Multiple Sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is the most common non-traumatic cause of neurological disability among young adults in the United States. Exacerbations of the disease occur when inflammatory foci form in the CNS resulting in demyelination and damage to neighboring axons. The vast majority of patients ultimately enter a progressive phase during which they gradually, but inexorably, accumulate disability. Clinical disability correlates most strongly with measures of axonal damage and neuronal loss. None of the disease modifying therapies (DMT) currently used to treat MS directly protect neurons or axons from injury or reverse damage once it occurs. Myelin associated inhibitors (MAIs), such as Nogo, MAG, and OMgp, constitute a family of proteins that bind cognate receptors (including Nogo receptors (NgRs) and paired immunoglobulin-like receptor B (PirB)) on axons to suppress neuronal sprouting and synaptic plasticity. Furthermore, engagement of LINGO-1, a component of the NgR1 signaling complex, on oligodendrocyte progenitor cells, inhibits oligodendrocyte differentiation and remyelination. More recently, NgRs have been found to play a role in inflammation. We propose that interactions between MAIs and their receptors (NgR1, NgR2, and PirB) both promote neuroinflammation and curtail neural and myelin repair in mice with experimental autoimmune encephalomyelitis (EAE), widely used as a model of MS.
The specific aims of our proposal are as follows: 1) To investigate the role of the decoy receptor, NgROMNI, in the development of clinical EAE. We will test the therapeutic efficacy of NgROMNI, a newly developed Nogo receptor Fc fusion protein that blocks binding of MAIs to NgRs and PirB, in relapsing-remitting and progressive forms of EAE. In addition to the impact of NgROMNI on the clinical course, we will assess its effects on myelin and axonal integrity and autoimmune Tcell priming. 2) To determine whether MAI-PirB interactions facilitate the activation, differentiation and CNS trafficking of leukocyte subsets in myelin immunized mice. PirB, a member of the immunoglobulin superfamily expressed on monocytes and other leukocytes, was recently identified as a receptor for Nogo, MAG and OMgp. In this aim, we will test our working hypothesis that PirB signaling into myeloid cells is necessary for the clinical manifestation of EAE. Specifically, we predict that PirB deficiency or blockade will inhibit the differentiation and biological activities of peripheral dendritic cells that prime encephalitogenic T cells, as well as suppress the activities of monocytes, macrophages and activated microglia that accumulate in CNS lesions during autoimmune demyelination. 3) To characterize the effects of NgROMNI on neuronal sprouting and remyelination in mice with EAE. In order to distinguish the direct effects of NgROMNI on glial cells and axons from those on hematopoietic cells, NgROMNI will be administered after peak disease in relapsing remitting EAE (well past the establishment of neuroinflammatory infiltrates) and during chronic stages of progressive EAE. In complimentary experiments EAE will be compared in WT-->NgR-/- and WT-->WT bone marrow chimeric mice. Ultimately we hope that the results of these preclinical studies will set the stage for clinical trals of NgR decoy proteins or other MAI antagonists in MS. If successful, NgR antagonists will represent the first class of agents used to treat MS that have both anti-inflammatory and neuroprotective/ neurorestorative properties.
Multiple Sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is the most common non-traumatic cause of neurological disability among young adults. The Veteran's Administration Healthcare System cares for over 40,000 veterans with MS. None of the treatments currently used to treat MS directly protect CNS resident cells from injury or reverse damage once it occurs. Myelin associated inhibitors (MAIs) constitute a family of proteins that bind cognate receptors (including Nogo receptors (NgRs) and paired immunoglobulin-like receptor B (PirB)) on axons to suppress neuronal sprouting and synaptic plasticity. Recently, NgRs have been found to play a role in inflammation. The goal of the current proposal is to conduct preclinical studies of NgROMNI, a novel decoy fusion protein that blocks interactions between MAIs with NgRs and PirB, in animal models of MS. The data generated could lead the way for the development of the first class of agents used to treat MS that have both anti-inflammatory and neuroprotective properties.
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