The Effects of Low-Dose IL-2 Therapy on Beta Cell Dysfunction in Type 1 Diabetes

低剂量 IL-2 治疗对 1 型糖尿病 β 细胞功能障碍的影响

基本信息

批准号：
10380607
负责人：
Farhan Qureshi
金额：
$ 5.18万
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：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10380607
关键词：
Address Affect Aftercare American Apoptosis Autoimmune Diseases Autoimmunity Beta Cell Biology Biomedical Research Blood Blood Glucose Cell Communication Cell Count Cell Death Cell physiology Cells Chimeric Proteins Clinical Clinical Research Clinical Trials Cyclosporine Data Diabetes Mellitus Diagnosis Disease Disease Progression Dose Endocrine Endoplasmic Reticulum Environment Fasting Fluorescence-Activated Cell Sorting Foundations Functional disorder Goals Half-Life Health Homeostasis IL2RA gene Immune Immune Tolerance Immunosuppressive Agents Immunotherapy Impairment In Situ In Vitro Inbred NOD Mice Individual Infiltration Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Interleukin-2 Intervention Islets of Langerhans Knowledge Lymphocyte Mediating Modeling Monitor NOR Mouse Non obese Pancreas Pathogenesis Patients Pattern Phase I/II Clinical Trial Population Pre-Clinical Model Preparation Prevention Recombinant Interleukin-2 Regulatory T-Lymphocyte Science Signal Transduction Slice Stains Strategic Planning Stress Testing Time Tissues Treatment Efficacy Tumor-infiltrating immune cells United States National Institutes of Health Work analog autoimmune pathogenesis bench to bedside biological adaptation to stress blood glucose regulation cytokine diabetes pathogenesis diabetic effector T cell efficacy trial glucose tolerance immunoregulation insulin secretion insulitis islet neglect novel novel strategies novel therapeutics preclinical study preclinical trial preservation prevent response restoration single-cell RNA sequencing

项目摘要

Project Summary Type 1 diabetes (T1D) is a devastating autoimmune disease affecting over 1.25 million Americans that currently has no cure. Therapies which target autoimmunity in T1D have shifted away from broadly immunosuppressive agents such as cyclosporine, and now focus on enhancing immune tolerance. Low-doses of interleukin-2 (IL-2) have been shown in pre-clinical and clinical trials to induce proliferation of regulatory Tcells (Tregs) which promote immune tolerance and prevent autoimmune destruction of the insulin producing beta cell. Recently, it has been shown in preclinical models that an IL-2/CD25 fusion protein induces greater proliferation of Tregs and has a longer half-life than traditional recombinant IL-2. Studies on IL-2 and its analogues have focused on mechanisms of immune tolerance and how it prevents loss of beta cell mass. Recent clinical findings demonstrate that insulin secretion is impaired at least five years before diagnosis, while beta cell mass is still preserved, suggesting that beta cell dysfunction, in addition to loss of beta cell mass, is critically important to the pathogenesis of T1D. It is currently unknown how IL-2/CD25 therapy affects beta cell dysfunction. This represents a critical gap in knowledge that must be addressed. Preliminary data shows that IL-2/CD25 induces changes in the local immune infiltrate, increasing the proportion of Tregs and decreasing the proportion of effector T cells (Teffs) at the islets. In vitro studies have shown that pro-inflammatory cytokines are released by infiltrating Teffs and cause beta cell dysfunction via stress on the endoplasmic reticulum (ER). Therefore, I hypothesize that IL-2/CD25 works to delay T1D progression by preventing cytokine-mediated beta cell dysfunction, not just by averting cell death. I plan to test this hypothesis in the following specific aims: 1) Determine how IL-2/CD25 treatment preserves islet function and glucose homeostasis, 2) Determine how IL- 2/CD25 treatment preserves islet tissue homeostasis. Under the first aim, I will use a novel approach using living pancreas slices to analyze changes in insulin secretion and intracellular Ca2+ dynamics after IL-2/CD25 treatment. Under the second aim, I will identify the specific mechanisms involved in restoring islet homeostasis after IL-2/CD25 therapy by using immunostaining and single-cell RNA sequencing for markers of stress, proliferation, and dedifferentiation. My proposed study is significant because it will yield new information about how changes in local immune infiltration mediated by IL-2/CD25 affect islet biology. This contribution is significant because it will provide fundamental knowledge that will complete and revise models about immunotherapies for T1D. This study supports the strategic plans of the National Institutes of Health which include advancing opportunities in biomedical research by investing in fundamental science and developing treatments/cures for disease.

项目摘要 1型糖尿病（T1D）是一种毁灭性的自身免疫性疾病，影响超过125万美国人无法治愈。 T1D中靶向自身免疫性的疗法已从广泛的免疫抑制中转移诸如环孢霉素之类的药物，现在专注于增强免疫耐受性。低剂量白介素2（IL-2）在临床前和临床试验中已显示，以诱导调节性TCELLS（TREG）的扩散。促进免疫耐受性并防止产生β细胞的胰岛素自身免疫性破坏。最近，它在临床前模型中已显示IL-2/CD25融合蛋白会诱导Treg和比传统重组IL-2的半衰期更长。关于IL-2及其类似物的研究集中在免疫耐受性的机制及其如何防止β细胞质量的损失。最近的临床发现证明胰岛素分泌在诊断前至少五年受损，而β细胞量仍然是保留的，表明β细胞功能障碍除了β细胞质量的损失外，至关重要 T1D的发病机理。目前尚不清楚IL-2/CD25治疗如何影响β细胞功能障碍。这代表必须解决的知识的关键差距。初步数据表明IL-2/CD25诱导局部免疫浸润的变化，增加了Treg的比例，并减少了比例胰岛的效应T细胞（TEFF）。体外研究表明，促炎性细胞因子被释放通过内质网（ER）的应力渗透TEFF并引起β细胞功能障碍。因此，我假设IL-2/CD25通过防止细胞因子介导的β细胞来延迟T1D的进展功能障碍，不仅是通过避免细胞死亡。我计划在以下特定目的中检验这一假设：1）确定IL-2/CD25治疗方法如何保存胰岛功能和葡萄糖稳态，2）确定IL-如何 2/CD25治疗保护区胰岛组织稳态。在第一个目的下，我将使用一种新颖的方法使用生活胰腺切片以分析IL-2/CD25后胰岛素分泌和细胞内Ca2+动力学的变化治疗。在第二个目标下，我将确定恢复胰岛体内稳态涉及的具体机制通过使用免疫染色和单细胞RNA测序进行应力标记后，IL-2/CD25治疗后，扩散和去分化。我提出的研究很重要，因为它将产生有关的新信息 IL-2/CD25介导的局部免疫浸润的变化如何影响胰岛生物学。这项贡献很重要因为它将提供基本知识，以完成和修改有关免疫疗法的模型 T1D。这项研究支持美国国立卫生研究院的战略计划，包括前进生物医学研究的机会通过投资基础科学并开发治疗方法疾病。