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.

摘要 需要一种具有刺激调节细胞能力的广泛的免疫疗法来解决 干燥综合征(SjS)。在美国，SJS每年影响数百万人，其中女性是 比男性更容易受到影响。到目前为止，还没有疫苗或疗法来治愈Sjs，患者正在 依赖于终生治疗，专注于只治疗他们的症状。我们之前的工作表明，当 产肠毒素大肠杆菌的定植因子抗原I(CFA/I)菌毛经鼻腔或口服应用， 观察自身免疫性疾病的消退。为了能够在人体上进行测试，利用了益生菌方法， 由此优化了cfaI操纵子在乳酸乳球菌(LL-CFA/I)中的表达。在之前的资助中 周期中，我们展示了LL-CFA/I在SjS基因定义的模型中恢复唾液流动的能力， C57BL/6.NOD-Aec1Aec2小鼠。目前的工作旨在通过生成一个 L1构建带有插入到L1染色体中的优化的cfaI操纵子的结构，称为L1 301。为了更好地 了解LL-CFA/I的作用机制，CFA/I菌毛的TIP蛋白CfaE在异构体中得到表达 并发现对实验性类风湿性关节炎有很强的免疫调节作用。这些菌毛蛋白 被认为是通过诱导感染耐受来发挥作用，从而刺激抗原特异性调节性T细胞 分泌IL-10和转化生长因子-β的细胞(Treg)和调节性B细胞(Bregs)。这种旁观者的豁免权并不 造成全球免疫抑制，因此，适应性免疫反应能力保持不变。当经过测试时 在一种自发的、基因定义的SjS小鼠模型中，LL301和LLCfaE都显示出显著的 与野生型LL或LL载体治疗相比，唾液滞留。根据这些调查结果， 拟议的研究将检验CFA/I菌毛和CFAE诱导旁观者免疫的假设，进而 通过Tregs和Bregs产生IL-10和TGF-b来调节致病的CD4+和CD8+T细胞。为了测试这一点 假设，提出了三个具体目标。具体目标1的研究将确定LL301和 IL-CfaE经Tregs治疗早、晚期干燥综合征及其分子机制的研究 负责唾液流量的保存。对特定目标2的研究将确定其分布和程度 由LL 301和LL-CfaE诱导的Bregs提供的保护。对特定目标3的研究将决定 LL 301和LL-CfaE诱导的保护作用是FcgRIIb依赖的，因为发现CFA/I菌毛与 免疫调节FcgRIIb。这些研究将为将来在SjS患者中进行测试以及在 治疗SjS的新型FcgRIIb激动剂的开发