Alpha M Beta 2 integrin blockade for acute inflammatory neuropathies

描述（由申请人提供）：我们的目的是评价α M β 2整合素依赖性白细胞浸润外周神经的抑制是否是免疫介导疾病和神经性疼痛中观察到的急性外周神经炎症的特异性治疗。以急性炎症性脱髓鞘性多神经根神经病（AIDP;格林-巴利综合征[GBS]的最常见变体）为例，我们提出了一个基本问题：阻断<$M整合素（CD 11b）是否是急性周围神经炎的潜在治疗策略？基于我们使用体外和体内方法的令人兴奋的新的初步数据，我们提出了以下假设：在AIDP中，在活化的造血单核细胞和淋巴细胞上表达的<$M <$2整合素和在活化的神经内膜内皮细胞上表达的ICAM-1相互作用并招募致病性单核白细胞穿过血-神经屏障。作为这一点的延伸，我们提出，竞争性抑制与μ M整联蛋白单克隆抗体将减少致病性白细胞运输在血神经屏障。减少周围神经白细胞浸润将限制GBS中严重周围神经炎症、脱髓鞘和轴突损伤的有害后果。这一策略为开发AIDP和神经病理性疼痛的新型靶向治疗提供了机会。为了解决这一假设，我们将确定一个功能中和单克隆抗体对人的整合素减少运输未经治疗的AIDP患者外周血单核细胞在一个新的尼古丁刺激的人在体外血神经屏障模型，包括毛细血管流速。贩运活动将通过视频显微镜实时捕捉并量化。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μ M整联蛋白阻断对急性周围神经炎症、脱髓鞘和轴突损伤的行为、电生理和组织病理学特征的影响。目前用于GBS和其他周围神经炎性病症以及神经性疼痛的疗法是非特异性的并且部分有效。该提案是对整合素拮抗剂作为AIDP靶向抗炎治疗的临床前评价。抑制疾病特异性炎症通路有可能彻底改变急性严重外周神经炎症的治疗。拟议的工作可能导致开发新的单克隆抗体疗法，用于AIDP和其他炎性神经病的I期临床试验，如慢性炎性脱髓鞘性多神经根神经病（一种未被认识到的神经病，可能占65岁以上患者致残性神经病的14%）以及神经性疼痛。

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.