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 optic nerves, brain or spinal cord, resulting in demyelination and damage to neighboring axons. A critical step in the formation of MS lesions is adhesion molecule mediated transmigration of leukocytes from the bloodstream into the CNS. The current proposal tests our hypothesis that targeted blockade of a particular adhesion molecule interaction (between a4b7, expressed on CNS-infiltrating T cells, and MAdCAM-1, expressed on inflamed CNS blood vessels) will prevent exacerbations of autoimmune demyelination in a mouse model of MS (experimental autoimmune encephalomyelitis or EAE). To do so, we have engineered a chimeric fusion protein (MAdCAM-1-Fc), composed of the extracellular domain of MAdCAM-1-Fc linked to the Fc region of mouse immunoglobulin heavy chain. This reagent prevents MAdCAM-1 from binding a4b7 expressing T cells. We will determine whether systemic administration of MAdCAM-1-Fc or control fusion proteins suppresses relapses or progression of EAE. Furthermore, in a test of its safety, we will administer MAdCAM-1-Fc to mice infected with an alphavirus and determine whether the treatment impedes viral clearance and/ or triggers reactivation of latent virus in the CNS.
The specific aims of our proposal are as follows: 1. To study the temporal and spatial expression of a4b7 on CNS infiltrating CD4+ T cells and its cognate ligand, MAdCAM-1, on CNS vascular endothelium during the course of relapsing and chronic experimental autoimmune encephalomyelitis (EAE) in mice. Additional experiments are designed to examine the inflammatory factors that induce expression of a4b7 on myelin-specific effector cells and MAdCAM-1 on CNS endothelial cells. 2. To investigate the therapeutic consequences of a4b7 blockade in both relapsing and chronic EAE models. We will compare the therapeutic efficacy of a novel MAdCAM-1-Fc recombinant fusion protein (that specifically blocks a4b7 integrin) versus other adhesion molecule blocking agents, when given at different time points in the disease course. 3. To characterize the effects of systemic a4b7 blockade on acute viral infection of the CNS and reactivated latent viral infection in mice. We will use a mouse model of alphavirus infection to compare the effects of MAdCAM-1-Fc and other fusion proteins on anti-viral immunity and immunosurveillance.

Public Health Relevance

Multiple Sclerosis (MS), a relapsing 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 currently cares for over 40,000 veterans with MS. Approved disease modifying therapies used to suppress MS attacks are only modestly effective (i.e., beta interferon and glatiramer acetate) or have serious side effects, some of which are potentially lethal (i.e., mitoxantrone and natalizumab). The goal of the current proposal is to conduct preclinical studies of a novel chimeric fusion protein, MAdCAM-1-Fc, in an animal model of MS. The data generated could lead to the way for the development of a new class of immunomodulatory drugs in MS that are highly effective therapeutically and safer than agents currently in clinical use.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX000416-01A1
Application #
8088478
Study Section
Blank (RRD6)
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
096318480
City
Ann Arbor
State
MI
Country
United States
Zip Code
48105