Mechanistic and therapeutic role of the CD137-CD137L axis in Type 1 Diabetes

CD137-CD137L 轴在 1 型糖尿病中的机制和治疗作用

基本信息

批准号：
10650406
负责人：
Yi-Guang Chen
金额：
$ 63.49万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-21 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650406
关键词：
Acute Address Affect Age Alleles Antigen-Presenting Cells Attention Autoimmune Beta Cell Binding Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell physiology Cells Complex Congenic Mice Data Down-Regulation FOXP3 gene FRAP1 gene Gatekeeping Genes Grant Half-Life Homeostasis Human Immune Immune response Immune signaling Immunity Immunosuppressive Agents In Vitro Inbred NOD Mice Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Intervention Investigation Kinetics Knockout Mice Mediating Modeling Mus Myelogenous Natural Immunity Pathogenicity Pathway interactions Patients Peripheral Phenotype Production Progress Reports Proliferating Proteins Publishing Regulation Regulatory T-Lymphocyte Role Serum Signal Induction Signal Pathway Signal Transduction Source Structure of beta Cell of islet Surface System T cell anergy T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Effect Translating Work adaptive immunity autoimmune pathogenesis autoreactivity conditional knockout cytokine diabetes mellitus therapy diabetes pathogenesis diabetogenic effector T cell efficacy testing humanized mouse immune activation improved in vivo in vivo Model islet monocyte mouse model non-diabetic novel novel therapeutic intervention single-cell RNA sequencing targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY Our labs have been extensively studying CD137-CD137L immune signaling in T1D. These studies have uncovered additional critical mechanistic issues which we propose to study in this application. The regulation of the CD137-CD137L system is complex, mainly because both CD137 and CD137L signal into the cells expressing them, which must be taken into account in any analysis of CD137 and CD137L signaling. In our preliminary data we identify many specific instances in which the effect of CD137 or CD137L signaling differs according to the type of immune cells. FOXP3+ regulatory CD4 T cells (Tregs), antigen-presenting cells (APCs), and effector T cells all express different levels of these key molecules with distinct kinetics during the immune response. The details are critical for understanding how interventions in this system, most specifically with soluble CD137 (sCD137) which down-regulates immunity via CD137L, affect the course and progression of T1D. We have recently published that treatment with sCD137, which is expressed in vivo mainly by Tregs that constitutively express CD137, can ameliorate acute T1D. We demonstrate that sCD137 directly suppresses mouse CD4 and CD8 T cell activation through binding to CD137L expressed on these cells. Critically, we have recently proven that CD137L expression on T cells is critical for Treg mediated suppression. Similar to our findings in mice, we found that human CD25hi CD127low Tregs are the primary source of sCD137. As in mice, hu-sCD137 inhibited proliferation of human peripheral CD4 T cells. Importantly, we found that serum sCD137 was lower in human T1D patients compared to age-matched unrelated controls, analogous to our finding that serum sCD137 is decreased in NOD mice compared to NOD mice congenic for the T1D protective B10-derived Idd9.3 interval. In addition, we have recently published conclusive proof, using allele- specific knockout mice, that Tnfrsf9 (encoding CD137) is the diabetogenic gene in the NOD Idd9.3 interval. Overall, these results indicate that the biology of CD137 and the consequence of its interaction with CD137L are very similar in mouse and human T1D. Importantly, however, in our investigation of the biology of CD137L (the target of sCD137), we have recently published that T1D could not be transferred into mice lacking expression of CD137L on myeloid APCs. Moreover, CD137L expressing myeloid APCs are essential for accumulation of β-cell specific autoreactive CD8 T cells. These findings highlight the increasingly recognized role of innate immunity in the initiation and perpetuation of autoimmune T1D, and the need for additional mechanistic studies of CD137L on myeloid APCs, the critical gatekeeper for T cell entry into the islet. Given these findings we propose the following aims. Aim 1: Mechanism by which the CD137-positive Treg subset suppresses immune activation. Aim 2: Mechanistic role of CD137L-expressing myeloid APCs in T1D pathogenesis and as a target for therapeutic effect of sCD137. Aim 3: Use novel human and mouse soluble CD137-Fc proteins to test efficacy in humanized mouse models and on human monocytes and T cells.

项目摘要我们的实验室一直在广泛研究T1D中的CD137-CD137L免疫信号传导。这些研究有发现了我们建议在此应用中研究的其他关键机理问题。调节 CD137-CD137L系统很复杂，主要是因为CD137和CD137L信号都进入细胞表达它们，在CD137和CD137L信号传导的任何分析中都必须考虑到它们。在我们的初步数据我们确定了许多特定实例，其中CD137或CD137L信号的影响不同 FOXP3+调节性CD4 T细胞（Tregs），抗原呈递细胞（APC）和效应T细胞均表达不同水平的这些关键分子，在该过程中具有独特的动力学免疫反应。细节对于了解该系统中的干预措施（最具体地说是）至关重要与固体CD137（SCD137），通过CD137L下调免疫力，会影响过程和进展 T1D。我们最近发表了对SCD137的治疗，该治疗主要由Tregs表示组成型表达CD137可以改善急性T1D。我们证明了SCD137直接通过在这些细胞上表达的CD137L结合来抑制小鼠CD4和CD8 T细胞激活。至关重要的是，我们最近证明，T细胞上的CD137L表达对于Treg介导的抑制至关重要。与我们在小鼠中的发现相似，我们发现人CD25HI CD127LOW Tregs是主要来源 SCD137。与小鼠一样，HU-SCD137抑制了人外周CD4 T细胞的增殖。重要的是，我们发现与年龄匹配的无关对照相比，人类T1D患者的血清SCD137较低我们发现，与T1D相比的NOD小鼠相比，NOD小鼠的血清SCD137降低了保护性B10衍生的IDD9.3间隔。此外，我们最近使用等位基因发表了确凿的证据。特定的基因敲除小鼠，TNFRSF9（编码CD137）是点头IDD9.3间隔中的糖尿病基因。总体而言，这些结果表明CD137的生物学及其与CD137L相互作用的结果在小鼠和人类T1D中非常相似。但是，重要的是，在我们研究CD137L的生物学时（SCD137的目标），我们最近发布了T1D无法转移到缺乏的小鼠中 CD137L在髓样APC上的表达。此外，表达髓样APC的CD137L对于 β细胞特异性自动反应性CD8 T细胞的积累。这些发现突出了越来越明显的先天免疫在自动免疫T1D的主动性和永久性中的作用，以及需要额外的 CD137L在髓样APC上的机械研究，这是T细胞进入胰岛的关键网守。给出这些发现我们提出了以下目标。 AIM 1：CD137阳性Treg子集的机制抑制免疫激活。 AIM 2：T1D中表达CD137L的髓样APC的机械作用发病机理和SCD137治疗作用的靶标。目标3：使用新颖的人和老鼠可溶性 CD137-FC蛋白在人源性小鼠模型以及人类单核细胞和T细胞中测试效率。