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

富马酸二甲酯在1型糖尿病自身免疫靶向治疗中的应用 摘要：以T细胞为特征的自身免疫性疾病中的1型糖尿病(T1D) 破坏产生胰岛素的胰岛β细胞。先天免疫和适应性先天免疫 都参与了这一过程。到目前为止，免疫疗法还没有达到持久的效果。 在胰岛自身免疫方面，因此预防和逆转T1D仍然是一个未实现的目标。二甲基二甲基 富马酸(DMF)是FDA批准的治疗复发缓解性多发性硬化症的药物。多重 在动物模型和人类受试者中的硬化症数据表明，DMF靶标先天存在 和适应性免疫反应通过几种机制，包括下调 激活的髓样细胞和淋巴细胞中的有氧糖酵解(代谢抑制)。我们的预赛 数据有力地表明DMF是一种很有前途的治疗胰岛自身免疫的药物，并且 我们的长期目标是启动一项临床试验，以测试DMF是否在 T1D。作为先决条件，临床试验必须得到临床前数据的支持 在与疾病相关的模型中展示其有效性。因此，这项提案的目标是进行 广泛接受的T1D模型NOD小鼠模型的临床前研究 DMF是否可以对抗糖尿病发病时的自身免疫(糖尿病逆转)。这种方法 是否与临床环境直接相关，大多数新疗法正在考虑用于胰岛 自身免疫首先在新近发病的T1D患者的临床试验中进行测试。因此，我们的 具体目标是：1)充分检验DMF疗法逆转糖尿病的假设，并获得 NOD小鼠确切的可重复性疗效数据；2)表征其作用和机制 从免疫亚群、自身抗原特异性反应、胰腺研究DMF治疗的作用 病理和β细胞功能。这项研究具有重要意义，因为DMF尚未在T1D和 然而，IS似乎拥有许多令人向往的特性。拟议的项目也是创新的。 因为代表了一种新的治疗方法，通过一种作用机制来治疗这种疾病 包括代谢抑制。 0