Abstract
IntroductionTumor necrosis factor is a pleiotropic cytokine with potent immune regulatory functions. Although tumor necrosis factor inhibitors have demonstrated great utility in treating other autoimmune diseases, such as rheumatoid arthritis, there are conflicting results in Sjögren's syndrome. The aim of this study was to assess the effect of a locally expressed tumor necrosis factor inhibitor on the salivary gland function and histopathology in an animal model of Sjögren's syndrome.MethodsUsing in vivo adeno associated viral gene transfer, we have stably expressed soluble tumor necrosis factor-receptor 1-Fc fusion protein locally in the salivary glands in the Non Obese Diabetic model of Sjögren's syndrome. Pilocarpine stimulated saliva flow was measured to address the salivary gland function and salivary glands were analyzed for focus score and cytokine profiles. Additionally, cytokines and autoantibody levels were measured in plasma.ResultsLocal expression of tumor necrosis factor-receptor 1:immunoglobulin G fusion protein resulted in decreased saliva flow over time. While no change in lymphocytic infiltrates or autoantibody levels was detected, statistically significant increased levels of tumor growth factor-β1 and decreased levels of interleukin-5, interleukin-12p70 and interleukin -17 were detected in the salivary glands. In contrast, plasma levels showed significantly decreased levels of tumor growth factor-β1 and increased levels of interleukin-4, interferon-γ, interleukin-10 and interleukin-12p70.ConclusionsOur findings suggest that expression of tumor necrosis factor inhibitors in the salivary gland can have a negative effect on salivary gland function and that other cytokines should be explored as points for therapeutic intervention in Sjögren's syndrome.
Highlights
Tumor necrosis factor is a pleiotropic cytokine with potent immune regulatory functions
While no change in lymphocytic infiltrates or autoantibody levels was detected, statistically significant increased levels of tumor growth factor-β1 and decreased levels of interleukin-5, interleukin-12p70 and interleukin -17 were detected in the salivary glands
Construction, expression and biological activity of plasmid We previously reported the construction of recombinant Adeno Associated Virus-β galactosidase encoding β-galactosidase [17]
Summary
Tumor necrosis factor is a pleiotropic cytokine with potent immune regulatory functions. Tumor necrosis factor inhibitors have demonstrated great utility in treating other autoimmune diseases, such as rheumatoid arthritis, there are conflicting results in Sjögren's syndrome. The aim of this study was to assess the effect of a locally expressed tumor necrosis factor inhibitor on the salivary gland function and histopathology in an animal model of Sjögren's syndrome. Sjögren's syndrome (SS) is a systemic autoimmune disorder affecting secretory tissue, including the lacrimal and salivary glands (SGs), resulting in keratoconjunctivitis sicca and xerostomia. Anti-tumor necrosis factor (TNF) therapies have been widely and successfully used several chronic autoimmune diseases, such as rheumatoid arthritis (RA) and Crohn's disease. The use of anti-TNF agents in patients with the autoimmune disease SS has shown conflicting results [8,9]. Beneficial results were shown in an open study, while inefficacy of anti-TNF was shown in a randomized, double-blind, placebo-controlled trial
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