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基础广泛的免疫系统来解决 干燥综合征（SjS）。在美国，SjS每年影响数百万人，其中女性是女性的九倍。 比男性更容易受到影响。到目前为止，还没有疫苗或治疗方法来治愈SjS，患者 依赖于终生的治疗方法，只专注于治疗症状。我们以前的工作表明，当 定植因子抗原I（CFA/I）菌毛。大肠杆菌通过鼻腔或口腔施用， 观察到自身免疫性疾病的消退。为了能够在人类中进行测试，利用了益生菌方法， 其中cfaI操纵子被优化用于通过乳酸乳球菌（LL-CFA/I）表达。在此前的融资中， 周期，我们证明了LL-CFA/I在遗传定义的SjS模型中恢复唾液流的能力， C57 BL/6. NOD-Aec 1Aec 2小鼠。目前的工作试图通过产生一种新的酶来提高LL-CFA/I的活性和稳定性。 LL构建体，其携带插入LL染色体的优化cfaI操纵子，称为LL 301。更好地 了解LL-CFA/I的作用方式，CFA/I菌毛的顶端蛋白CfaE是游离型表达的 通过LL，并发现其对实验性类风湿性关节炎表现出有效的免疫调节作用。这些菌毛蛋白 被推测通过诱导感染耐受，导致刺激抗原特异性调节T细胞， 产生IL-10和TGF-B b的调节性B细胞（B细胞）。这种旁观者免疫力并不 使整体免疫抑制，因此，适应性免疫应答能力保持完整。测试时 在自发的、遗传上确定的SjS小鼠模型中，LL 301和LL-CfaE均显示出显著的 与用野生型LL或LL载体处理相比，根据这些发现， 拟议的研究将检验CFA/I菌毛和CfaE引起旁观者免疫的假设， 通过产生IL-10和TGF-b的Tcl 3和Bcl 3调节致病性CD 4+和CD 8 + T细胞。为了验证这一 假设，提出了三个具体目标。具体目标1的研究将确定LL 301的疗效， LL-CfaE介导的TcR在治疗早期和晚期SjS中的作用，并确定分子机制 负责维持唾液流。具体目标2中的研究将确定 由LL 301和LL-CfaE诱导的BcR赋予的保护。具体目标3的研究将确定是否 由LL 301和LL-CfaE引起的保护是FcgRIIb依赖性的，因为发现CFA/I菌毛结合至FcgRIIb。 免疫调节性FcgRIIb。这些研究将为将来在SjS患者中进行测试提供基础， 用于治疗SjS的新型FcgRIIb激动剂的开发。