Biography:

Jianrong Li is an Associate Professor in Neuroscience at Texas A&M University. She received her PhD in Biochemistry from University of Hawaii and Post-doctoral training from University of Pittsburgh and Children’s Hospital Boston, Harvard Medical School. Her research interests include elucidating the molecular basis of oligodendroglial cell injury in developmental and demyelinating diseases, and uncovering key pathways for myelin repair. She has been awarded multiple research grants from the National Multiple Sclerosis Society and National Institutes of Health and has authored over 40 peer-reviewed research articles. 

Abstract:

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Local inflammatory reactions induced by infiltrating leukocytes and activated glia are believed to be the main culprit for myelin destruction and axonal damage. Recent studies suggest that galectins, the ß-galactoside-binding lectins, can modulate immune tolerance and inflammatory responses. Galectin-9 is significantly elevated in MS lesions, however, its function in CNS immune responses and demyelination remains largely unexplored. We found that galectin-9 was markedly induced in microglia and reactive astrocytes during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as well as in reactive astrocytes and microglia/macrophages surrounding active MS lesions. Pro-inflammatory cytokines such as TNF and IL-1b triggered galectin-9 production from astrocytes, which in turn acted in a feed-forward fashion to further enhance microglial TNF production. TNF-stimulated Lgals9^+/+ astrocytes induced greater extent of encephalitogenic T-cell apoptosis and proliferation arrest than that of Lgals9^-/- astrocytes, indicating that galectin-9 negatively regulates encephalitogenic T cells. During MOG_35-55-induced EAE, Lgals9^-/- mice exhibited worse clinical symptoms, which were associated with heightened Th17 responses in the CNS and demyelination when compared with littermate Lgals9^+/+ controls. In autoimmunity-independent toxin models of CNS demyelination, spontaneous remyelination was delayed in Lgals9^-/- mice. Immunohistochemistry analyses revealed that although Lgals9^-/- mice had similar number of oligodendrocyte precursor cells in the lesions as control mice, the number of mature oligodendrocytes was significantly reduced. Consistently, recombinant galectin-9 promoted oligodendrocyte maturation in mixed glial cultures. Collectively, our data suggest a role for galectin-9 in suppressing T lymphocytes in the CNS and facilitating oligodendrocyte maturation and myelin repair

Biography:

William Tyor is a Professor of Neurology at the Emory University School of Medicine and the Atlanta VA Medical Center. He is the Co-Director of the Emory/Atlanta VA MS Center and the Emory Center for AIDS Research NeuroAIDS Scientific Work Group. His research has focused on basic and translational investigations of neuro-inflammatory diseases of the central nervous system including clinical trials in multiple sclerosis (MS) and translational studies in MS and HIV associated neurocognitive disorders (HAND). His NIH and VA grant funding has focused primarily on the pathogenesis and treatment of HAND using a mouse model and neuronal culture systems. He attends outpatient clinics in his subspecialty of CNS inflammatory disorders at the Atlanta VA and Emory Clinic as well as General Neurology Patient Management in the VA Residents’ Clinic and VA Inpatient Consult Service.

Abstract:

Interferon-alpha (IFNα) is a pleiotropic cytokine expressed by a wide variety of cell types during inflammatory events, especially viral infections. In the central nervous system IFNα can be expressed by infiltrating leukocytes, glia and even neurons. When IFNα has been used as therapy for various diseases (e.g., hepatitis) and can be measured in the cerebrospinal fluid (CSF), it invariably causes cognitive dysfunction that is reversible when treatment is discontinued. IFNα has been measured in the CSF of people living with HIV and correlates with cognitive dysfunction. Both animal studies and in vitro investigations indicate that IFNα is toxic to neurons. We have shown that in a mouse model of HIV associated neurocognitive disorders (HAND), brain IFNα levels correlate with errors made in maze testing. Furthermore, behavioral abnormalities and histopathology can be ameliorated by treating these mice with neutralizing antibody to IFNα. In vitro studies using rat neurons reveal that IFNα exposure leads to dendritic simplification, which is likely a cellular correlate to memory loss. This dendritic simplification is not only mediated through the Type I IFN receptor, but also through the GluN2A subunit of the N-methyl-D-aspartate receptor. Preliminary studies in the HAND mouse model suggest that combined antiretroviral therapy (cART) plus an IFNα binding protein, B18R, are superior to cART alone in improving neuropathological markers. Our most recent unpublished data show that B18R can reverse abnormal behavioral seen with object recognition testing in HAND mice. Treatment of IFNα neurotoxicity may not only be effective in humans with HAND, but in other neurological disorders associated with cognitive dysfunction.

Biography:

Dr. Yumin Zhang, is an Associate Professor in the Department of Anatomy, Physiology and Genetics and the Department of Neuroscience at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Dr. Zhang obtained his MD in Binzhou Medical School, China, PhD in Hebrew University of Jerusalem, Israel, and postdoc study in the Children’s Hospital, Harvard Medical School. The major research interest in Dr. Zhang’s lab is to study how modulation of the arachidonic acid metabolism and the endocannabinoid system can impact the pathogenesis and treatment for neurological diseases, including traumatic brain injury and multiple sclerosis.

