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 需要一种具有刺激调节细胞能力的基础广泛的免疫疗法来解决这个问题 干燥综合征 (SjS)。 SjS 每年影响美国数百万人，其中女性是其九倍 比男性更容易受到影响。迄今为止，尚无治愈 SjS 的疫苗或治疗方法，患者 依赖于仅针对症状的终生治疗。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) 菌毛经鼻或口服施用， 观察到自身免疫性疾病的消退。为了能够在人体中进行测试，采用了益生菌方法， 其中 cfaI 操纵子针对乳酸乳球菌 (LL-CFA/I) 的表达进行了优化。在之前的融资中 循环中，我们证明了 LL-CFA/I 在 SjS 基因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生成一个 LL 构建体带有插入 LL 染色体的优化 cfaI 操纵子，称为 LL 301。 了解 LL-CFA/I 的作用模式，CFA/I 菌毛的尖端蛋白 CfaE 是附加型表达的 LL 发现其对实验性类风湿性关节炎具有有效的免疫调节作用。这些菌毛蛋白 据推测，它们通过诱导感染耐受来发挥作用，从而刺激抗原特异性调节 T 产生 IL-10 和 TGF-b 的细胞 (Treg) 和调节性 B 细胞 (Breg)。这种旁观者免疫力并不 导致整体免疫抑制，因此适应性免疫反应能力保持完整。测试时 在自发的、基因定义的 SjS 小鼠模型中，LL 301 和 LL-CfaE 均表现出显着的表现 与野生型 LL 或 LL 载体治疗相比，唾液流滞留。根据这些发现， 拟议的研究将检验 CFA/I 菌毛和 CfaE 引发旁观者免疫力的假设，从而反过来 通过产生 IL-10 和 TGF-b 的 Tregs 和 Bregs 调节致病性 CD4+ 和 CD8+ T 细胞。为了测试这个 假设，提出了三个具体目标。具体目标 1 的研究将确定 LL 301 和 在治疗早期和晚期 SjS 期间通过 Tregs 进行 LL-CfaE，并确定其分子机制 负责唾液流量的保存。具体目标 2 的研究将确定 LL 301 和 LL-CfaE 诱导的 Bregs 赋予的保护。具体目标 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 菌毛与 免疫调节 FcgRIIb。这些研究将为未来在 SjS 患者中进行测试以及在 开发用于治疗 SjS 的新型 FcgRIIb 激动剂。