Lodde B M, Mineshiba F, Wang J, Cotrim A P, Afione S, Tak P P, Baum B J
GTTB/NIDCR, National Institutes of Health, 10 Center Drive, Room 1N114, MSC 1190, Bethesda, MD 20892-1190, USA.
Ann Rheum Dis. 2006 Feb;65(2):195-200. doi: 10.1136/ard.2005.038232. Epub 2005 Jun 23.
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.
To determine whether gene transfer of vasoactive intestinal peptide (VIP), based on its immunomodulatory properties, might be useful in the management of SS.
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.
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.
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.
干燥综合征（SS）是一种主要影响泪腺和唾液腺的自身免疫性外分泌腺病，可导致眼干和口干（干燥性角结膜炎和口干症）。其病因和发病机制尚不清楚；目前仅有姑息治疗方法。
基于血管活性肠肽（VIP）的免疫调节特性，确定其基因转移是否有助于干燥综合征的治疗。
构建编码人VIP转基因的重组2型腺相关病毒（rAAV2hVIP），并将其逆行注入颌下腺后，在雌性非肥胖糖尿病（NOD）小鼠干燥综合征模型中测试其疗效。在8周龄（涎腺炎发作前）时，每只腺体给予10(10)个颗粒的rAAV2hVIP或rAAV2LacZ（编码β-半乳糖苷酶；对照载体）。在载体注射前和死亡时（16周）测定唾液流速。死亡后，收集唾液、血清和颌下腺。分析唾液分泌量、炎症浸润（灶性评分）、VIP蛋白表达、细胞因子谱和血清抗VIP抗体。
与对照载体相比，rAAV2hVIP显著改善了唾液流速，增加了颌下腺和血清中VIP的表达，并降低了颌下腺细胞因子白细胞介素（IL）2、IL10、IL12（p70）和肿瘤坏死因子α，以及血清调节激活正常T细胞表达和分泌的趋化因子（RANTES）。在灶性评分或凋亡率方面未发现差异；未检测到中和抗体。
局部递送rAAV2hVIP可对NOD小鼠干燥综合征模型的颌下腺产生疾病修饰和免疫抑制作用。预防性使用VIP的新策略可能有助于理解和治疗干燥综合征的唾液成分。
