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原可诱导外周耐受，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耐受宿主。为了实现更有效的递送耐受原的方法，我们设计了单剂量方法来诱导口服或鼻内耐受以刺激调节性T细胞的诱导。先前的研究表明，粘膜诱导组织上的M细胞是口服耐受所需的，在没有派尔集合淋巴结的情况下，不能诱导耐受。因此，我们假设靶向粘膜诱导组织对于耐受诱导是重要的。使用M细胞配体来检验这一假设，与呼肠孤病毒血清型3的粘附素或血凝素蛋白（蛋白s1（ps1））基因融合的蛋白质使宿主耐受。我们的数据表明，口服或鼻腔应用的融合蛋白，卵清蛋白（OVA）-ps1，刺激T和B细胞对OVA无反应。鉴于这些发现，我们假设ps1交付的自身抗原可以诱导耐受性，是唾液酸结合依赖性的，耐受性是通过靶细胞和可能的局部抗原呈递细胞（APC）的凋亡，这反过来又被其他APC摄取。为了实现这一努力，特定目标1中的研究将显示ps1需要M细胞和/或唾液酸（SA）来实现耐受性诱导。Specific Aim 2中的研究将表明，ps1通过APC和/或上皮细胞的凋亡介导耐受诱导。《特定目标3》中的研究将表明，由ps1介导的预防性与治疗性保护机制的不同之处在于其对适应性和先天性免疫细胞的依赖性。公共卫生相关性：对自身抗原的耐受性的诱导通常受到重复或大剂量的自身抗原刺激T细胞无应答性的损害。在本申请中，我们已经鉴定了蛋白质可以遗传融合的衔接子分子，并且当粘膜施用时，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，用于引发耐受性，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。干燥综合征的患病率估计为2-4百万个体，其代表美国第二大自身免疫性风湿性疾病。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，干燥综合征具有限制疾病的调节性T细胞成分。因此，一旦我们能够建立ps1输送技术，我们将继续使用目前的干燥综合征模型来测试是否可以减少疾病进展。

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.