Our objective is to evaluate whether inhibition of CD11d-dependent leukocyte infiltration into peripheral nerves is a specific therapy for peripheral nerve inflammation seen in chronic immune-mediated disorders and neuropathic pain. Using chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as an example of persistent peripheral nerve inflammation that results in significant chronic neuropathic pain and long-term disability, we propose to address a fundamental question: Is competitive antagonism of CD11d a potential treatment strategy for chronic peripheral neuritis? Based on our exciting new preliminary data using human in vitro and in situ approaches, we propose the following hypothesis: CD11d expressed by pathogenic CIDP patient monocytes and lymphocytes actively participate in their selective trafficking across the blood-nerve barrier in peripheral nerves. As an extension of this, we propose that competitive inhibition with a function neutralizing monoclonal antibody would reduce leukocyte trafficking at the blood-nerve barrier. Modulating leukocyte infiltration would limit harmful consequences of chronic peripheral nerve inflammation, demyelination and axonal injury. This strategy provides an opportunity to develop a novel targeted therapy for CIDP and neuropathic pain. In order to address this hypothesis, we will determine that CD11d antagonism reduces trafficking of untreated CIDP patient peripheral blood mononuclear leukocytes in an established human in vitro blood-nerve barrier model that incorporates hydrodynamic flow. Trafficking events would be captured real-time and quantified by video microscopy. We will also evaluate the effect of CD11d antagonism on the neurobehavioral, electrophysiological and histopathological features of progressive chronic peripheral nerve inflammation, demyelination and axonal injury in a severe, reliable CIDP mouse model, using our published methods. Current therapies for CIDP and other peripheral nerve inflammatory disorders, including chronic neuropathic pain are non-specific and partly effective. This proposal is a preclinical evaluation of CD11d antagonism as a targeted molecular anti-inflammatory therapy for CIDP. Inhibiting disease-specific inflammatory pathways has the potential to revolutionize the treatment of chronic peripheral nerve inflammation. The proposed work could lead towards an NINDS CREATE Bio grant to develop novel therapeutic drugs for phase I clinical trials in CIDP and other chronic inflammatory neuropathies, as well as the consequential chronic neuropathic pain.
The purpose of our work is to discover a new treatment for an under-recognized, but severe disabling nerve inflammation disease called chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CIDP equally affects both sexes, all ages, racial/ ethnic groups and socioeconomic status. By finding new treatments for CIDP, we can hopefully better treat or cure this problem, improve the lives of patients and their families, and reduce the financial burden of this disorder and its consequential chronic neuropathic pain and disability on the health care system nationally and internationally.
