Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection

被引:15
作者
Bracy, JL
Chase, CM
Russell, PS
Mauiyyedi, S
Colvin, RB
Iacomini, J
机构
[1] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA
[2] Harvard Univ, Sch Med, Boston, MA USA
[3] Massachusetts Gen Hosp, Dept Surg, Transplant Unit, Boston, MA 02114 USA
[4] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA
关键词
tolerance; antibodies; xenotransplantation; gene therapy;
D O I
10.1038/sj.gt.3301581
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In order for xenotransplantation to become a clinical reality, and fulfill its promise of overcoming shortages of human organs and tissues, rejection mediated by the host's immune system must first be overcome. In primates, preformed natural antibodies that bind the carbohydrate antigen Gal alpha1-3Gal beta1-4GlcNAc-R (alpha Gal), which is synthesized by UDP galactose:beta -D-galactosyl-1,4-N-acetyl-D-glucosaminide alpha (1-3)galactosyltransferase (E.C. 2.4.1.151) or simply alpha GT, mediate rigorous rejection of transplanted pig organs and tissues. In alpha GT knockout mice (GT(0) mice), which like humans contain in their serum antibodies that bind aGal, expression of a retrovirally transduced alpha GT in bone marrow-derived cells is sufficient to prevent production of alpha Gal-reactive antibodies. Here, we demonstrate that reconstitution of lethally irradiated GT(0) mice with alpha GT-transduced bone marrow cells from GT(0) littermates prevents antibody-mediated rejection of cardiac transplants from wild-type mice. These data suggest that gene therapy can be used to induce immunological tolerance to defined antigens and thereby overcome transplant rejection.
引用
收藏
页码:1738 / 1744
页数:7
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