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Blockade of colony stimulating factor 1 receptor to reduce inflammatory nerve injury

阻断集落刺激因子 1 受体以减少炎症神经损伤

基本信息

批准号：
10195632
负责人：
KAZIM A SHEIKH
金额：
$ 42.9万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195632
关键词：
Acute Adhesions Affinity Animal Model Antibodies Antigens Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Axon Behavior Binding Cell Lineage Cell physiology Cells Chemotaxis Chronic Inflammatory Demyelinating Polyradiculoneuropathy Clinical Trials Colony-Stimulating Factors Development Disease Electrophysiology (science)Elements Gangliosides Glycolipids Guillain Barré Syndrome Human Immune Immunological Models Immunotherapy Inflammation Inflammatory Injury Innate Immune System Integrins Intravenous Immunoglobulins Knockout Mice Left Ligands Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Malignant Neoplasms Mediating Modality Modeling Monoclonal Antibodies Mus Myelin Myelinated nerve fiber Nature Nerve Nerve Fibers Neurologic Neuropathy Outcome Paralysed Pathogenesis Pathologic Patients Peripheral Peripheral Nerves Pharmaceutical Preparations Pharmacology Phase Phosphotransferases Play Poliomyelitis Polyneuropathy Polysaccharides Population Publishing Recovery Regulation Resistance Role Schwann Cells Signal Pathway Signal Transduction Specificity T cell response T-Lymphocyte Testing Therapeutic Tissues Variant Walking animal data autoreactive T cell axon injury base cell motility efficacy evaluation experimental study immunomodulatory therapies ineffective therapies inhibitor/antagonist innate immune pathways macrophage migration monocyte morphometry nerve injury neutralizing antibody novel therapeutics receptor recruit response small molecule inhibitor synergism therapeutic target treatment strategy

项目摘要

ABSTRACT With the near-eradication of polio, Guillain-Barré syndrome (GBS) has become the most frequent cause of acute flaccid paralysis. There are two major forms of GBS, demyelinating and axonal, based on the primary injury to myelin/Schwann cells or axon of the myelinated nerve fibers, respectively. Current immunomodulatory treatments are only effective in a proportion of patients. For example IVIG–a first line treatment modality in GBS–hasten recovery in only ~50% of those treated with this medication. Despite availability of current of immunotherapies, a significant proportion of patients are left with severe and permanent neurologic sequelae, including inability to walk independently. There is a dire need for newer/additional immune treatments that can target relevant pathophysiologic mechanisms and limit the neural injury in acute phase of the disease. Cellular inflammatory effectors are invoked to play major role in the pathogenesis of demyelinating GBS, whereas autoantibodies against gangliosides/glycolipids are involved in the pathogenesis of axonal GBS. Human pathologic studies and data from animal modelling indicate that macrophage lineage cells are final executioner of nerve injury in demyelinating and axonal GBS. Colony stimulating factor 1 receptor (CSF1R) plays critical role in proliferation, survival and function of monocytes and fully differentiated macrophages including transmigration in response to its ligand(s). We hypothesize that blockade of this receptor on macrophage lineage cells can alter the proinflammatory state of these cells and reduce inflammatory nerve injury. This hypothesis will be tested by the following specific aims: Aim 1 will examine the efficacy of CSF1R blockade (with a neutralizing antibody and small molecule inhibitor) in anti-ganglioside antibody-mediated model of axonal GBS. Aim 2 will examine the efficacy of CSF1R blockade (with a neutralizing antibody and small molecule inhibitor) in a T-lymphocyte orchestrated animal model of inflammatory demyelinating neuropathy. CSF1R blocking stratgies in this project are translatable as the small molecuel inhibitor proposed for these studies is already in a clinical trial and a number of monoclonal CSF1R neutralizing antibodies are in clinincal development for cancer. This project may help in developing a new treatment strategy that has relevance not only to GBS but other immune neuropathies including CIDP.

摘要随着脊髓灰质炎的几乎根除，格林-巴利综合征（GBS）已成为最常见的脊髓灰质炎病因。急性弛缓性麻痹GBS有两种主要形式，脱髓鞘和轴突，基于原发性分别损伤髓鞘/雪旺细胞或有髓鞘神经纤维的轴突。当前免疫调节治疗仅对一部分患者有效。例如，IVIG-- GBS-加速恢复只有~50%的人用这种药物治疗。尽管目前免疫疗法，一个显着比例的患者留下严重的和永久性的神经后遗症，包括无法独立行走迫切需要更新/额外的免疫治疗，靶向相关的病理生理机制并限制疾病急性期的神经损伤。蜂窝炎症效应物在脱髓鞘GBS的发病机制中起主要作用，而抗神经节苷脂/糖脂的自身抗体参与轴突GBS的发病机制。人类病理学研究和动物模型数据表明巨噬细胞系细胞是最终的执行者脱髓鞘和轴突型GBS的神经损伤。集落刺激因子1受体（CSF 1 R）在细胞增殖中起着关键作用。在单核细胞和完全分化的巨噬细胞的增殖、生存和功能中的作用，包括在其配体的反应中的迁移。我们推测，阻断巨噬细胞上的这种受体，谱系细胞可以改变这些细胞的促炎状态并减少炎性神经损伤。这将通过以下具体目的检验假设：目的1将检查CSF 1 R阻断的功效 (with中和抗体和小分子抑制剂）在抗神经节苷脂抗体介导的轴突GBS。目的2将检查CSF 1 R阻断的功效（用中和抗体和小剂量的CSF 1 R阻断剂）。分子抑制剂）在炎性脱髓鞘性神经病的T淋巴细胞协调的动物模型中的作用。本项目中的CSF 1 R阻断策略可翻译为针对这些疾病提出的小分子抑制剂。研究已经在临床试验中，许多单克隆CSF 1 R中和抗体正在临床试验中。癌症的发展。该项目可能有助于开发一种新的治疗策略，仅对GBS，但对包括CIDP的其他免疫性神经病。