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

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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