T CELL AND B CELL TOLERANCE TO GAL??1,3GAL-EXPRESSING HEART XENOGRAFTS IS ACHIEVED IN ??1,3-GALACTOSYLTRANSFERASE-DEFICIENT MICE BY NONMYELOABLATIVE INDUCTION OF MIXED CHIMERISM1
- 1 June 2001
- journal article
- research article
- Published by Wolters Kluwer Health in Transplantation
- Vol. 71 (11), 1532-1542
- https://doi.org/10.1097/00007890-200106150-00009
Abstract
Background. We have previously demonstrated that mixed xenogeneic chimerism and donor-specific T-cell tolerance can be induced in the rat-to-mouse species combination by using a relatively nontoxic, nonmyeloablative conditioning regimen. However, natural antibodies (NAbs) against Galα1,3Gal (Gal) pose an additional major barrier to pig-to-human vascularized xenograft acceptance. Methods. To determine whether the mixed chimerism approach could also overcome this humoral barrier, T cell-depleted rat (GalT+/+) bone marrow cells (BMC) were transplanted to α1,3-galactosyltransferase deficient (GalT-/-) mice conditioned with a nonmyeloablative regimen, consisting of transient T cell and natural killer (NK) cell depletion, 3 Gy whole body irradiation, and 7 Gy thymic irradiation. Results. By giving a high dose (180×106) of rat BMC, persistent mixed chimerism could be induced in GalT-/- mice, although the level of donor-type hematopoietic repopulation declined over time. Induction of mixed chimerism was associated with a rapid disappearance of anti-Gal and anti-rat NAb in the sera. Both anti-Gal Ab-producing cells and B cells with receptors recognizing Gal were undetectable in mixed chimeras, even when the chimerism levels declined, suggesting that a very low level of chimerism could effectively maintain B-cell tolerance to Gal, probably by clonal deletion and/or receptor editing. Mixed chimeras accepted subsequently transplanted donor-type rat hearts (>100 days) without immunosuppressive therapy, whereas delayed vascular and even hyperacute rejection of rat hearts occurred in conditioned control GalT-/- mice. Cellular rejection occurred by 5–6 days in conditioned control wild-type mice. Conclusions. These findings demonstrate that induction of mixed chimerism with a nonmyeloablative regimen can prevent vascularized xenograft rejection by cellular and anti-Gal Ab-dependent pathways in GalT+/+-to-GalT-/- species combinations.Keywords
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