Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis.
Immunoglobulins can serve as tolerogenic carriers for antigens, and B cells can function as tolerogenic antigen-presenting cells. We used this principle to design a strategy for gene therapy of experimental autoimmune uveitis, a cell-mediated autoimmune disease model for human uveitis induced with the uveitogenic interphotoreceptor retinoid-binding protein (IRBP). A retroviral vector was constructed containing a major uveitogenic IRBP epitope in frame with mouse IgG1 heavy chain. This construct was used to transduce peripheral B cells, which were infused into syngeneic recipients. A single infusion of transduced cells, 10 days before uveitogenic challenge, protected mice from clinical disease induced with the epitope or with the native IRBP protein. Protected mice had reduced antigen-specific responses, but showed no evidence for a classic Th1/Th2 response shift or for generalized anergy. Protection was not transferable, arguing against a mechanism dependent on regulatory cells. Importantly, the treatment was protective when initiated 7 days after uveitogenic immunization or concurrently with adoptive transfer of primed uveitogenic T cells. We suggest that this form of gene therapy can induce epitope-specific protection not only in naive, but also in already primed recipients, thus providing a protocol for treatment of established autoimmunity.
Agarwal
R K
RK
Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland, USA.
Kang
Y
Y
Zambidis
E
E
Scott
D W
DW
Chan
C C
CC
Caspi
R R
RR
D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D001402:B-Lymphocytes / Q000276:immunology / Q000637:transplantation; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D005136:Eye Proteins; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D017710:Lymphocyte Transfusion; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D014605:Uveitis / Q000628:therapy*; D000099214:Retinol-Binding Proteins, Interstitial
D000939:Epitopes; D005136:Eye Proteins; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial