Oral GABA treatment as a novel and safe therapy to ameliorate Sjögren’s syndrome

项目摘要 干燥综合征是一种慢性自身免疫性疾病，其特征是免疫细胞浸润到外分泌 腺体，特别是唾液腺和泪腺，导致分泌功能严重丧失， 随之而来的口腔和眼部健康问题。这种疾病影响了400万美国人，其中超过90%的人 影响了自己的女性身份目前，还没有有效的治疗方法来抑制或逆转干燥病的进程。 综合征治疗仅限于改善疾病的症状，可能需要终身。 因此，需要开发新的干燥综合征治疗方法， 控制潜在的炎症反应最近，已经认识到T细胞和抗原- 提呈细胞表达γ-氨基丁酸受体（GABA-Rs），这些受体的激活 受体具有几种抑制炎症的期望效果，包括1）抑制Th 17和Th 1 在一些实施方案中，所述方法包括以下步骤：1）降低APC促炎活性，2）降低APC促炎活性，和3）促进CD 4+和CD 8 + Treg应答。这些 免疫调节作用使得口服GABA能够逆转慢性T细胞介导的免疫缺陷。 自身免疫性疾病，如1型糖尿病（T1 D），多发性硬化症（MS），类风湿性关节炎后， 这些疾病的小鼠模型中临床症状的发作。人T细胞也表达GABA-Rs， GABA已被证明以类似的方式调节它们。GABA的免疫调节作用是适度的， 不会导致免疫耗竭，GABA可安全供人类食用。口服GABA治疗T1 D的临床试验 目前正在进行中。鉴于GABA-R激动剂逆转不同慢性自身免疫性疾病的能力， 疾病模型，其中每一种都具有不同的病因，并且发生在具有不同遗传背景的小鼠中， 口服GABA治疗可以提供一种新且安全的治疗方法， 干燥综合征这项建议将测试口服GABA治疗改善两种不同疾病的能力。 在疾病的早期和晚期给予干燥综合征的小鼠模型。一个证据 由于GABA消耗的安全性，这一原则可能导致快速的临床转化。

PROJECT SUMMARY Sjögren's syndrome is a chronic autoimmune disease characterized by immune cell infiltration into exocrine glands, particularly the salivary and lacrimal glands which leads to severe loss of secretory function and consequent oral and ocular health problems. The disease affects four million Americans with over 90% of those affected being female. Currently, there are no effective therapies to inhibit or reverse the course of Sjögren's syndrome. Treatments are limited to ameliorating the disease's symptoms and may be needed life-long. Accordingly, there is a need to develop new therapeutic approaches for Sjögren's syndrome that can safely control the underlying inflammatory responses. Recently, it has become appreciated that T cells and antigen- presenting cells express gamma-amino-butyric acid receptors (GABA-Rs) and that the activation of these receptors has several desirable effects for inhibiting inflammation, including 1) inhibiting Th17 and Th1 responses, 2) reducing APC proinflammatory activity, and 3) promoting CD4+ and CD8+ Treg responses. These immunoregulatory actions have enabled oral GABA administration to reverse chronic T cell-mediated autoimmune diseases such as type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis after the onset of clinical symptoms in mouse models of these disorders. Human T cells also express GABA-Rs, and GABA has been shown to regulate them in a similar fashion. GABA's immunomodulatory effects are modest, do not cause immuno-depletion, and GABA is safe for human consumption. Clinical trials of oral GABA for T1D are currently underway. Given the ability of GABA-R agonists to reverse disease in different chronic autoimmune disease models, each of which have different etiologies and occur in mice with different genetic backgrounds, it is reasonable to posit that oral GABA treatment could provide a novel and safe therapy to help ameliorate Sjögren's syndrome. This proposal will test the ability of oral GABA therapy to ameliorate disease in two different mouse models of Sjögren's syndrome when given at early and advanced stages of the disease. A proof-of- principle could lead to rapid clinical translation due to the safety of GABA consumption.