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

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。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Blockade of Rho-associated kinase prevents inhibition of axon regeneration of peripheral nerves induced by anti-ganglioside antibodies.
  • DOI:
    10.4103/1673-5374.382258
  • 发表时间:
    2024-04
  • 期刊:
  • 影响因子:
    6.1
  • 作者:
    Berardo A;Bacaglio CR;Báez BB;Sambuelli R;Sheikh KA;Lopez PHH
  • 通讯作者:
    Lopez PHH
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KAZIM A SHEIKH其他文献

KAZIM A SHEIKH的其他文献

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{{ truncateString('KAZIM A SHEIKH', 18)}}的其他基金

Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury
FcRn 的调节:预防自身抗体介导的神经损伤的策略
  • 批准号:
    8684787
  • 财政年份:
    2014
  • 资助金额:
    $ 42.9万
  • 项目类别:
Modulation of FcRn: A strategy to prevent autoantibody-mediated nerve injury
FcRn 的调节:预防自身抗体介导的神经损伤的策略
  • 批准号:
    8806622
  • 财政年份:
    2014
  • 资助金额:
    $ 42.9万
  • 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
  • 批准号:
    8446439
  • 财政年份:
    2011
  • 资助金额:
    $ 42.9万
  • 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
  • 批准号:
    8245788
  • 财政年份:
    2011
  • 资助金额:
    $ 42.9万
  • 项目类别:
Non-Invasive Imaging to Quantify Peripheral Nerve Injury and Repair in Clinic
无创成像在临床上量化周围神经损伤和修复
  • 批准号:
    8106764
  • 财政年份:
    2011
  • 资助金额:
    $ 42.9万
  • 项目类别:
Biologic Effects of Anti-Ganglioside Antibodies
抗神经节苷脂抗体的生物学效应
  • 批准号:
    8761854
  • 财政年份:
    2007
  • 资助金额:
    $ 42.9万
  • 项目类别:
Biologic effects of anti-ganglisiode antibodies
抗神经节苷脂抗体的生物学效应
  • 批准号:
    7695001
  • 财政年份:
    2007
  • 资助金额:
    $ 42.9万
  • 项目类别:
Biologic effects of anti-ganglisiode antibodies
抗神经节苷脂抗体的生物学效应
  • 批准号:
    7844987
  • 财政年份:
    2007
  • 资助金额:
    $ 42.9万
  • 项目类别:
Biologic Effects of Anti-Ganglioside Antibodies
抗神经节苷脂抗体的生物学效应
  • 批准号:
    8874311
  • 财政年份:
    2007
  • 资助金额:
    $ 42.9万
  • 项目类别:
Biologic effects of anti-ganglisiode antibodies
抗神经节苷脂抗体的生物学效应
  • 批准号:
    7320622
  • 财政年份:
    2007
  • 资助金额:
    $ 42.9万
  • 项目类别:

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