Multiple sclerosis (MS) is the most common non-traumatic neurological disorder affecting young adults. Yet because both symptoms and conventional MR imaging findings of MS are nonspecific and do not always correspond to each other, prompt diagnosis of disease activity and treatment follow-up present significant challenges. Furthermore, current therapies for MS are only partially effective and patients often have breakthrough disease activity. Myeloperoxidase (MPO) is a highly oxidizing enzyme abundantly secreted by active macrophages/microglial cells and certain monocytes in inflammation, and is found in active inflammatory MS lesions. We have recently shown that the MR imaging agent, bis-5HT-DTPA-Gd (MPO-Gd) is highly specific and sensitive to MPO activity in in vitro and in vivo experiments. We have found that MPO-Gd to be nontoxic, possesses high Gd stability, and is well tolerated by animals even at high doses. We found that MPO-Gd imaging can detect and confirm preclinical disease, and can identify 40% more and 40% smaller lesions compared to conventional MR contrast imaging in the mouse experimental autoimmune encephalomyelitis (EAE) model. We and others have also found that myeloperoxidase activity is highly associated with areas of microglia/macrophage infiltration and demyelination both in MS and animal models of MS. Preliminary studies administering an MPO-specific inhibitor in mice induced with EAE reduced inflammatory cell recruitment and ameliorated symptoms. Therefore, we hypothesize that MPO is not only an ideal biomarker to track MS disease activity, but may also play an important role in the pathogenesis of demyelination. As current immunomodulatory therapies for MS target predominately lymphocytes, targeting macrophage/microglial inflammation by modifying the end product of macrophage/microglia function (i.e., MPO activity), may represent a new area for treating MS. In addition, this strategy may be combined with therapies targeting lymphocytes to potentially achieve synergistic beneficial effects, thus allowing lower doses of each therapy to be used to decrease drug toxicity. Therefore, using the EAE mouse model, this proposal aims to 1) establish MPO as a biomarker for inflammatory demyelination by tracking and modulating MPO activity as the disease exacerbates and remits, correlating imaging, biochemical, and histopathological changes to inflammatory and anti-inflammatory markers and immune cell populations shifts, and 2) establish MPO-Gd imaging as a superior method for tracking treatment effects, and design novel synergistic therapeutic regimen to treat both lymphocytic and macrophage/microglial inflammation. We expect the results of this proposal will validate MPO as an imaging biomarker and treatment target, change drug development strategies that are currently focused on lymphocytes and validated using nonspecific conventional imaging, and set the stage for future translation of MPO-Gd imaging and MPO treatment to human MS.

Public Health Relevance

This proposal seeks to validate the MR imaging agent MPO-Gd that is highly sensitive and specific to myeloperoxidase (MPO) activity, to noninvasively track inflammatory disease activity in a mouse model of multiple sclerosis and to better understand the roles MPO plays in the pathogenesis of active demyelination. This proposal will further identify optimized therapeutic regimens to improve current therapy. As human MPO is many times more active than mouse MPO, MPO-Gd imaging is potentially translational. The results of this study could improve tracking of treatment changes, allow more timely and accurate diagnosis of subclinical active inflammation in MS patients, and open up a new area for therapy by targeting macrophage/microglial function that may be used either alone or in synergy with current therapy to reduce dose and toxicity, and ultimately lead to better outcome for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070835-03
Application #
8272542
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$378,731
Indirect Cost
$164,356
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Li, Anning; Wu, Yue; Linnoila, Jenny et al. (2016) Surface biotinylation of cytotoxic T lymphocytes for in vivo tracking of tumor immunotherapy in murine models. Cancer Immunol Immunother 65:1545-1554
Kim, HyeonJu; Wei, Ying; Lee, Ji Yong et al. (2016) Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke. J Pharmacol Exp Ther 359:262-272
Zhang, Yinian; Seeburg, Daniel P; Pulli, Benjamin et al. (2016) Myeloperoxidase Nuclear Imaging for Epileptogenesis. Radiology 278:822-30
Kuijten, Maayke M P; Hannah Degeling, M; Chen, John W et al. (2015) Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging. Sci Rep 5:17220
Pulli, Benjamin; Ali, Muhammad; Iwamoto, Yoshiko et al. (2015) Myeloperoxidase-Hepatocyte-Stellate Cell Cross Talk Promotes Hepatocyte Injury and Fibrosis in Experimental Nonalcoholic Steatohepatitis. Antioxid Redox Signal 23:1255-69
Pulli, Benjamin; Bure, Lionel; Wojtkiewicz, Gregory R et al. (2015) Multiple sclerosis: myeloperoxidase immunoradiology improves detection of acute and chronic disease in experimental model. Radiology 275:480-9
Forghani, Reza; Kim, Hyeon Ju; Wojtkiewicz, Gregory R et al. (2015) Myeloperoxidase propagates damage and is a potential therapeutic target for subacute stroke. J Cereb Blood Flow Metab 35:485-93
Li-ChunHsieh, Kevin; Schob, Stefan; Zeller, Matthias W G et al. (2015) Gelsolin decreases actin toxicity and inflammation in murine multiple sclerosis. J Neuroimmunol 287:36-42
Lartey, Frederick M; Ahn, G-One; Shen, Bin et al. (2014) PET imaging of stroke-induced neuroinflammation in mice using [18F]PBR06. Mol Imaging Biol 16:109-17
Lartey, Frederick M; Ahn, G-One; Ali, Rehan et al. (2014) The relationship between serial [(18) F]PBR06 PET imaging of microglial activation and motor function following stroke in mice. Mol Imaging Biol 16:821-9

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