Alpha M Beta 2 integrin blockade for acute inflammatory neuropathies

描述(申请人提供)：我们的目标是评估抑制依赖αMβ2整合素的白细胞向周围神经的渗透是否是免疫介导性疾病和神经病理性疼痛中出现的急性周围神经炎的特异性治疗方法。以急性炎症性脱髓鞘多神经根神经病(AIDP；格林-巴利综合征[GBS]最常见的变种)为例，我们提出了一个基本问题：阻断M整合素(CD11b)是治疗急性周围神经炎的潜在治疗策略吗？基于我们用体外和体内方法获得的令人兴奋的新的初步数据，我们提出了以下假设：AIDP中，表达在激活的血源性单核细胞和淋巴细胞上的M？2整合素和表达在激活的神经内皮细胞上的ICAM-1相互作用并跨越血-神经屏障募集致病单核白细胞。作为这一点的延伸，我们提出，M整合素单抗的竞争性抑制将减少病理性白细胞在血-神经屏障上的运输。减少周围神经的白细胞浸润将限制周围神经严重炎症、脱髓鞘和轴突损伤的有害后果。这一策略为开发一种新的针对AIDP和神经病理性疼痛的靶向治疗提供了机会。为了解决这一假设，我们将在一种新的细胞因子刺激的人体外血-神经屏障模型上确定抗人M整合素的功能中和单抗减少未经治疗的AIDP患者外周血单核白细胞的转运。贩运活动将被实时捕捉，并通过视频显微镜进行量化。我们还将使用我们发表的方法，评估M整合素阻断对严重、可靠的GBS小鼠模型中急性周围神经炎症、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。目前治疗GBS和其他周围神经炎症性疾病以及神经病理性疼痛的方法都是非特异性的，部分有效。这项建议是对M整合素拮抗剂作为AIDP的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、严重周围神经炎的治疗方法。这项拟议的工作可能导致为AIDP和其他炎症性神经病的I期临床试验开发新的单抗疗法，例如慢性炎症性脱髓鞘多根神经病(一种未被充分认识的神经病，可能占65岁以上患者致残性神经病的14%)，以及神经病理性疼痛。

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.