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

Gene Therapy volume 8, pages 1738–1744 (2001)Cite this article

Abstract

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 Galα1-3Galβ1-4GlcNAc-R (αGal), which is synthesized by UDP galactose:ß-D-galactosyl-1,4-N-acetyl-D-glucosaminide α(1-3)galactosyltransferase (E.C. 2.4.1.151) or simply αGT, mediate rigorous rejection of transplanted pig organs and tissues. In αGT knockout mice (GT0 mice), which like humans contain in their serum antibodies that bind αGal, expression of a retrovirally transduced αGT in bone marrow-derived cells is sufficient to prevent production of αGal-reactive antibodies. Here, we demonstrate that reconstitution of lethally irradiated GT0 mice with αGT-transduced bone marrow cells from GT0 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.

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Acknowledgements

The authors wish to thank Drs Richard C Mulligan and Jeng-Shin Lee for providing the MMP retroviral vector and packing system, as well as for large scale production of VSV-g pseudotyped viruses, Drs David H Sachs and Joren Madsen for critically reading the manuscript, Patricia DellaPella for preparing histology specimens, and members of the Iacomini Laboratory for helpful discussions. This work was supported in part by NIH grants AI44268 and AI43619 to JI. Jennifer L Bracy is supported in part by NIH Training grant T32 AI 07529.

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Authors and Affiliations

  1. Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    JL Bracy, PS Russell & J Iacomini

  2. Department of Surgery, Transplant Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    CM Chase

  3. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    S Mauiyyedi & RB Colvin

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  1. JL Bracy
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  2. CM Chase
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  6. J Iacomini
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Bracy, J., Chase, C., Russell, P. et al. Induction of molecular chimerism by gene therapy prevents antibody-mediated heart transplant rejection. Gene Ther 8, 1738–1744 (2001). https://doi.org/10.1038/sj.gt.3301581

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