Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy.
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.
Bagley
Jessamyn
J
Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Tian
Chaorui
C
Sachs
David H
DH
Iacomini
John
J
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D005260:Female; D005805:Genes, MHC Class I; D015316:Genetic Therapy / Q000379:methods; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D007108:Immune Tolerance; D007519:Isoantigens / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D018183:Transplantation Chimera
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; D007519:Isoantigens