TY - JOUR
T1 - Retroviral gene therapy with an immunoglobulin-antigen fusion construct protects from experimental autoimmune uveitis
AU - Agarwal, Rajeev K.
AU - Kang, Yubin
AU - Zambidis, Elias
AU - Scott, David W.
AU - Chan, Chi Chao
AU - Caspi, Rachel R.
PY - 2000/7
Y1 - 2000/7
N2 - 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 nor only in naive, but also in already primed recipients, thus providing a protocol for treatment of established autoimmunity.
AB - 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 nor only in naive, but also in already primed recipients, thus providing a protocol for treatment of established autoimmunity.
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U2 - 10.1172/JCI9168
DO - 10.1172/JCI9168
M3 - Article
C2 - 10903340
AN - SCOPUS:0033927572
SN - 0021-9738
VL - 106
SP - 245
EP - 252
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -