T cell and B cell tolerance to Galα1,3Gal-expressing heart xenografts is achieved in α1,3-galactosyltransferase-deficient mice by nomyeloablative induction of mixed chimerism

被引:55
作者
Ohdan, H [1 ]
Yang, YG [1 ]
Swenson, KG [1 ]
Kitamura, H [1 ]
Sykes, M [1 ]
机构
[1] Harvard Univ, Sch Med,Massachusetts Gen Hosp, Surg Serv,Transplantat Biol Res Ctr, Bone Marrow Transplantat Sect, Boston, MA 02129 USA
关键词
D O I
10.1097/00007890-200106150-00009
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 Gal alpha1,3Gal (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 alpha1,3-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 (180x10(6)) 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.
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页码:1532 / 1542
页数:11
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