H Ohdan1, Y G Yang, K G Swenson, H Kitamura, M Sykes. 1. Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East, Building 149-5102, 13th Street, Boston, MA 02129, USA.
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 Galalpha1,3Gal (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 (180x106) 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.
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 Galalpha1,3Gal (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 (180x106) 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-ratNAb 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.
Authors: Hong Xu; Ziqiang Zhu; Yiming Huang; Larry D Bozulic; Lala-Rukh Hussain; Jun Yan; Suzanne T Ildstad Journal: Transplantation Date: 2012-03-15 Impact factor: 4.939
Authors: Hironosuke Watanabe; Yuichi Ariyoshi; Thomas Pomposelli; Kazuhiro Takeuchi; Dilrukshi K Ekanayake-Alper; Lennan K Boyd; Scott J Arn; Hisashi Sahara; Akira Shimizu; David Ayares; Marc I Lorber; Megan Sykes; David H Sachs; Kazuhiko Yamada Journal: Xenotransplantation Date: 2019-09-23 Impact factor: 3.907