Use of use of dimethyl fumarate for targeting autoimmunity in type 1 diabetes

富马酸二甲酯用于靶向 1 型糖尿病自身免疫的用途

• 批准号: 10354282
• 负责人: Allison Lorayne Bayer
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354282
• 关键词: Acute; Adaptive Immune System; Animal Model; Animals; Attenuated; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Award; Beta Cell; Cell physiology; Cells; Chronic; Citric Acid Cycle; Clinical; Clinical Trials; Data; Development; Diabetes Mellitus; Diabetes prevention; Diagnosis; Disease; Down-Regulation; Esters; Experimental Autoimmune Encephalomyelitis; Experimental Models; FDA approved; Fumarates; Fumaric acid; Funding; Future; Goals; Human; Immune; Immune response; Immune system; Immunotherapy; Inbred NOD Mice; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Lesion; Life; Lymphoid Cell; Magnetic Resonance Imaging; Mediating; Metabolic; Modeling; Multiple Sclerosis; Mus; Myeloid Cells; Natural Immunity; Natural Killer Cells; Oral; Pancreas; Pathogenesis; Pathology; Patients; Pharmacotherapy; Pilot Projects; Prevention; Process; Property; Regulatory T-Lymphocyte; Relapse; Relapsing-Remitting Multiple Sclerosis; Reproducibility; Research; Risk; Serum; Structure of beta Cell of islet; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Agents; Time; Treatment Efficacy; Universities; adaptive immune response; adaptive immunity; aerobic glycolysis; blood glucose regulation; cytokine; drug action; efficacy evaluation; human subject; immunoregulation; improved; innovation; insulin dependent diabetes mellitus onset; insulin secretion; insulitis; islet autoimmunity; mouse model; multiple sclerosis treatment; novel strategies; novel therapeutics; optimal treatments; pre-clinical; preservation; prevent; response; success

Title: Use of use of dimethyl fumarate for targeting autoimmunity in type 1 diabetes Abstract: Type 1 diabetes (T1D) in an autoimmune disease characterized by T-cell mediated destruction of insulin producing pancreatic beta-cells. Both innate and adaptive innate immunity are involved in this process. Immunotherapies so far have failed to achieve long-lasting effects on islet autoimmunity, so that prevention and reversal of T1D remain an unmet goal. Dimethyl fumarate (DMF) is an FDA-approved treatment for relapsing remitting multiple sclerosis. Multiple sclerosis data in both animal models and human subjects have shown that DMF targets innate and adaptive immune responses through several mechanisms, including the downregulation of aerobic glycolysis in activated myeloid and lymphoid cells (metabolic inhibition). Our preliminary data strongly suggests that DMF is a promising drug for the treatment of islet autoimmunity, and our long-term goal is to launch a clinical trial to test whether DMF preserves insulin secretion in T1D. As a pre-requisite, a clinical trial would have to be supported by preclinical data that demonstrate its efficacy in a disease-relevant model. Thus, the goal of this proposal is to conduct preclinical investigations in the NOD mouse model, a widely accepted model of T1D, to test whether DMF can antagonize autoimmunity at diabetes onset (diabetes reversal). This approach is the directly relevant to the clinical setting, where most new therapies being considered for islet autoimmunity are first tested in clinical trials of patients with recent T1D onset. Therefore, our specific aims are: 1) To fully test the hypothesis that DMF therapy reverses diabetes and obtain definitive reproducible efficacy data in NOD mice; 2) To characterize the effects and mechanisms of action of DMF therapy by studying immune subsets, autoantigen specific responses, pancreas pathology and β-cell function. This study is significant since DMF has not been tested in T1D and yet is appears to possess many desirable properties. The proposed project is also innovative since represents a new approach in treating the disease through a mechanism of action which includes metabolic inhibition. 0

标题：富马酸二甲酯用于靶向1型糖尿病自身免疫的用途 翻译后摘要：1型糖尿病（T1 D）的自身免疫性疾病的特点是T细胞介导的 破坏产生胰岛素的胰腺β细胞。先天免疫和适应性先天免疫 参与了这个过程。迄今为止，免疫疗法未能取得持久的效果 因此，预防和逆转T1 D仍然是一个未实现的目标。二甲基 富马酸盐（DMF）是FDA批准的用于复发缓解型多发性硬化症的治疗。多 动物模型和人类受试者的硬化数据均表明，DMF靶向先天性 和适应性免疫反应通过几种机制，包括下调 活化的髓样和淋巴样细胞中的有氧糖酵解（代谢抑制）。我们的初步 数据强烈表明DMF是治疗胰岛自身免疫的有前景的药物， 我们的长期目标是开展一项临床试验，以测试DMF是否能保护胰岛素分泌， T1D作为先决条件，临床试验必须得到临床前数据的支持， 证明其在疾病相关模型中的有效性。因此，本提案的目标是进行 NOD小鼠模型（一种广泛接受的T1 D模型）的临床前研究， DMF是否可以拮抗糖尿病发作时的自身免疫（糖尿病逆转）。这种方法 与临床环境直接相关，其中大多数新疗法被认为是用于胰岛 自身免疫首先在近期T1 D发作患者的临床试验中进行测试。所以我们的 具体目的是：1）充分检验DMF治疗逆转糖尿病的假设， NOD小鼠中确定的可重现疗效数据; 2）表征效应和机制 通过研究免疫亚群、自身抗原特异性应答、胰腺 病理学和β细胞功能。本研究具有重要意义，因为尚未在T1 D中检测DMF， 但它似乎具有许多所需的性质。拟议的项目也具有创新性 因为它代表了一种通过作用机制治疗疾病的新方法， 包括代谢抑制。 0