COSTIMULATORY MOLECULES IN INFLAMMATORY LUNG DISEASE

炎症性肺病中的协同刺激分子

基本信息

批准号：
8669032
负责人：
Jonathan M. Green
金额：
$ 37.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8669032
关键词：
1-Phosphatidylinositol 3-Kinase Acute Allergic Antibody Formation Asthma B-Lymphocytes Binding Biochemical CD28 gene CD80 gene Cell physiology Clinical Clinical Trials Collaborations Controlled Study Critical Pathways Cytoplasmic Tail Data Development Disease Distal Effector Cell Elements Event Family Gene Targeting Generations Goals Homing Immune Immune response Immune system Immunity In Vitro Infection Inflammation Inflammatory Inflammatory Response Ligands Lung Inflammation Lung diseases Macrophage Activation Mediating Molecular Mus Mutation Myelogenous NOS2A gene Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Phase Phosphotransferases Play Process Production Proline Proteins Regulation Resolution Role STAT1 gene Signal Pathway Signal Transduction Stimulus Suppressor-Effector T-Lymphocytes System T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte Therapeutic Time Tyrosine Work allergic airway inflammation base cytokine design fighting human NOS2A protein in vivo inhibitor/antagonist macrophage member migration mutant novel novel therapeutics prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): T cell responses are highly regulated to assure appropriate and effective responses to infectious and inflammatory stimuli. A key component of this is the B7:CD28 receptor family, consisting of activating (CD28 and ICOS) and inhibitory (CTLA-4, PD-1 and BTLA) members and their ligands (B7 proteins). These receptors play a critical role in regulating lung inflammation by determining whether an immune response is initiated, and once initiated, its resolution. The goal of the studies proposed in this application is to define novel mechanisms by which the B7:CD28 family regulates the initiation and resolution of lung inflammation, and determine how this can be manipulated to therapeutic advantage. To study the molecular mechanisms controlling the initiation of inflammation, we developed gene targeted CD28-mutant knockin mice. Using these we established which signaling motifs mediate specific in vitro and in vivo CD28-dependent functions. In contrast to the prevailing dogma that PI3 kinase signaling initiated by the proximal tyrosine (Y170) motif is the critical pathway activated by CD28, we demonstrated that it is in fact dispensable for CD28 function. However, we showed that the distal proline (PYAP) motif initiated a non- redundant signaling pathway required for normal CD28-dependent responses. Despite mutation of this motif, some function remains the biochemical basis for which is unknown. Therefore, we hypothesize that novel pathways activated independent of the distal proline motif regulate CD28-dependent T cell proliferation and cytokine secretion. We further found that signaling initiated by the distal proline motif is essential for T cell: B cell collaboration and T-dependent antibody production. The signaling pathways that mediate these responses will be determined in specific aim 1 of this proposal. Ongoing inflammation can be inhibited by therapeutic manipulation of the B7:CD28 pathway using the recently approved drug CTLA4Ig, (abatacept, OrenciaTM). This drug binds to B7-1 (CD80) and B7-2 (CD86), and has been presumed to function by preventing CD28 engagement on the T cell, thereby preventing a CD28-mediated signal to the T cell. While this mechanism is true for initial T cell activation, we have established that in fact CTLA4Ig inhibits effector responses by a novel CD28-independent, inducible nitric oxide synthase (NOS2)-dependent mechanism. We further show that IFN3/STAT1 signaling is central in this response. We hypothesize that B7 engagement by CTLA4Ig induces INF3 dependent activation of macrophages or myeloid derived suppressor cells (MDSCs), and that these inhibit allergic lung inflammation by a NOS2-dependent mechanism. In this application, we propose cellular, molecular and in vivo studies to determine the mechanism of the novel mode of action for CTLA4Ig., which may have broad applicability to therapeutic manipulation of inflammatory lung disease

描述（由申请人提供）：T细胞反应受到高度调节，以确保对感染性和炎症性刺激的适当有效反应。其中的一个关键组成部分是B7：CD28受体家族，由激活（CD28和ICOS）和抑制（CTLA-4，PD-1和BTLA）成员及其配体（B7蛋白）组成。这些受体通过确定是否启动免疫反应并启动其解决方案来调节肺部炎症。本应用中提出的研究的目的是定义新的机制，通过该机制，B7：CD28家族调节肺部炎症的起始和分辨率，并确定如何将其操纵以进行治疗优势。为了研究控制炎症起始的分子机制，我们开发了靶向基因CD28突变敲蛋白小鼠。使用这些，我们确定了哪些信号基序在体外和体内CD28依赖性函数中介导了特异性。与近端酪氨酸（Y170）基序引发的PI3激酶信号传导的普遍教条相反，CD28激活的临界途径，我们证明了它实际上对于CD28功能是可分配的。但是，我们表明远端脯氨酸（PYAP）基序启动了正常CD28依赖性响应所需的非冗余信号通路。尽管存在突变，但某些功能仍然是未知的生化基础。因此，我们假设这种新型途径与远端脯氨酸基序一起激活，调节CD28依赖性T细胞增殖和细胞因子分泌。我们进一步发现，远端脯氨酸基序引发的信号对于T细胞至关重要：B细胞协作和T依赖性抗体的产生。介导这些响应的信号通路将在本提案的特定目的1中确定。使用最近批准的药物CTLA4IG（Abatacept，Orenciatm）对B7：CD28途径的治疗操作可以抑制持续的炎症。该药物与B7-1（CD80）和B7-2（CD86）结合，并被认为是通过防止CD28在T细胞上参与的功能，从而阻止了CD28介导的信号对T细胞。尽管这种机制对于初始T细胞激活是正确的，但我们已经确定CTLA4IG实际上通过新型CD28独立的，可诱导的一氧化氮合酶（NOS2）依赖性机制抑制了效应子响应。我们进一步表明，IFN3/STAT1信号在此响应中是核心。我们假设CTLA4IG的B7参与会诱导INF3依赖性巨噬细胞或髓样衍生的抑制细胞（MDSC）的激活，并且这些抑制了NOS2依赖性机制。在此应用中，我们提出了细胞，分子和体内研究，以确定CTLA4IG的新型作用方式的机制，该方法可能对炎性肺部疾病的治疗操作具有广泛的适用性