This is a Phase I STTR to investigate the preclinical efficacy of a novel immunomodulator, DR?1-MOG, in a clinically relevant thromboembolic stroke model in mice. We have previously shown that T cells are activated after stroke, infiltrate brain, and exacerbate ischemic brain damage. Strategies that reduce T cell activation and brain tissue infiltration have been investigated as potential therapeutic strategies for stroke; however, non- specific inhibition of T cell function is immunosuppressive. We therefore developed Recombinant T cell receptor (TCR) Ligands (RTLs), which are partial MHC II molecules comprised of covalently linked ?1 and ?1 chains tethered to antigenic peptides. Early RTL constructs were successful in protecting against ischemia-induced brain injury but only if the RTL contains a neuroantigen peptide and the matched Class II MHC moiety of the recipient. A significant limitation for using these early RTL constructs to treat human stroke is the need to rapidly match recipient MHC class II with the ?1 domain of the pMHC construct. We, therefore, designed a novel recombinant protein comprised of the HLA-DR?1 domain linked to MOG-35-55 peptide (DR?1-MOG) but lacking the ?1 domain found in pMHC. Because the DR?1 domain is present in all humans and would not be recognized as foreign, treatment using DR?1 constructs would not require HLA screening of potential recipients. In a proof of principle study, we demonstrated that four daily treatments with DR?1-MOG significantly reduced infarct size after stroke in mice. That study, however, was conducted using the intraluminal middle cerebral artery occlusion (MCAO) model, which causes mechanical, rather than thromboembolic occlusion, the most common cause of human stroke. To more faithfully mimic clinical stroke, we have developed a novel thromboembolic model of stroke in mouse, which will form the basis of the current proposal. Furthermore, aging and biological sex are well documented key determinants of stroke outcome, in part by exerting differential influences on stroke-induced inflammatory response. The proposed STTR will further characterize the protective effect of DR?1-MOG using the clinically relevant thromboembolic model of stroke, and the clinically important variables of time of initial treatment, sex and age to estimate how broadly DR?1-MOG could be used to treat stroke patients.
Public Health Relevance Statement: Stroke causes inflammation in brain, which makes stroke worse. The inflammatory cells responsible for brain inflammation after stroke include a cell type called T cells. Inhibiting T cells indiscriminately causes reduced immunity and infections. We have developed a novel therapeutic agent which causes selective inhibition of some of T cell functions, which leads to reduced inflammation after stroke selectively without affecting overall immunity. We will use a novel model of stroke which mimics human stroke to show that this drug reduces brain damage and improves functions after stroke in both young and old males and females.
Project Terms: Affect; Age; age effect; Age-Months; aged; Aging; Agonist; Alleles; Alpha Cell; autoreactive T cell; Behavioral; Binding; Biological; Blood; Brain; Brain Injuries; brain tissue; Caring; Cell physiology; cell type; Cells; Clinical; Clinical Trials Design; clinically relevant; Cognitive deficits; Coupled; design; Diagnosis; Dose; Encephalitis; Female; Hemorrhage; Histocompatibility Testing; HLA-DR2 Antigen; Human; Immune; Immune response; Immunity; Immunomodulators; immunoregulation; Immunosuppressive Agents; improved; improved functioning; Infarction; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Ischemia; Ischemic Brain Injury; Ischemic Stroke; ITGAM gene; Ligands; Link; male; Measures; Mechanics; Medical; MHC Class II Genes; Middle Cerebral Artery Occlusion; migration; Migration Inhibitory Factor; Modeling; motor deficit; Mus; Myelin; Natural immunosuppression; Neurologic Deficit; neuroprotection; novel; novel therapeutics; oligodendrocyte-myelin glycoprotein; Outcome; Patients; Peptide Receptor; Peptide/MHC Complex; Peptides; Peripheral; Pharmaceutical Preparations; Phase; post stroke; preclinical efficacy; protective effect; receptor; Recombinant Proteins; Recombinants; response; screening; sex; Signal Transduction; Small Business Technology Transfer Research; somatosensory; stroke; stroke treatment; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Therapeutic Agents; Thromboembolism; Thrombosis; Time; Weight; Wild Type Mouse; young adult
