Multiple sclerosis (MS) is a progressive paralytic human demyelinating disease may be caused or made worse due by an autoimmune attack on the central nervous system (CNS). This attack produces severe inflammation in the brain and spinal cord that is mediated by white blood cells, called T lymphocytes, which are programmed to recognize and damage components of the myelin sheath. Our laboratory has designed and developed a novel family of molecules, called RTLs (Recombinant T cell receptor Ligands), that can selectively block the inflammatory effects of these damaging white blood cells. Therapeutic effects of RTL have been evaluated in mice undergoing Experimental Autoimmune Encephalomyelitis (EAE), an animal model for MS that involves a paralytic chronic or relapsing disease course and progressive damage to myelin and nerve cells of the central nervous system. RTL treatment after onset of EAE reversed paralytic clinical signs and changed the properties of the damaging T lymphocytes to become non-pathogenic. In addition to direct modulation of T cell activation through the T cell receptor (as designed), RTLs were recently discovered to induce changes in the T cells by first binding to other blood cells that then 'present' unique signals specifically to the T cells. Additionally, RTL therapy was shown to reverse inflammation, cellular infiltration and myelin and axonal damage in EAE, suggesting a neuroprotective effect on the entire CNS. The overall goal of this proposal is to characterize the RTL signaling events that cause these critical changes in the pathogenic T cells. To address this goal, it is proposed to: 1) evaluate the process through which RTLs bind to antigen presenting cells from blood and induce changes that render the pathogenic T lymphocytes harmless, and 2) evaluate in mice how RTL therapy can affect the blood brain barrier in order to prevent entry of inflammatory cells and thus protect the CNS from T cell damage to myelin and nerves. The work proposed is crucial to our understanding of how RTL therapy changes T cell functions and reverses inflammation and myelin damage in CNS. These studies will provide unique insights and approaches to document effects of RTL therapy in subjects with MS.

Public Health Relevance

Project Narrative Multiple sclerosis (MS) is a progressive paralytic human demyelinating disease may be caused or made worse due by an autoimmune attack on the central nervous system (CNS). Activation of T lymphocytes (a subtype of white blood cell) with specific receptors for myelin peptides can result in inflammation and severe damage to myelin and nerves in the brain and spinal cord of subjects with MS. Our studies in an experimental model of MS have demonstrated that treatment of paralyzed mice with a novel drug (RTL) can reverse clinical and histological damage and promote clinical improvement and regeneration of myelin and nerves in the spinal cord. The ability of RTL to reverse progression of the MS-like disease suggested that this drug might be highly effective for treating subjects with MS, including Veterans being treated in VA Hospitals nationwide. Based on these and other pre-clinical data that were patented and published, Artielle ImmunoTherapeutics, Inc (the company that has a worldwide exclusive license from VA and OHSU for the RTL platform technology) has obtained an IND#100128 'RTL1000 'Recombinant T Cell Receptor Ligand' from FDA and has initiated a human Phase 1 safety study for use of RTL1000 in subjects with MS. The study is enrolling 5 cohorts of 6 MS subjects, 4 receiving drug and 2 receiving placebo in each cohort. Each succeeding cohort receives an increasing dose of RTL1000 given i.v., starting with the lowest dose of 2mg given as a single injection (starting dose determined by preclinical studies from the previous MR grant), and escalating to 6, 20, 60, and 200mg. At this writing (August, 2008), cohorts 1, 2 and 3 have been completed without safety issues, and cohort 4 is midway without apparent safety concerns. Further information on this trial can be viewed at clinicaltrials.gov (key in 'Multiple Sclerosis') or on the National Multiple Sclerosis website under current clinical trials in MS. This study represents a direct translation of VA funded research into a human clinical study that may have direct application to Veterans with MS.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000226-03
Application #
8195878
Study Section
Neurobiology C (NURC)
Project Start
2009-04-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
3
Fiscal Year
2011
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239
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