1122. Transgenic Vasoactive Intestinal Peptide Shows Local Disease Modifying Effects in a Murine Model of Sjögren's Syndrome

Abstract

Top of pageAbstract Objective: Sj|[ouml]|gren's syndrome (SS), an autoimmune exocrinopathy mainly affecting lacrimal and salivary glands, results in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The etiology and pathogenesis are largely unknown; currently, only palliative treatment is available. Gene transfer of vasoactive intestinal peptide (VIP), based on its immunomodulatory properties, potentially may be useful in management of SS. Methods: A serotype 2 recombinant adeno-associated virus encoding the human VIP transgene (rAAV2hVIP) was constructed and its efficacy tested in the female non-obese diabetic (NOD) mouse model for SS following retrograde instillation in submandibular glands (SMGs). 1010 particles/gland of rAAV2hVIP or rAAV2LacZ (encoding |[szlig]|-galactosidase; control vector) were administered at 8 weeks of age (before sialadenitis onset). Salivary flow rates were determined before vector delivery and at time of sacrifice (16 weeks of age). After sacrifice, saliva, serum and SMGs were harvested. Analysis of salivary output, inflammatory infiltrates (focus scores), VIP protein expression, cytokine profile in gland extracts, and serum anti-VIP antibodies was performed. Results: rAAV2hVIP led to significantly improved salivary flow, increased SMG expression of VIP, and reduction of SMG cytokines IL-2, IL-10, IL-12(p70) and TNF-|[alpha]|, and serum RANTES, compared to control vector. There was no difference in focus scores between groups and neutralizing antibodies were not detected. Conclusion: This study shows that local delivery of rAAV2hVIP can have disease-modifying effects in SMGs of the NOD mouse model of SS. This is the first report employing VIP as a potential treatment for SS. This strategy may be useful for both understanding and managing the salivary component of SS.