Specific unresponsiveness to a retrovirally-transferred class I antigen is controlled through the helper pathway.
To investigate the potential role for gene therapy in induction of tolerance to solid organ grafts, we used a murine model based on the introduction of an allogeneic MHC class I gene (H-2Kb) into hematopoietic cells of congenic animals differing only at the class I locus. The H-2Kb gene was placed into a retroviral vector under the control of regulatory sequences of the myeloproliferative sarcoma virus long terminal repeat. Transplantation of H-2Kb retrovirus-transduced autologous bone marrow into B10.AKM (Kk Ik Dq) recipients resulted in detectable levels of H-2Kb RNA and cell surface protein in lymphoid and myeloid lineages. H-2Kb expression was significant, although variable, in bone marrow Mac1+ cells, in splenic B cells, and in CD4+/CD8+ thymocytes 8 wk post-bone marrow transplantation. The recipients of the H-2Kb-transduced bone marrow showed specifically delayed rejection of B10.MBR (Kb Ik Dq) skin grafts disparate only for Kb. However, B10.MBR skin grafts were rapidly rejected when grafted simultaneously with skin grafts from B10 (Kb Ib Db) mice, a strain bearing additional third party alloantigens in association with Kb. Our experiments suggest that the hyporesponsive state induced by using the retrovirally mediated gene transfer model is characterized by the persistence of H-2Kb-specific cytolytic T cell precursors, which may be inactive because of deficient T cell help. Tolerance to Kb induced by this approach may therefore be restricted to T helper cell lineages.
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston 02129.
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Fraser
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Sykes
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Lee
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Sachs
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LeGuern
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D005260:Female; D005822:Genetic Vectors; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology; D012091:Repetitive Sequences, Nucleic Acid; D009053:Sarcoma Viruses, Murine / Q000235:genetics; D016038:Skin Transplantation / Q000276:immunology*
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D011993:Recombinant Fusion Proteins