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.
The purpose of our work is to discover a new treatment for the most common peripheral nerve inflammatory disease called Guillain-Barr? syndrome (GBS). GBS equally affects both sexes, all ages, racial/ ethnic groups and socioeconomic status. By finding new treatments for GBS, we can hopefully better treat or cure this problem, improve the lives of patients and their families, and reduce the financial burden of this and similar diseases, such as Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and neuropathic pain, on the health care system nationally and internationally.
|Dong, Chaoling; Palladino, Steven P; Helton, Eric Scott et al. (2016) The pathogenic relevance of Î±M-integrin in Guillain-BarrÃ© syndrome. Acta Neuropathol 132:739-752|
|Greathouse, Kelsey M; Palladino, Steven P; Dong, Chaoling et al. (2016) Modeling leukocyte trafficking at the human blood-nerve barrier in vitro and in vivo geared towards targeted molecular therapies for peripheral neuroinflammation. J Neuroinflammation 13:3|
|Ubogu, Eroboghene E (2015) Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention. Acta Neuropathol 130:445-68|
|Yuan, Furong; Yosef, Nejla; Lakshmana Reddy, Chetan et al. (2014) CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-BarrÃ© syndrome. PLoS One 9:e90463|
|Chiang, Sharon; Ubogu, Eroboghene E (2013) The role of chemokines in Guillain-BarrÃ© syndrome. Muscle Nerve 48:320-30|
|Ubogu, Eroboghene E (2013) The molecular and biophysical characterization of the human blood-nerve barrier: current concepts. J Vasc Res 50:289-303|
|Ubogu, Eroboghene E (2013) Chemokine-dependent signaling pathways in the peripheral nervous system. Methods Mol Biol 1013:17-30|
|Reddy, Chetan Lakshmana; Yosef, Nejla; Ubogu, Eroboghene E (2013) VEGF-A165 potently induces human blood-nerve barrier endothelial cell proliferation, angiogenesis, and wound healing in vitro. Cell Mol Neurobiol 33:789-801|
|Yosef, Nejla; Ubogu, Eroboghene E (2013) An immortalized human blood-nerve barrier endothelial cell line for in vitro permeability studies. Cell Mol Neurobiol 33:175-86|
|Ubogu, Eroboghene E (2012) Translational strategies in peripheral neuroinflammation and neurovascular repair. Transl Neurosci 3:373-383|
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