PREVENTION OF AUTOIMMUNE-DISEASE BY RETROVIRAL-MEDIATED GENE-THERAPY

T lymphocytes have been implicated in a variety of autoimmune diseases , and therefore one potential therapeutic approach would be to toleriz e the pathogenic self-reactive T cells, In this study, we examined whe ther retroviral gene therapy could be used to induce tolerance and pre vent autoimmunity using a transgenic mouse model for experimentally in duced diabetes. In this model, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) is expressed on the p-islet cells of the panc reas under the control of the rat insulin promoter (RIP), Previous wor k showed that the T cells specific for the gp remain unaware of the tr ansgenic gp Ag expressed by the islet cells, and infection with LCMV l eads to immune-mediated diabetes, To tolerize the gp-specific pathogen ic T cells, a retroviral vector (RV) expressing the LCMV gp was constr ucted, RV-gp, Replication-defective recombinant retroviruses were used to transduce bone marrow cells, which were subsequently infused into host RIP-gp transgenic animals. Unlike control animals, RV-gp chimeric animals did not possess T cells specific for the gp Ag as measured by proliferation and cytotoxic function, and further analysis suggested that tolerance of the gp-specific self-reactive T cells occurred by cl onal deletion. Further experiments demonstrated that chimeric RIP-gp t ransgenic animals generated using bone marrow transduced with RV-gp di d not develop experimentally induced diabetes. Our animal model demons trates that retroviral gene therapy may cure immune-mediated diabetes by providing long lasting Ag-specific tolerance.