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 tol erance to solid organ grafts, we used a murine model based on the intr oduction of an allogeneic MHC class I gene (H-2K(b)) into hematopoieti c cells of congenic animals differing only at the class I locus. The H -2K(b) gene was placed into a retroviral vector under the control of r egulatory sequences of the myeloproliferative sarcoma virus long termi nal repeat. Transplantation of H-2K(b) retrovirus-transduced autologou s bone marrow into B10.AKM (K-k I-k D-q) recipients resulted in detect able levels of H-2K(b) RNA and cell surface protein in lymphoid and my eloid lineages. H-2K(b) 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-2K(b)-transduced bone marrow showed specifically delayed rejecti on of B10.MBR (K-b I-k D-q) skin grafts disparate only for K-b. Howeve r, B10.MBR skin grafts were rapidly rejected when grafted simultaneous ly with skin grafts from B10 (K-b I-b D-b) mice, a strain bearing addi tional third party alloantigens in association with K-b. Our experimen ts suggest that the hyporesponsive state induced by using the retrovir ally mediated gene transfer model is characterized by the persistence of H-2K(b)-specific cytolytic T cell precursors, which may be inactive because of deficient T cell help. Tolerance to K-b induced by this ap proach may therefore be restricted to T helper cell lineages.