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Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy
Jessamyn Bagley1, Chaorui Tian, David H Sachs
1Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Induction of immunologic tolerance to alloantigens is a major goal in the field of transplantation. Here, we demonstrate that efficient transduction and expression of a retrovirally transduced major histocompatibility complex (MHC) class I gene (H-2K(b)) in bone marrow (BM)-derived cells, resulting in a permanent state of hematopoietic molecular chimerism, induces stable tolerance to the transduced gene product. Reconstitution of lethally irradiated syngeneic recipients with BM transduced with virus encoding H-2K(b) resulted in life-long expression of the retroviral gene product on the surface of BM-derived hematopoietic lineages including Sca-1(+), lineage negative, hematopoietic progenitors. T cells from mice receiving MHC-transduced BM were unable to kill targets expressing H-2K(b) but were able to respond to third-party controls. Mice reconstituted with H-2K(b)-transduced BM exhibited long-term acceptance of H-2K(b) mismatched skin grafts but were able to rapidly reject third-party control grafts. Thus, gene therapy approaches may be used to induce T-cell tolerance.
Induction of immunologic tolerance to alloantigens is a major goal in the field of transplantation. Here, we demonstrate that efficient transduction and expression of a retrovirally transduced major histocompatibility complex (MHC) class I gene (H-2K(b)) in bone marrow (BM)-derived cells, resulting in a permanent state of hematopoietic molecular chimerism, induces stable tolerance to the transduced gene product. Reconstitution of lethally irradiated syngeneic recipients with BM transduced with virus encoding H-2K(b) resulted in life-long expression of the retroviral gene product on the surface of BM-derived hematopoietic lineages including Sca-1(+), lineage negative, hematopoietic progenitors. T cells from mice receiving MHC-transduced BM were unable to kill targets expressing H-2K(b) but were able to respond to third-party controls. Mice reconstituted with H-2K(b)-transduced BM exhibited long-term acceptance of H-2K(b) mismatched skin grafts but were able to rapidly reject third-party control grafts. Thus, gene therapy approaches may be used to induce T-cell tolerance.