Regulatory Cell Therapy for Sjogrens Syndrome

干燥综合征的调节细胞疗法

• 批准号: 10898203
• 负责人: David W Pascual
• 金额: $ 35.08万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10898203
• 关键词: Abate; Address; Affect; Agonist; Anti-Inflammatory Agents; Antibody Response; Antigens; Arthritis; Atrophic; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Bacterial Adhesins; Bacterial Infections; Binding; Biological Response Modifiers; Bystander Suppression; CD8-Positive T-Lymphocytes; Cell Death; Cell Therapy; Cell physiology; Cells; Chromosomes; Chronic; Data; Dendritic Cells; Development; Diarrhea; Disease; Disease Progression; Early treatment; Engineering; Epithelial Cells; Eragrostis; Etiology; Exhibits; Experimental Models; Fibrinogen; Foundations; Funding; Future; General Population; Goals; Helper-Inducer T-Lymphocyte; Human; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Intervention; Knowledge; Lacrimal gland structure; Lactococcus; Lactococcus lactis; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Nose; Operon; Oral; Outcome; Pathogenicity; Patients; Persons; Postmenopause; Probiotics; Production; Property; Proteins; Regulatory T-Lymphocyte; Resolution; Rheumatoid Arthritis; Risk; Role; Salivary; Salivary Glands; Salmonella; Sjogren' s Syndrome; Source; Submandibular gland; Symptoms; T-Lymphocyte; Testing; Therapeutic; Transforming Growth Factor beta; Vaccines; Woman; Work; adaptive immune response; anergy; clinical heterogeneity; clinical translation; colonization factor antigens; conventional therapy; cytokine; efficacy evaluation; enterotoxigenic Escherichia coli; immunological intervention; immunoregulation; improved; insight; men; mouse model; novel; preservation; prevent; research clinical testing; symptom treatment; therapeutic development; vector

ABSTRACT A broad-based immunotherapeutic with the capacity to stimulate regulatory cells is needed to resolve Sjögren's syndrome (SjS). SjS impacts several million people annually in the US with women being nine times more likely to be affected than men. To date, no vaccines or therapeutics exist to cure SjS, and patients are dependent on lifelong therapies focused on treating only their symptoms. Our previous work has shown that when colonization factor antigen I (CFA/I) fimbriae from enterotoxigenic E. coli are applied either nasally or orally, resolution of autoimmune diseases is observed. To enable testing in humans, a probiotic approach is exploited, whereby the cfaI operon was optimized for expression by Lactococcus lactis (LL-CFA/I). In the previous funding cycle, we demonstrated LL-CFA/I's ability to restore salivary flow in a genetically defined model for SjS, C57BL/6.NOD-Aec1Aec2 mice. Current work seeks to improve LL-CFA/I's activity and stability by generating a LL construct bearing the optimized cfaI operon inserted into the LL chromosome, referred to as, LL 301. To better understand the mode of action of LL-CFA/I, the tip protein from CFA/I fimbriae, CfaE, was episomally expressed by LL, and found to exhibit potent immune regulation of experimental rheumatoid arthritis. These fimbrial proteins are presumed to act by inducing infectious tolerance, resulting in the stimulation of antigen-specific regulatory T cells (Tregs) and regulatory B cells (Bregs) producing IL-10 and TGF-b. Such bystander immunity does not render global immunosuppression, and thus, the adaptive immune response capacity remains intact. When tested in a spontaneous, genetically defined murine model for SjS, both LL 301 and LL-CfaE showed remarkable retention in salivary flow compared to treatment with wild-type LL or LL vector. Based upon these findings, the proposed studies will test the hypothesis that CFA/I fimbriae and CfaE elicit bystander immunity, which in turn regulates pathogenic CD4+ and CD8+ T cells via Tregs and Bregs producing IL-10 and TGF-b. To test this hypothesis, three Specific Aims are proposed. Studies in Specific Aim 1 will determine the efficacy of LL 301 and LL-CfaE via Tregs during treatment of early and late stage SjS, and identify the molecular mechanisms responsible for salivary flow preservation. Studies in Specific Aim 2 will determine the distribution and degree of protection conferred by Bregs induced by LL 301 and LL-CfaE. Studies in Specific Aim 3 will determine whether protection elicited by LL 301 and LL-CfaE are FcgRIIb-dependent since CFA/I fimbriae were found to bind to the immunoregulatory FcgRIIb. These studies will provide the basis for future testing in SjS patients, and in the development of novel FcgRIIb agonists for treating SjS.

抽象的 需要一个具有刺激调节细胞能力的广泛的免疫治疗性来解决 Sjögren综合征（SJS）。 SJ每年在美国影响数百万人，而妇女则为九次 比男性更有可能受到影响。迄今为止，没有治愈SJ的阴道或治疗，患者是 依赖终身疗法的重点是仅治疗其症状。我们以前的工作表明，什么时候 来自肠毒素大肠杆菌的定植因子抗原I（CFA/I）fimbriae鼻或口服应用 观察到自身免疫性疾病的分辨率。为了在人类中进行测试，利用了益生菌方法， 因此，通过乳酸乳酸（LL-CFA/I）优化了CFAI歌剧以表达表达。在以前的资金中 循环，我们证明了LL-CFA/I在SJS的一般定义模型中恢复唾液流量的能力， C57BL/6.NOD-AEC1AEC2小鼠。当前的工作旨在通过产生A来改善LL-CFA/I的活动和稳定性 LL结构带有优化的CFAI操纵子插入LL染色体，称为LL 301。 了解LL-CFA/I的作用方式，CFA/I Fimbriae的TIP蛋白CFAE在偶发表达 通过LL，发现表现出实验性类风湿关节炎的有效免疫调节。这些纤维蛋白 通过诱导感染性耐受性来起作用，从而刺激抗原特异性调节t 产生IL-10和TGF-B的细胞（Treg）和调节B细胞（Bregs）。这样的旁观者免疫不 呈现全球免疫抑制，因此，适应性免疫反应能力保持完整。测试时 在SJS的赞助，一般定义的鼠模型中，LL 301和LL-CFAE都表现出了显着 与使用野生型LL或LL载体的处理相比，唾液流动的保留。基于这些发现， 拟议的研究将检验以下假设：CFA/I Fimbriae和CFAE会引起旁观者的免疫力 通过产生IL-10和TGF-B的Tregs和Bregs调节致病性CD4+和CD8+ T细胞。测试这个 假设提出了三个具体目标。特定目标1的研究将确定LL 301的效率和 早期和晚期SJ的治疗期间通过Tregs通过Tregs进行LL-CFAE，并确定分子机制 负责唾液流程保存。特定目标2的研究将确定分布和程度 由LL 301和LL-CFAE诱导的Bregs提供的保护。特定目标3的研究将确定是否 LL 301和LL-CFAE引起的保护是FCGRIIB依赖性的，因为发现CFA/I Fimbriae与 免疫调节FCGRIIB。这些研究将为SJS患者以及 开发用于治疗SJS的新型FCGRIIB激动剂。