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（T1 D）影响130万患者，这些患者因肾脏、心血管、眼部和/或神经系统并发症而表现出发病率增加和过早死亡。这种T细胞介导的疾病通过自身免疫性破坏胰岛的产生胰岛素的B细胞而引起血糖失调而被注意。虽然刺激免疫调节途径可以成功地干预治疗自身免疫性疾病，但目前T1 D的对策主要依赖于胰岛素替代疗法。实施致耐受性方案对于治疗人自身免疫性疾病仍然存在问题。一种替代方法是以旁观者的方式刺激免疫无反应性，而不施加全局免疫抑制。这种方法特别有吸引力，因为不需要自身抗原的先验知识，并且可以使用无害的抗原，例如来自肠致病性大肠杆菌的定殖因子抗原I（CFA/I）菌毛来实现。杆菌我们过去的自身免疫研究表明，CFA/I菌毛可以建立一个有利于建立疾病特异性调节性T细胞（T细胞）的环境。当经鼻或口服给药时，CFA/I菌毛通过刺激产生IL-10的调节性树突状细胞（DC）诱导TCFs产生IL-10和TGF-β来减轻实验性自身免疫性疾病。为了促进其在人类中的最终使用，产生了表达CFA/I菌毛的乳酸乳球菌菌株（乳球菌-CFA/I），并且发现其在赋予针对自身免疫性疾病的保护方面上级可溶性菌毛。基于乳球菌的疗法已经被测试用于治疗人类自身免疫性疾病，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T1 D治疗的基础。这将通过检验CFA/I菌毛在与组织DC相互作用后促进调节微环境的假设来实现，所述调节微环境进而激活T1 D特异性Tcl 3以产生TGF-β、IL-10和/或IL-35，所述TGF-β、IL-10和/或IL-35抑制致病性CD 4+和CD 8 + T细胞或使致病性CD 4+和CD 8 + T细胞无反应。为了验证这一假设，提出了两个具体目标。特定目标1的研究将表明，由乳球菌-CFA/I介导的旁观者免疫可以通过疾病特异性Tcl 3预防和阻止T1 D。特定目标2的研究将确定负责DC和TdR赋予T1 D保护的机制。这项工作的影响将辨别这些驱动疾病特异性TdR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.