Fimbriae Countermeasures for Type 1 Diabetes

1 型糖尿病的菌毛对策

• 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
• 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' 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

 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（由申请人提供）：在美国，1 型糖尿病 (T1D) 影响着 130 万患者，这些患者由于肾脏、心血管、眼部和/或神经系统并发症而表现出发病率和过早死亡率增加。这种 T 细胞介导的疾病的特点是胰岛中产生胰岛素的 b 细胞受到自身免疫性破坏，导致血糖失调。虽然刺激免疫调节通路可以成功干预治疗自身免疫性疾病，但目前针对 T1D 的对策主要依赖胰岛素​​替代疗法。实施耐受性方案对于治疗人类自身免疫性疾病仍然存在问题。一种替代方案是以旁观者的方式刺激免疫无反应，而不施加整体免疫抑制。这种方法特别有吸引力，因为不需要事先了解自身抗原，并且可以使用无害抗原来完成，例如来自产肠毒素大肠杆菌的定植因子抗原 I (CFA/I) 菌毛。我们过去的自身免疫研究表明，CFA/I 菌毛可以建立有利于建立疾病特异性调节性 T 细胞 (Treg) 的环境。当经鼻或口服给药时，CFA/I 菌毛通过刺激产生 IL-10 的调节性树突细胞 (DC) 诱导 Tregs 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应用，产生了表达 CFA/I 菌毛的乳酸乳球菌菌株（Lactococcus-CFA/I），并发现其在预防自身免疫性疾病方面优于可溶性菌毛。基于乳球菌的疗法已经过用于治疗人类自身免疫性疾病的测试，并且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 菌毛作为 T1D 治疗的基础。这将通过测试以下假设来实现：CFA/I 菌毛在与组织 DC 相互作用时促进调节性微环境，进而激活 T1D 特异性 Tregs 产生 TGF-b、IL-10 和/或 IL-35，从而抑制或激活致病性 CD4+ 和 CD8+ T 细胞。为了检验这一假设，提出了两个具体目标。具体目标 1 中的研究将表明，由 Lactococcus-CFA/I 介导的旁观者免疫可以通过疾病特异性 Tregs 来预防和阻止 T1D。具体目标 2 的研究将确定 DC 和 Tregs 赋予 T1D 保护的机制。这项工作的影响将是辨别这些驱动疾病特异性 Tregs 的新方法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

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.