mixed chimerism

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References (59)

Publisher
Wiley
Copyright
Copyright © 2001 Wiley Subscription Services, Inc., A Wiley Company
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1034/j.1399-3089.2001.00006.x
Publisher site
See Article on Publisher Site

Abstract

Abstract: 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 × 106) of allogeneic wild‐type BMC. Achievement of persistent chimerism was associated with high levels of anti‐Gal IgG1 pretransplant, suggesting an inhibitory effect of non‐complement‐fixing IgG1 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.

Journal

Xenotransplantation – Wiley

Published: Nov 1, 2001

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