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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：
10493364
负责人：
Yi-Guang Chen
金额：
$ 63.37万
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/10493364
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 Proteins Publishing Regulation Regulatory T-Lymphocyte Role Serum 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 autoreactive B cell 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T1 D中的CD 137-CD 137 L免疫信号传导。这些研究揭示了我们在本申请中提出研究的其他关键机制问题。调控 CD 137-CD 137 L系统是复杂的，主要是因为CD 137和CD 137 L都向细胞内发出信号表达它们，这在任何CD 137和CD 137 L信号传导的分析中必须考虑。在我们初步的数据，我们确定了许多具体的情况下，CD 137或CD 137 L信号的影响不同根据免疫细胞的类型。FOXP 3+调节性CD 4 T细胞（TCF 4），抗原呈递细胞（APCs）和效应T细胞都以不同的动力学表达不同水平的这些关键分子。免疫反应这些细节对于理解该系统中的干预措施至关重要，可溶性CD 137（sCD 137）通过CD 137 L下调免疫，影响病程和进展的T1 D。我们最近发表了用sCD 137治疗，sCD 137在体内主要由T细胞表达，组成性表达CD 137的细胞，可以改善急性T1 D。我们证明sCD 137直接通过与表达在这些细胞上的CD 137 L结合来抑制小鼠CD 4和CD 8 T细胞活化。重要的是，我们最近已经证明，T细胞上的CD 137 L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CD 25 hi CD 127 low T淋巴细胞是CD 127的主要来源。 sCD 137。如在小鼠中一样，hu-sCD 137抑制人外周CD 4 T细胞的增殖。重要的是，我们发现与年龄匹配的无关对照组相比，人类T1 D患者的血清sCD 137较低，我们发现NOD小鼠的血清sCD 137比T1 D同源的NOD小鼠降低，保护性B10衍生Idd9.3间期。此外，我们最近发表了确凿的证据，使用等位基因- 特异性敲除小鼠中，Tnfrsf 9（编码CD 137）是NOD Idd9.3区间内致糖尿病基因。总之，这些结果表明，CD 137的生物学及其与CD 137 L相互作用的后果是，在小鼠和人类T1 D中非常相似。然而，重要的是，在我们对CD 137 L生物学的研究中， (the靶向sCD 137），我们最近发表了T1 D不能转移到缺乏 CD 137 L在骨髓APC上的表达。此外，表达CD 137 L的髓样APC对于 β细胞特异性自身反应性CD 8 T细胞的积累。这些发现凸显了人们日益认识到的先天免疫在自身免疫性T1 D的启动和持续中的作用，以及对额外免疫的需要。 CD 137 L对骨髓APC的机制研究，骨髓APC是T细胞进入胰岛的关键守门人。给定根据这些发现，我们提出了以下目标。目的1：CD 137阳性Treg亚群抑制免疫激活目的2：表达CD 137 L的髓样APC在T1 D中的机制作用发病机制和作为sCD 137的治疗效果的靶点。目的3：使用新的人和小鼠可溶性 CD 137-Fc蛋白，以测试在人源化小鼠模型中以及对人单核细胞和T细胞的功效。