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- Title
Engraftment of Genetically Modified Bone Marrow Cells in Sensitized Hosts
- Authors
Bracy, Jennifer L.; Iacomini, John
- Abstract
Expression of retrovirally transduced genes in bone marrow-derived cells can be used to establish stable long-term B- and T-cell tolerance. To determine whether preexisting antibodies may prohibit the use of gene therapy to establish tolerance, we examined the extent to which preexisting antibodies specific for the carbohydrate antigen Galα1-3Galβ1-4GlcNAc-R (αGal) could affect engraftment and development of bone marrow progenitors expressing the enzyme UDPgalactose:β-D-galactosyl-1,4-N-acetyl-D-glucosaminide α(1-3)galactosyltransferase (E.C. 2.4.1.151), or simply αGT, which synthesizes the αGal epitope. Groups of αGT knockout mice (GT0 mice) lacking αGal were presensitized to αGal by immunization and then lethally irradiated and reconstituted with varying numbers of αGT-transduced syngeneic bone marrow cells. Whereas unimmunized controls were reconstituted with as few as 2×106 transduced cells, a significant fraction of immunized mice reconstituted with 2×106 or 4×106 αGT-transduced cells failed to undergo bone marrow engraftment and died. Immunized mice in which radiation protection was achieved failed to express αGal. However, radiation protection and expression of αGal on bone marrow-derived cells, resulting in tolerance, could be achieved by increasing the number of transduced cells used to reconstitute immunized mice. Thus, although high levels of preexisting antibodies can be a significant barrier to engraftment, this barrier can be overcome by increasing the number of transduced cells used for reconstitution.
- Subjects
BONE marrow cells; GENETIC transduction; RETROVIRUSES
- Publication
Molecular Therapy, 2002, Vol 6, Issue 2, p252
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1006/mthe.2002.0651