Mixed hematopoietic molecular chimerism results in permanent transgene expression from retrovirally transduced hepatocytes in mice
2006
Background
Cytotoxic immune elimination of transduced hepatocytes may limit gene therapy for inherited liver diseases. Using β-galactosidase as a marker gene, we studied whether creation of mixed β-galactosidase molecular hematopoietic chimerism could induce tolerance to β-galactosidase-transduced hepatocytes.
Methods
Molecular hematopoietic chimerism was established in irradiated recipient mice by transplantation of either a mixture of wild-type and β-galactosidase-transgenic bone marrow or autologous bone marrow stem cells that were transduced with β-galactosidase lentiviral vectors. After transplantation, mice were hepatectomized and injected with β-galactosidase recombinant retroviruses to transduce regenerating hepatocytes. We monitored the presence of β-galactosidase-expressing hepatocytes as well as the appearance of anti-β-galactosidase antibodies during the time.
Results
In control animals, anti-β-galactosidase antibodies and cytotoxic T-lymphocyte (CTL) response developed as early as 3 weeks after gene transfer. Transduced hepatocytes disappeared concomitantly. In bone marrow transplanted mice, tolerance could be observed in a significant proportion of animals. Tolerance resulted in permanent liver transgene expression and was absent unless a chimerism above 1% was achieved, demonstrating a threshold effect.
Conclusions
Creation of a molecular hematopoietic chimerism can result in transgene tolerance and evade immune rejection of retrovirally transduced hepatocytes. This strategy may be useful for hepatic inherited diseases in which the transgene product behaves as a non-self protein. Copyright © 2006 John Wiley & Sons, Ltd.
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