Role of Innate Lymphoid Cells in Autoimmunity

先天淋巴细胞在自身免疫中的作用

基本信息

批准号：
8637675
负责人：
JEFFREY A BLUESTONE
金额：
$ 23.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637675
关键词：
Accounting Address Adoptive Transfer Adverse effects Affect Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Backcrossings Beta Cell Biological Categories Cell Death Cells Cellular Structures Chronic Chronic Disease Clinical Coculture Techniques Combined Modality Therapy Data Dendritic Cells Development Diabetes Mellitus Disease Dose Eosinophilia Eragrostis Family Functional disorder Health Helper-Inducer T-Lymphocyte Homeostasis Human IL2RA gene Immune Immune response Immune system Immunity Immunotherapy In Vitro Inbred NOD Mice Incidence Infection Infiltration Inflammation Insulin Insulin-Dependent Diabetes Mellitus Interleukin 2 Receptor Gamma Interleukin-13 Interleukin-17 Interleukin-2 Interleukin-5 Islets of Langerhans Lymphoid Lymphoid Cell Measures Modeling Morphology Mus Natural Killer Cells Non obese Pancreas Pathogenesis Pathway interactions Patients Phase I Clinical Trials Phenotype Play Population Production Property Regulation Regulatory T-Lymphocyte Reporter Reporting Research Personnel Role Self Tolerance Signal Transduction Sirolimus Site Staging T-Lymphocyte Therapeutic Time Tissues Work autoreactive T cell clinical effect cytokine diabetic eosinophil improved in vivo innovation insulin dependent diabetes mellitus onset interleukin-22 islet monocyte mouse model new therapeutic target novel pathogenic bacteria public health relevance receptor research study response safety testing therapy design

项目摘要

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disease resulting in the destruction of pancreatic islet insulin- producing beta cells. T1D is mainly drive by autoreactive T cells but components of the innate immune system have been implicated as well, including monocytes, dendritic cells and natural killer (NK) cells. NK cells belong to the innate lymphoid cell (ILC) family, which consists in innate cells that share a lymphoid morphology and other properties. Novel populations of ILCs have been defined recently and ILCs are now subdivided in three main categories: ILC1 cells (NK cells); ILC2 cells (IL-13- and IL-5-producing GATA-3+ innate helper cells, and ILC3 cells (RORγt+ ILCs, which include distinct subsets of IL-22- and/or IL-17-producing ILCs). Functionally, ILC2s and ILC3s are involved in protective immunity against infections but they can also induce or control chronic inflammation depending on the circumstances. Importantly, the role of ILCs in autoimmunity is largely unknown. Thus, in this proposal we will address the overall hypothesis that ILC populations play a critical role in the development and progression of autoimmune diabetes. We will take advantage of innovative mouse models that include reporter mice allowing the identification and deletion of RORγt+ ILC3s and IL-5/13-producing ILC2 cells selectively. Most significantly, we observe that ILCs are the first cells found in the pancreas of T1D-susceptible non-obese diabetic (NOD) mice suggesting a potential role in disease initiation. Finally, we will address another key hypothesis, namely, that ILC2 cells, present in tissues, including the pancreas, are critically involved in the negative side effects of IL-2 therapies designed to promote regulatory T cells (Tregs). Recent studies to test the safety of IL-2 therapy in new-onset T1D patients have validated mouse work demonstrating increased numbers of Tregs..However, in some instances, the treatment resulted in transient β cell dysfunction, increased Th17 cells and eosinophilia. Importantly, our preliminary studies suggest that ILC2s present in the pancreas of NOD mice respond to IL-2 treatment and may be responsible for some of these unwanted effects. In this R21 Revised application we propose the following specific aims to address these hypotheses. 1) To characterize the ILC2 and ILC3 subsets in the NOD mouse; 2) To determine the functional effect of ILC2s on the development and regulation of autoimmune diabetes; and 3) To examine the effect of IL-2 therapy on ILC2s and the role of ILC2s in the biological and clinical effect of IL-2 therapy. These studies will characterize novel ILC subsets i the pancreas during diabetes and identify their influence on disease. To our knowledge, this will be the first characterization of ILC2s and RORγt+ ILC3s in autoimmune diabetes. The results of our study may shift the current T1D dogma from a T cell-centric paradigm to one that includes an involvement of ILCs. Additionally, our studies could have important clinical implications by identifying novel therapeutic targets in T1D and allowing better a prediction of "off-target" effecs of therapy directed at pathways shared by ILCs and T cells.

描述（由适用提供）：1型糖尿病（T1D）是一种自身免疫性疾病，导致胰岛胰岛素产生β细胞的破坏。 T1D主要由自动反应性T细胞驱动，但也已经实施了先天免疫系统的组成部分，包括单核细胞，树突状细胞和天然杀伤（NK）细胞。 NK细胞属于先天淋巴样细胞（ILC）家族，该家族由具有淋巴样形态和其他特性的先天细胞组成。最近已经定义了新的ILC人群，并且ILC现在细分为三个主要类别：ILC1细胞（NK细胞）； ILC2 cells (IL-13- and IL-5-producing GATA-3+ innate helper cells, and ILC3 cells (RORγt+ ILCs, which include distinct subsets of IL-22- and/or IL-17-producing ILCs). Functionally, ILC2s and ILC3s are involved in protected immunology against infections but they can also induce or control chronic infection depending on重要的是，ILC在自身免疫中的作用很大程度上是未知的。 ILC2细胞最重要的是，我们观察到ILC是在T1D可抑制的非肥胖糖尿病（NOD）小鼠的胰腺中发现的第一个细胞，这表明在疾病倡议中可能存在潜在的作用。调节性T细胞（Tregs）。在新发行T1D患者中测试IL-2治疗安全性的最新研究已经验证了小鼠的工作，证明了Treg的数量增加。.在某些情况下，该治疗导致短暂的β细胞功能障碍，TH17细胞和嗜酸性粒细胞增长。重要的是，我们的初步研究表明，NOD小鼠胰腺中存在的ILC2对IL-2治疗做出了反应，并可能导致其中一些不良影响。 R21修订的应用程序我们提出了以下特定目的旨在解决这些假设。 1）表征点小鼠中的ILC2和ILC3子集； 2）确定ILC2对自身免疫性糖尿病的发育和调节的功能作用； 3）检查IL-2治疗对ILC2的影响以及ILC2在IL-2治疗的生物学和临床效应中的作用。这些研究将表征糖尿病期间新型ILC子集I胰腺，并确定其对疾病的影响。据我们所知，这将是自身免疫性糖尿病中ILC2S和RORγT+ ILC3的首次表征。我们的研究结果可能会将当前的T1D教条从以T细胞为中心的范式转移到包括ILC参与的范例。此外，我们的研究可以通过鉴定T1D中的新型治疗靶标，并可以更好地预测针对ILCS和T细胞共享途径的“脱靶”效率来具有重要的临床意义。