The potential usefulness of bone marrow transplantation (BMT) as a means for inducing specific transplantation tolerance across major histocompatibility (MHC) barriers is severely limited by the alternative problems of failure of engraftment and the occurrence of lethal graft-versus-host disease. Both of these problems could potentially be eliminated by a genetic engineering approach to this problem, involving transfer of MHC genes rather than immunocompetent cells. The major goal of this application is to induce tolerance to the product of the Kb class I MHC gene by retroviral mediated gene transfer and to study the mechanism of such tolerance induction. Irradiated B10.AKM mice are reconstituted with syngeneic bone marrow transduced with a Kb-containing retroviral vector. To test tolerance, these animals receive skin grafts from the recently-derived intra-MHC recombinant strain B10.MBR, which differs from B10.AKM only for this Kb gene. The effect of gene transfer on expression of kb in bone marrow-derived lineages in recipient mice is also tested.
The specific aims are thus to: 1) Establish conditions permitting engraftment and long-term persistence of retrovirally transduced bone marrow cells in syngeneic recipients; 2) Determine the relationship between persistence of Kb gene expression in bone marrow-derived cells and prolongation of B10.MBR skingrafts in recipient mice; and 3) Study the relative importance of gene expression in various lineages of bone marrow-derived cells in the induction of transplantation tolerance. For this purpose the investigators have constructed a retroviral vector based on the modified MuLV vector, N2, further modified by insertion of a B19 promoter down stream from the Neo reporter gene followed by the 1.6 kb cDNA coding for the Kb class I molecule. The investigators preliminary data utilizing this vector indicate that transfer of the Kb gene into B10.AKM bone marrow cells, followed by reconstitution of irradiated B10.AKM mice with the transduced bone marrow, induces both expression of Kb in peripheral lymphoid populations and specific prolongation of B10.MBR skin graft survival in recipient mice. In addition to its practical importance for the field of transplantation, the application efficient gene transfer technology to the induction of tolerance may provide a powerful new approach toward the understanding of factors responsible for self-nonselfdiscrimination with respect to MHC gene products.
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