Therapeutic Intervention of the JAK/STAT Pathway for Neuroinflammation

JAK/STAT 通路对神经炎症的治疗干预

• 批准号: 8630636
• 负责人: Etty N Benveniste
• 金额: $ 32.15万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630636
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Attenuated; Autoimmune Process; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CNS autoimmunity; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Clinical; Cytokine Signaling; Data; Demyelinations; Development; Disease; Documentation; Employee Strikes; Experimental Autoimmune Encephalomyelitis; Foundations; Funding; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune; Immune response; Immune system; Immunization; Infiltration; Inflammation; Inflammatory Infiltrate; Interferons; Interleukin-12; Interleukin-6; Intervention; JAK1 gene; JAK2 gene; Janus kinase; Lead; Lesion; Microglia; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Myeloid Cells; Neurologic Dysfunctions; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Production; Property; Regulation; Regulatory T-Lymphocyte; Relapse; Research Project Grants; Role; STAT protein; Severities; Severity of illness; Signal Pathway; Signal Transduction; Spinal Cord; Symptoms; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Th1/Th2 Differentiation Pathway; Therapeutic; Therapeutic Intervention; Time; Transcriptional Activation; Translational Research; Treatment Efficacy; arm; autoreactive T cell; base; cell type; chemokine; clinical efficacy; clinically relevant; cytokine; design; human disease; immunoregulation; in vivo; inhibitor/antagonist; interleukin-23; kinase inhibitor; macrophage; neuroinflammation; novel therapeutics; pre-clinical; prevent; programs; public health relevance; response; trafficking; translational study; treatment strategy

PROJECT SUMMARY/ABSTRACT Multiple Sclerosis (MS) is characterized by focal inflammatory infiltrates of the CNS, demyelinating lesions and axonal damage, leading to neurologic dysfunction. Cells of the innate and adaptive immune system are involved in MS pathogenesis. MS is also characterized by production of cytokines that activate immune cells, including IFN-¿, IL-6, GM-CSF, IL-12 and IL-23. The JAK/STAT pathway is used by cytokines for signaling, and is critical for the development, regulation and termination of immune responses. In the previous funding period, we developed a model of Experimental Autoimmune Encephalomyelitis (EAE) in which the JAK/STAT pathway is aberrantly activated in myeloid cells, with functional consequences for Th1 and Th17 cell differentiation. This model presents as a non-resolving form of atypical EAE. In this atypical model with heightened activation of the JAK/STAT pathway, we demonstrate that AZD1480, an inhibitor of the JAK/STAT pathway, suppresses disease severity, prevents entry of immune cells into the CNS, suppresses differentiation of Th1 and Th17 cells, decreases STAT activation, and reduces expression of cytokines/chemokines. Furthermore, we have tested AZD1480 in four other EAE models (Classical, Relapsing-Remitting (RR), Adoptive Transfer of Th1 or Th17 cells) and observed striking clinical efficacy. Another JAK/STAT inhibitor, AZD5776, also inhibits EAE clinical symptoms. We hypothesize that inappropriate activation of the JAK/STAT pathway promotes aberrant responses of cells of the innate and adaptive immune systems, leading to the neuroinflammation seen in MS, and that therapeutic intervention of this pathway will alter the progression of MS. In this revised, competing renewal, we will evaluate two distinct JAK inhibitors, AZD1480 and AZD5776, in five EAE models. AZD1480 is a JAK1 and JAK2 inhibitor, and AZD5776 inhibits JAK1. In Aim 1, the therapeutic efficacy of targeting the JAK/STAT pathway in active EAE (classical, atypical, RR) will be examined. We will evaluate 1) which JAKs/STATs are involved in disease pathogenesis; 2) in which cell type(s) (CD4+ T-cells, macrophages, microglia, DCs) activation of the JAK/STAT pathway is detrimental; and 3) the molecular basis for the therapeutic benefit of the JAK inhibitors. In Aim 2, the role of the JAK/STAT pathway in regulating the pathogenic potential of Th1 and Th17 cells will be tested. Both Th1 and Th17 cells have the capacity to induce CNS autoimmunity, but have differential pathogenic mechanisms. Our preliminary results indicate that AZD1480 is effective in inhibiting both Th1-induced and Th17-induced EAE. We will assess how in vivo treatment with AZD1480/AZD5776 in the context of MOG-immunization regulates the developmental program and/or pathogenicity of Th1 and Th17 cells. In Aim 3, the mechanism by which the JAK inhibitors AZD1480 and AZD5776 regulate immune cell function will be examined. Macrophages and DCs obtained from na¿ve mice treated with JAK inhibitors will be evaluated for their antigen presentation capability, polarization into proinflammatory or anti-inflammatory phenotypes, and potential neuroprotective properties. CD4+ T-cells derived from JAK inhibitor treated mice will be examined for their subsequent ability to differentiate into pathogenic and/or protective T-cell subsets. These studies will establish the pre-clinical foundation necessary to ultimately test inhibitors of the JAK/STAT pathway in human MS.

