EXTENDED REPORT

Effect of human vasoactive intestinal peptide gene transfer in a murine model of Sjögren’s syndrome

B M Lodde^1,2, F Mineshiba¹, J Wang^1,*, A P Cotrim¹, S Afione¹, P P Tak², B J Baum¹

¹ Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda, Maryland 20892-1190, USA
² Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands

Correspondence to:
Dr B M Lodde
GTTB/NIDCR, National Institutes of Health, 10 Center Drive, Room 1N114, MSC 1190, Bethesda, MD 20892-1190, USA; blodde{at}nidcr.nih.gov

Background: Sjögren’s syndrome (SS), an autoimmune exocrinopathy mainly affecting lachrymal and salivary glands, results in ocular and oral dryness (keratoconjunctivitis sicca and xerostomia). The aetiology and pathogenesis are largely unknown; currently, only palliative treatment is available.

Objective: To determine whether gene transfer of vasoactive intestinal peptide (VIP), based on its immunomodulatory properties, might be useful in the management of SS.

Methods: A recombinant serotype 2 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 after retrograde instillation in submandibular glands (SMGs). 10¹⁰ particles/gland of rAAV2hVIP or rAAV2LacZ (encoding ß-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 death (16 weeks). After death, saliva, serum, and SMGs were harvested. Salivary output, inflammatory infiltrates (focus scores), VIP protein expression, cytokine profile, and serum anti-VIP antibodies were analysed.

Results: rAAV2hVIP significantly improved the salivary flow, increased SMG and serum expression of VIP, and reduced SMG cytokines interleukin (IL) 2, IL10, IL12 (p70), and tumour necrosis factor , and serum RANTES, compared with the control vector. No difference in focus scores or apoptotic rates was found; neutralising antibodies were not detected.

Conclusions: Local delivery of rAAV2hVIP can have disease modifying and immunosuppressive effects in SMGs of the NOD mouse model of SS. The new strategy of employing VIP prophylactically may be useful for both understanding and managing the salivary component of SS.

Abbreviations: AAV, adeno-associated virus; ELISA, enzyme linked immunosorbent assay; IFN, interferon ; IL, interleukin; NOD, non-obese diabetic; SMG, submandibular gland; SS, Sjögren’s syndrome; TNF, tumour necrosis factor ; VIP, vasoactive intestinal peptide

Keywords: vasoactive intestinal peptide; Sjögren’s syndrome; gene transfer; adeno-associated virus; autoimmune disease

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Cotrim, A. P., Baum, B. J. (2008). Gene Therapy: Some History, Applications, Problems, and Prospects. Toxicol Pathol 36: 97-103 [Abstract] [Full Text]  
• Gonzalez-Rey, E., Anderson, P., Delgado, M. (2007). Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy. Ann Rheum Dis 66: iii70-iii76 [Abstract] [Full Text]  
• Lodde, B M, Baum, B J, Tak, P P, Illei, G (2006). Experience with experimental biological treatment and local gene therapy in Sjogren's syndrome: implications for exocrine pathogenesis and treatment. Ann Rheum Dis 65: 1406-1413 [Abstract] [Full Text]