Fimbriae Countermeasures for Type 1 Diabetes

1 型糖尿病的菌毛对策

基本信息

批准号：
9242580
负责人：
David W Pascual
金额：
$ 18.18万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242580
关键词：
Abate Accounting Adoptive Transfer Adverse effects Affect Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Antigens Arthritis Atherosclerosis Attenuated Autoantibodies Autoimmune Diseases Autoimmune Process Automobile Driving B-Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular system Cell physiology Cells Clinical Collagen-Induced Arthritis Data Dendritic Cells Development Diabetes Mellitus Disease Dose Engineering Environment Eragrostis Escherichia coli Escherichia coli Infections Etiology Exhibits Experimental Autoimmune Encephalomyelitis Experimental Models FOXP3 gene Glutamate Decarboxylase Goals Human I-antigen Immune Immune Tolerance Immunity Immunization Immunosuppression Impairment Inbred NOD Mice Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Interleukin-10 Intervention Islets of Langerhans Kidney Kidney Diseases Knowledge Lactococcus Lactococcus lactis Lymphoid Lymphoid Tissue Mediating Medical Methods Mind Modeling Morbidity - disease rate Multiple Sclerosis Mus Neurologic Neuropathy Non obese Nose Oral Outcome Pathogenicity Pathology Patients Peripheral Preclinical Testing Predisposition Premature Mortality Production Recombinants Regimen Regulatory Pathway Regulatory T-Lymphocyte Replacement Therapy Retinal Diseases Salmonella Sjogren&apos s Syndrome Source Specific qualifier value Specificity Structure of beta Cell of islet Symptoms T-Lymphocyte Testing Therapeutic Thymus Gland Tissues To autoantigen Transforming Growth Factor beta Tretinoin Vaccines Work adaptive immune response autoreactive T cell base colonization factor antigens conventional therapy cytokine diabetic diabetogenic enterotoxigenic Escherichia coli experimental study fighting immunoregulation imprint islet novel novel strategies preconditioning prevent public health relevance receptor success vector vaccine

项目摘要

DESCRIPTION (provided by applicant): In the US, type 1 diabetes (T1D) impacts 1.3 million patients who exhibit increased morbidity and premature mortality due to renal, cardiovascular, ocular, and/or neurological complications. This T cell-mediated disease is noted by the autoimmune destruction of the insulin-producing b cells of the pancreatic islets leading to glycemic dysregulation. Although stimulation of immune regulatory pathways can successfully intervene to treat autoimmune diseases, current countermeasures for T1D mostly rely on insulin replacement therapies. Implementing a tolerogenic regimen still remains problematic for treating human autoimmune diseases. One alternative is to stimulate immune unresponsiveness in a bystander fashion without imposing global immunosuppression. Such an approach is particularly attractive since prior knowledge of the auto-Ag is not required and can be accomplished using an innocuous antigen, such as colonization factor antigen I (CFA/I) fimbriae from enterotoxigenic E. coli. Our past autoimmune studies have shown CFA/I fimbriae can establish an environment conducive to establishing disease-specific regulatory T cells (Tregs). When administered nasally or orally, CFA/I fimbriae mitigate experimental autoimmune diseases by inducing Tregs to produce IL-10 and TGF-b via the stimulation of IL-10-producing regulatory dendritic cells (DCs). To facilitate its eventual use in humans, a Lactococcus lactis strain expressing CFA/I fimbriae (Lactococcus-CFA/I) was generated and found to be superior to soluble fimbriae in conferring protection against autoimmune diseases. Lactococcus-based therapeutics has already been tested for treating autoimmune diseases in humans, and is generally regarded as safe. Given the success of this approach, the proposed studies will establish CFA/I fimbriae as the basis for a therapeutic for T1D. This will be accomplished by testing the hypothesis that CFA/I fimbriae promote a regulatory microenvironment upon interaction with tissue DCs, which in turn, activate T1D-specific Tregs to produce TGF-b, IL-10, and/or IL-35 which suppress or anergize pathogenic CD4+ and CD8+ T cells. To test this hypothesis, two Specific Aims are proposed. Studies in Specific Aim 1 will show that bystander immunity mediated by Lactococcus-CFA/I can prevent and stop T1D via disease-specific Tregs. Studies in Specific Aim 2 will determine mechanisms responsible for DCs and Tregs for conferring T1D protection. The impact of this work will discern whether these novel approaches in driving disease-specific Tregs can prevent further pancreatic islet destruction, and reduce the reliance on insulin replacement therapy.

描述（由应用提供）：在美国，1型糖尿病（T1D）影响了130万患者，他们因肾脏，心血管，眼和/或神经系统并发症而导致的发病率和早亡率增加。这种T细胞介导的疾病通过自身免疫性破坏胰岛产生的胰岛素B细胞导致血糖失调。尽管刺激免疫调节途径可以成功干预以治疗自身免疫性疾病，但当前T1D的对策主要依赖于胰岛素替代疗法。实施耐受性方案仍然有问题治疗人自身免疫性疾病。一种替代方法是以旁观者的方式刺激免疫塑料，而不会施加全球免疫抑制。这种方法特别有吸引力，因为不需要对自动AG的先验知识，并且可以使用无害的抗原（例如肠毒素大肠杆菌中的抗原因子I（CFA/I）fimbriae来实现。我们过去的自身免疫性研究表明，CFA/I Fimbriae可以建立用于建立疾病特异性调节性T细胞（TREG）的环境。当通过鼻或口服给药时，CFA/I fimbriae通过刺激IL-10产生的调节性树突状细胞（DC）来诱导Treg诱导Treg产生IL-10和TGF-B，从而减轻实验性自身免疫性疾病。为了促进其最终在人类中的使用，产生了表达CFA/I脂肪的乳酸菌菌株（Lactococococcus-CFA/I），并发现在针对自身免疫性疾病的会议保护中比固体纤维高于固体纤维。基于乳酸菌的治疗剂已经对治疗人类的自身免疫性疾病进行了测试，通常被认为是安全的。鉴于这种方法的成功，拟议的研究将建立CFA/i fimbriae作为T1D治疗的基础。这将通过测试CFA/I Fimbriae在与组织DC相互作用后促进调节性微环境的假设来实现，这又激活了T1D特异性Tregs以产生TGF-B，IL-100，IL-10和/或IL-35，并抑制或Anergize或Anergize抑制或Anergize Patiloinic CD4+ CD4+和CD8+ T细胞。为了检验这一假设，提出了两个具体目标。特定目标1中的研究将表明，lactocococococcus-cfa/i介导的旁观者免疫力可以通过疾病特异性的Treg进行预防并阻止T1D。特定目标2中的研究将确定负责DC和Tregs T1D保护的机制。这项工作的影响将辨别这些新颖的方法在推动特异性疾病的Treg中是否可以防止进一步的胰岛破坏，并减少对胰岛素替代疗法的依赖。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oral probiotic promotes indoleamine 2,3-dioxygenase- and TGF-β-Producing plasmacytoid dendritic cells to initiate protection against type 1 diabetes.

DOI：
10.1016/j.imlet.2021.07.009
发表时间：
2021-11
期刊：
IMMUNOLOGY LETTERS
影响因子：
4.4
作者：
Nelson, Andrew S.;Akgul, Ali;Maddaloni, Massimo;Bhagyaraj, Ella;Hoffman, Carol;Pascual, David W.
通讯作者：
Pascual, David W.