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Alpha M Beta 2 integrin blockade for acute inflammatory neuropathies

Alpha M Beta 2 整合素阻断治疗急性炎症性神经病

基本信息

批准号：
8812344
负责人：
Eroboghene Ekamereno Ubogu
金额：
$ 13.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8812344
关键词：
Alpha Beta integrin blockade acute

项目摘要

DESCRIPTION (provided by applicant): Our objective is to evaluate whether inhibition of alpha M beta2integrin-dependent leukocyte infiltration into peripheral nerves is a specific therapy for acute peripheral nerve inflammation seen in immune-mediated disorders and neuropathic pain. Using acute inflammatory demyelinating polyradiculoneuropathy (AIDP; the most common variant of Guillain-Barr¿ syndrome [GBS]) as an example of acute severe peripheral nerve inflammation, we propose to address a fundamental question: Is blockade of ¿M integrin (CD11b) a potential treatment strategy for acute peripheral neuritis? Based on our exciting new preliminary data using in vitro and in vivo approaches, we propose the following hypothesis: ¿M¿2 integrin expressed on activated hematogenous monocytes and lymphocytes and ICAM-1 expressed on activated endoneurial endothelial cells interact and recruit pathogenic mononuclear leukocytes across the blood-nerve barrier in AIDP. As an extension of this, we propose that competitive inhibition with an ¿M integrin monoclonal antibody would reduce pathogenic leukocyte trafficking at the blood-nerve barrier. Reduction in leukocyte infiltration ino peripheral nerves would limit the harmful consequences of severe peripheral nerve inflammation, demyelination and axonal injury in GBS. This strategy provides an opportunity to develop a novel targeted therapy for AIDP and neuropathic pain. In order to address this hypothesis, we will determine that a function neutralizing monoclonal antibody against human ¿M integrin reduces trafficking of untreated AIDP patient peripheral blood mononuclear leukocytes on a novel cytokine-stimulated human in vitro blood-nerve barrier model that incorporates capillary flow rates. Trafficking events would be captured in real-time and quantified by video microscopy. We will also evaluate the effect of ¿M integrin blockade on the behavioral, electrophysiological and histopathological features of acute peripheral nerve inflammation, demyelination and axonal injury in a severe, reliable GBS mouse model, using our published methods. Current therapies for GBS and other peripheral nerve inflammatory disorders, as well neuropathic pain are non-specific and partly effective. This proposal is a preclinical evaluation of ¿M integrin antagonism as a targeted anti-inflammatory therapy for AIDP. Inhibiting disease-specific inflammatory pathways has the potential to revolutionize the treatment of acute, severe peripheral nerve inflammation. The proposed work could lead towards the development of novel monoclonal antibody therapies for phase I clinical trials in AIDP and other inflammatory neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (an under-recognized neuropathy that may account for 14% of disabling neuropathies in patients over 65 years of age), as well as neuropathic pain.

描述（由申请人提供）：我们的目的是评估抑制α M β 2整合素依赖的白细胞浸润周围神经是否是免疫介导疾病和神经性疼痛中出现的急性周围神经炎症的特异性治疗。以急性炎症性脱髓鞘性多根神经病变（AIDP，吉兰-巴尔综合征[GBS]的最常见变体）为例，我们提出解决一个基本问题：阻断M整合素（CD11b）是急性周围神经炎的潜在治疗策略吗？基于我们使用体外和体内方法的令人兴奋的新初步数据，我们提出以下假设：活化的造血单核细胞和淋巴细胞上表达的¿M¿2整合素和活化的神经内皮细胞上表达的ICAM-1相互作用，并在AIDP中通过血神经屏障招募致病性单核白细胞。作为这一研究的延伸，我们提出用一种¿M整合素单克隆抗体进行竞争性抑制可以减少血神经屏障处的致病性白细胞运输。减少外周神经中白细胞的浸润将限制GBS严重外周神经炎症、脱髓鞘和轴索损伤的有害后果。这一策略为开发AIDP和神经性疼痛的新型靶向治疗提供了机会。为了解决这一假设，我们将确定一种针对人¿M整合素的功能中和单克隆抗体，在一种新的细胞因子刺激的人体外血液-神经屏障模型上，结合毛细血管流速，可以减少未经治疗的AIDP患者外周血单核白细胞的运输。贩运事件将通过视频显微镜实时捕获和量化。我们还将使用我们已发表的方法，在严重、可靠的GBS小鼠模型中评估¿M整合素阻断剂对急性周围神经炎症、脱髓鞘和轴索损伤的行为、电生理和组织病理学特征的影响。目前治疗GBS和其他周围神经炎症性疾病以及神经性疼痛的方法是非特异性的，部分有效。该建议是对整合素拮抗剂作为AIDP靶向抗炎治疗的临床前评估。抑制疾病特异性炎症通路有可能彻底改变急性，严重周围神经炎症的治疗。拟议的工作可能会导致开发新的单克隆抗体治疗AIDP和其他炎性神经病变的I期临床试验，如慢性炎性脱髓鞘性多根神经病变（一种未被认识的神经病变，可能占65岁以上患者致残神经病的14%），以及神经性疼痛。