项目总结/摘要 多发性硬化（MS）的特征在于CNS的局灶性炎性浸润、脱髓鞘病变和轴突损伤。 损伤导致神经功能障碍先天性和适应性免疫系统的细胞参与MS 发病机制MS的特征还在于产生激活免疫细胞的细胞因子，包括IFN-γ，IL-6，GM-CSF， IL-12和IL-23。JAK/STAT信号通路是细胞因子信号转导的重要途径，对细胞因子的发育、调控和调节起着关键作用。 和免疫反应的终止。在上一个资助期，我们开发了一个实验性自身免疫模型， 脑脊髓炎（EAE），其中JAK/STAT通路在髓样细胞中异常激活，具有功能性 Th 1和Th 17细胞分化的结果。该模型表现为非典型EAE的非消退形式。在这 在JAK/STAT通路激活增强的非典型模型中，我们证明了AZD 1480，一种JAK/STAT通路抑制剂， JAK/STAT途径，抑制疾病严重程度，阻止免疫细胞进入CNS，抑制分化 Th 1和Th 17细胞，降低STAT活化，并降低细胞因子/趋化因子的表达。而且我们 我在其他四种EAE模型（经典、复发缓解（RR）、Th 1或Th 17的连续转移）中测试了AZD 1480 细胞），并观察到显著的临床疗效。另一种JAK/STAT抑制剂AZD 5776也可抑制EAE临床症状。 我们假设JAK/STAT通路的不适当激活促进了细胞的异常反应， 先天性和适应性免疫系统，导致MS中观察到的神经炎症， 干预这一途径将改变MS的进展。在这一修订，竞争性更新，我们将评估两个 不同的JAK抑制剂AZD 1480和AZD 5776在五种EAE模型中的作用。AZD 1480是JAK 1和JAK 2抑制剂，AZD 5776 抑制JAK 1。在目的1中，靶向JAK/STAT途径在活动性EAE（经典的，非典型的， RR）将进行检查。我们将评估1）哪些JAK/STAT参与疾病发病机制; 2）哪些细胞类型 (CD4+ T细胞、巨噬细胞、小胶质细胞、DC）JAK/STAT途径的激活是有害的;和3）分子基础 JAK抑制剂的治疗效果。在目的2中，JAK/STAT通路在调节细胞凋亡中的作用被证实。 将测试Th 1和Th 17细胞的致病潜力。Th 1和Th 17细胞都具有诱导CNS的能力 自身免疫，但有不同的致病机制。我们的初步结果表明，AZD 1480是有效的， 抑制Th 1诱导和Th 17诱导的EAE。我们将评估AZD 1480/AZD 5776的体内治疗如何在 MOG免疫的背景调节Th 1和Th 17细胞的发育程序和/或致病性。在目标3中， JAK抑制剂AZD 1480和AZD 5776调节免疫细胞功能的机制将是 考察将评价从用JAK抑制剂处理的未处理小鼠获得的巨噬细胞和DC的抗原 呈现能力，极化为促炎或抗炎表型，以及潜在的神经保护作用。 特性.将检查源自JAK抑制剂处理的小鼠的CD 4 + T细胞随后的分化能力 转化为致病性和/或保护性T细胞亚群。这些研究将建立必要的临床前基础 最终测试人MS中JAK/STAT通路的抑制剂。