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 princip le to design a strategy for gene therapy of experimental autoimmune uveitis , a cell-mediated autoimmune disease model for human uveitis induced with t he uveitogenic interphotoreceptor retinoid-binding protein (IRBP). A retrov iral vector was constructed containing a major uveitogenic IRBP epitope in frame with mouse IgG1 heavy chain. This construct was used to transduce per ipheral B cells, which were infused into syngeneic recipients. A single inf usion 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 transf er 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 alre ady primed recipients, thus providing a protocol for treatment of establish ed autoimmunity.