Effect of human vasoactive intestinal peptide gene transfer in a murine model of Sjogren's syndrome.
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). 10(10) particles/gland of rAAV2hVIP or rAAV2LacZ (encoding beta-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 alpha, 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.
GTTB/NIDCR, National Institutes of Health, 10 Center Drive, Room 1N114, MSC 1190, Bethesda, MD 20892-1190, USA. blodde@nidcr.nih.gov
B M
BM
Lodde
F
F
Mineshiba
J
J
Wang
A P
AP
Cotrim
S
S
Afione
P P
PP
Tak
B J
BJ
Baum
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000097:blood; D017209:Apoptosis; D016207:Cytokines / Q000032:analysis / Q000097:blood; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D016688:Mice, Inbred NOD; D023421:Models, Animal; D012859:Sjogren's Syndrome / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013363:Submandibular Gland / Q000276:immunology / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes; D014660:Vasoactive Intestinal Peptide / Q000032:analysis / Q000097:blood / Q000235:genetics*
D000906:Antibodies; D016207:Cytokines; D014660:Vasoactive Intestinal Peptide