Prevention of autoimmune disease by retroviral-mediated gene therapy
Ally, B.A.; Hawley, T.S.; McKall-Faienza, K.J.; Kündig, T.M.; Oehen, S.U.; Pircher, H.; Hawley, R.G.; Ohashi, P.S.
Journal of Immunology 155(11): 5404-5408
1995
ISSN/ISBN: 0022-1767 PMID: 7594557 Document Number: 451759
T lymphocytes have been implicated in a variety of autoimmune diseases, and therefore one potential therapeutic approach would be to tolerize the pathogenic self-reactive T cells. in this study, we examined whether retroviral gene therapy could be used to induce tolerance and prevent autoimmunity using a transgenic mouse model for experimentally induced diabetes. In this model, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) is expressed on the beta-islet cells of the pancreas under the control of the rat insulin promoter (RIP). Previous work showed that the T cells specific for the gp remain unaware of the transgenic gp Ag expressed by the islet cells, and infection with LCMV leads to immune-mediated diabetes. To tolerize the gp-specific pathogenic T cells, a retroviral vector (RV) expressing the LCMV gp was constructed, 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 clonal deletion. Further experiments demonstrated that chimeric RIP-gp transgenic animals generated using bone marrow transduced with RV-gp did not develop experimentally induced diabetes. Our animal model demonstrates that retroviral gene therapy may cure immune-mediated diabetes by providing long lasting Ag-specific tolerance.