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

基本信息

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
项目类别：
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

项目摘要

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：使用富马酸二甲基二甲基用于靶向1型糖尿病的自身免疫性摘要：以T细胞介导的自身免疫性疾病中的1型糖尿病（T1D）胰岛素产生胰腺β细胞的破坏。先天和适应性的先天免疫参与了此过程。到目前为止，免疫疗法未能达到持久效果在胰岛自身免疫性上，预防和T1D的逆转仍然是一个未满足的目标。二甲基富马酸盐（DMF）是FDA批准的治疗方法，用于复发恢复多发性硬化症。多种的动物模型和人类受试者中的硬化数据表明，DMF靶向先天以及通过几种机制的自适应免疫调查，包括下调有氧糖酵解在活化的髓样和淋巴样细胞中（代谢抑制）。我们的初步数据强烈表明，DMF是治疗自身免疫性的有前途的药物，并且我们的长期目标是发起临床试验，以测试DMF是否保存胰岛素分泌。 T1D。作为先决条件，临床试验必须由临床前数据支持在与疾病相关的模型中证明其有效性。那是该提议的目的是进行 NOD小鼠模型（一种广泛接受的T1D模型）中的临床前研究，以测试 DMF是否可以在糖尿病发作（糖尿病逆转）处拮抗自身免疫性。这种方法与临床环境直接相关，在该环境中，大多数新疗法都被考虑用于胰岛自身免疫性首先在最近发作的患者的临床试验中测试。因此，我们的具体目的是：1）充分检验DMF治疗逆转糖尿病并获得的假设 NOD小鼠的确定可重复效率数据； 2）表征效果和机制通过研究免疫亚群，自身抗原特定反应，胰腺的作用病理和β细胞功能。这项研究很重要，因为DMF尚未在T1D和然而，似乎拥有许多理想的特性。拟议的项目也是创新的由于代表了一种通过作用机制来治疗疾病的新方法包括代谢抑制。 0