Expression of TNF inhibitor gene in the lacrimal gland promotes recovery of tear production and tear stability and reduced immunopathology in rabbits with induced autoimmune dacryoadenitis.

Abstract

Background: The most common cause of ocular morbidity in developed countries is dry eye, many cases of which are due to lacrimal insufficiency. Dry eye affects approximately 10 million in the United States, most of whom are women. In the U.S. alone, an estimated 2 million Sjögren's syndrome patients have dysfunctional lacrimal glands and severe dry eye, and there is no satisfactory treatment. These patients would benefit if their lacrimal tissue function could be restored.

Methods: The effect of adenovirus-mediated transfer of tumor necrosis factor (TNF)-alpha inhibitor gene on induced autoimmune dacryoadenitis was evaluated in a rabbit model. Soluble transgene protein was detected in tears by ELISA for 7 days following transduction.

Results: Two weeks after induction of disease with activated lymphocytes, tear production, as determined by Schirmer testing, was reduced by about 40%, while tear film stability, as measured by tear breakup time (BUT), declined by 43%. Adenovirus-mediated gene therapy using AdTNFRp55-Ig given 2 weeks after disease induction, resulted in the return of tear production to normal levels by week 4. In the treated disease group, tear BUT improved significantly by week 4. Rose bengal scores, an indicator of corneal surface defects, increased after disease induction and declined after gene therapy. In the lacrimal gland, the CD4 to CD8 T cell ratio was 4:1 in the disease group compared to 1:2 in the treated group. Infiltration of T cells and CD18+ cells was reduced approximately 50% after gene therapy.

Conclusion: We concluded that therapeutic levels of soluble TNF inhibitor were achieved in the lacrimal gland and on the corneal surface. Anti-inflammatory cytokine gene expression might offer a potential therapeutic modality for the treatment of autoimmune dacryoadenitis, once suitable vectors become available.