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.
AuthorsR K Agarwal, Y Kang, E Zambidis, D W Scott, C C Chan, R R Caspi
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 106 Issue 2 Pg. 245-52 (Jul 2000) ISSN: 0021-9738 [Print] United States
PMID10903340 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Epitopes
  • Eye Proteins
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Retinol-Binding Proteins
  • interstitial retinol-binding protein
  • Animals
  • Autoimmune Diseases (therapy)
  • B-Lymphocytes (immunology, transplantation)
  • Epitopes (genetics, immunology, therapeutic use)
  • Eye Proteins
  • Female
  • Genetic Therapy (methods)
  • Humans
  • Immune Tolerance
  • Immunoglobulin G (genetics, immunology, therapeutic use)
  • Immunoglobulin Heavy Chains (genetics, immunology, therapeutic use)
  • Lymphocyte Transfusion
  • Mice
  • Peptide Fragments (genetics, immunology, therapeutic use)
  • Recombinant Fusion Proteins (immunology, therapeutic use)
  • Retinol-Binding Proteins (genetics, immunology, therapeutic use)
  • Uveitis (therapy)

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