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 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 iselt 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.
Ally
B A
BA
Ontario Cancer Institute, Department of Medical Biophysics, Toronto, Canada.
Hawley
T S
TS
McKall-Faienza
K J
KJ
Kündig
T M
TM
Oehen
S U
SU
Pircher
H
H
Hawley
R G
RG
Ohashi
P S
PS
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D001483:Base Sequence; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000517:prevention & control*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007108:Immune Tolerance; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011828:Radiation Chimera; D051381:Rats; D012190:Retroviridae / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology
D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins