Mucosal Therapy for Autoimmunity

描述（由申请人提供）：过去的研究表明，口服或鼻腔应用耐受性原可以诱导外周耐受性，这些方法已成功用于治疗过敏。这种方法的一个限制是通常需要相对大量的材料来成功地容忍宿主。为了更有效地提供耐受性原，我们设计了一种单剂量方法来诱导口服或鼻腔耐受性，以刺激调节性T细胞的诱导。既往研究表明，口腔耐受需要粘膜诱导组织上的M细胞，在没有Peyer’s贴片的情况下，无法诱导耐受。因此，我们假设靶向粘膜诱导组织对耐受诱导很重要。利用M细胞配体来验证这一假设，基因融合到呼肠孤病毒血清型3的黏附素或血凝素蛋白s1 （ps1）的蛋白质能够耐受宿主。我们的数据表明，口服或鼻腔应用融合蛋白卵清蛋白(OVA)-ps1，刺激T细胞和B细胞对OVA的无反应性。鉴于这些发现，我们假设ps1递送的自身抗原可以诱导耐受性，并且是唾液酸结合依赖性的，并且耐受性通过靶细胞和可能的局部抗原呈递细胞（APCs）的凋亡而促进，而APCs又被其他APCs摄入。为了实现这一目标，在Specific Aim 1中的研究将表明ps1需要M细胞和/或唾液酸（SA）来实现耐受性诱导。在Specific Aim 2中的研究将表明ps1通过APCs和/或上皮细胞的凋亡介导耐受性诱导。特异性目的3的研究将显示ps1介导的预防与治疗保护机制在其对适应性和先天免疫细胞的依赖上有所不同。公共卫生相关性：对自身抗原的耐受性诱导常常被反复或大剂量的自身抗原刺激T细胞的无反应性所破坏。在这个应用中，我们已经确定了一种适配器分子，蛋白质可以在其上进行遗传融合，当应用于粘膜时，甚至可以用单剂量诱导耐受性。这项工作的总体目标将是开发一种简单的方法和载体来引发耐受性，并设计一种方案，可以预防和/或治疗口腔和唾液腺的自身免疫性疾病或过敏。据估计，格林综合征的患病率为200万至400万人，是美国第二大自身免疫性风湿病。这种疾病在女性中的发病率几乎是男性的十倍。最近的数据表明，Sj" green 's Syndrome有一种调节性T细胞成分来限制疾病。因此，一旦我们能够建立ps1传递技术，我们将继续使用目前的格林综合征模型来测试疾病进展是否可以减少。

DESCRIPTION (provided by applicant): Past studies have shown that oral or nasal application of tolerogens can induce peripheral tolerance, and these methods have been successfully used for treatment of allergies. One limitation of such approaches is relatively large amounts of materials are often needed to successfully tolerize the host. To enable a more efficient method to deliver tolerogens, we have devised a single dose method to induce oral or nasal tolerance to stimulate the induction of regulatory T cells. Previous studies have shown that M cells on mucosal inductive tissues are required for oral tolerance, and in the absence of Peyer's patches, tolerance cannot be induced. Thus, we hypothesized that targeting mucosal inductive tissues is important for tolerance induction. Using an M cell ligand to test this hypothesis, proteins genetically fused to the adhesin or hemagglutinin protein from reovirus serotype 3, protein s1 (ps1), tolerize the host. Our data show that oral or nasal application of the fusion protein, ovalbumin (OVA)-ps1, stimulates T and B cell unresponsiveness to OVA. Given these findings, we hypothesize that ps1 delivered autoantigens can induce tolerance and is sialic acid binding-dependent, and tolerance is facilitated via apoptosis of target cells and, possibly, local antigen-presenting cells (APCs), which in turn are ingested by other APCs. To enable this effort, studies in Specific Aim 1 will show ps1 requires M cells and/or sialic acid (SA) to enable tolerance induction. Studies in Specific Aim 2 will show that ps1 mediates tolerance induction via apoptosis of APCs and/or epithelial cells. Studies in Specific Aim 3 will show that prophylatic versus therapeutic mechanisms of protection mediated by ps1 differ in its dependency on adaptive and innate immune cells. PUBLIC HEALTH RELEVANCE: Induction of tolerance to auto-antigens is often compromised by repeated or large dosages of auto- antigens to stimulate T cell unresponsiveness. Herein this application, we have identified an adapter molecule to which proteins can be genetically fused and when applied mucosally, tolerance can even be induced with a single dose. The overall goals of this work will be to develop a simple method and carrier for eliciting tolerance and to design a regimen that can prevent and/or treat autoimmune diseases or allergies of the oral cavity and salivary glands. The prevalence of Sj"gren's Syndrome is estimated at 2-4 million individuals, which represents the second leading autoimmune rheumatic disease in the US. This disease is nearly ten times more prevalent in females than males. Recent data suggests that Sj"gren's Syndrome has a regulatory T cell component to limit disease. Thus, once we are able to establish the ps1 delivery technology, we will move forward to use current models for Sj"gren's Syndrome to test if disease progression can be reduced.