Abstract:

Modulation of the endocannabinoid system has emerged as an attractive strategy for the treatment of many neurological diseases, but its role in the management of traumatic brain injury is still in its infancy. The endocannabinoids 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide, AEA) are elevated after brain injury and believed to be protective. However, the compensatory effect of the endocannabinoids is transient due to their rapid degradation by hydrolytic enzymes.  In a mouse model of traumatic brain injury (TBI), we found that post-injury chronic treatment with WWL70 and PF3845, the respective and selective inhibitors of the 2-AG and AEA hydrolytic enzymes alpha/beta hydrolase domain 6 (ABHD6) and fatty acid amide hydrolase (FAAH), improved locomotor function, working memory and anxiolytic behavior. The treatment reduced lesion volume in the cortex and neuronal death in the hippocampal dendate gyrus. It also suppressed the expression of inducible nitric oxide synthase and cyclooxygenase-2 and enhanced the expression of arginase-1 in the ipsilateral cortex at 3, 7 and 14 days post-TBI, suggesting microglia/macrophages are shifted from a proinflammatory (M1) to an anti-inflammatory (M2) phenotype. Treatment with PF3845 also suppressed the increased production of amyloid precursor protein, prevented dendritic loss and restored the levels of synaptophysin in the ipsilateral dentate gyrus. The beneficial effects of WWL70 and PF3845 were mediated by activation of cannabinoid type 1 and type 2 receptors and might be attributable to the phosphorylation of the extracellular signal regulated kinase (ERK1/2) and the serine/threonine protein kinase (AKT). These results suggest that fine-tuning of 2-AG and AEA signaling by regulating ABHD6 and FAAH activity can afford anti-inflammatory and neuroprotective effects in TBI.

Biography:

Ahmad Bassiouny has completed his PhD in Medical Sciences from University of Nebraska Medical Center, USA and postdoctoral studies from Max-Plank Institute, Germany. He is a full professor of Molecular Therapeutics & Immunology. He is the contact person of International ISIS Master in Neuroscience and Biotechnology with Bordeaux University, France. He was the PI of GESP Grant with Professor Detlef Gabel, University of Bremen, Germany. April 2011-April 2013. He was also the principal investigator of national grant from STDF project # 513 and Co-PI of STDF project ID: 4237: "Study on possible APE1-mediated molecular mechanism(s) implication in neuroinflammation". He has been chosen to be included in the special 30th Pearl Anniversary Edition of Who's Who in the World, 2013. Presenting author details 

Abstract:

Parkinson's disease is a progressive disorder of the nervous system that affects motor function in basal ganglia. The aim of this study was to examine the effects of ginger extract on neuroinflammatory-induced damage of dopaminergic (DA) neurons in Parkinson's disease (PD) mouse C57/BL/6 models. Animals were injected intraperitoneally (IP) with a total cumulative dose of 150 mg/kg MPTP. The levels of dopamine were determined by HPLC. Chronic exposure to neurotoxins increase α-synuclein (αS) aggregation concomitant with upregulation of miR-155 and downregulation of miR-7 and -153 and increase in intracellular reactive oxygen species (ROS). Seven days after the last MPTP injection, behavioral testings were performed.  The levels of TNF-α, COX-2 and iNO and miR-7, miR-153, miR-155 were analyzed both in Substantia nigra pars compacta (SNpc) and globus pallidus (GP) by real time PCR. Results: Here we show that Ginger extract can alleviate αS-induced toxicity, downregulate miR-155, and upregulate miR-7 and miR-153, reduce ROS levels and protect cells against apoptosis. It significantly increased the level of dopamine in GP and striatum and suppressed TNF-α and NO levels. In C57/BL mice, treatment with Ginger extract reversed MPTP-induced changes in motor coordination and bradykinesia. Moreover, Ginger extract significantly inhibited the MPTP-induced microglial activation and increases in the levels of TNF-α, NO, iNOS, and COX-2 in both SNpc and GP. It upregulated the level of miR-153 and miR-7 indicating a protective effect. Conclusion:  Our results may indicate that miR155 has a possible central role in the inflammatory response to αS and αS-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to αS. Our findings implicate miR-155, miR-153 and miR-7 are potential therapeutic targets for regulating the inflammatory response in PD. Ginger extract exerts neuroprotective effects on DA neurons in in vivo PD model. 

Biography:

Pooja Jain is a tenured Professor in the Department of Microbiology and Immunology at the Drexel University College of Medicine, USA. She also holds joint appointment as a Professor of Neurobiology and Anatomy at DrexelMed. She is well respected in the field of Neurovirology/Neuroimmunology and made seminal contributions with her studies on HTLV-associated cancer and neuroinflammation with prime focus on the dendritic cells. She provided first live in vivo imaging evidence of dendritic cells’ trafficking into the central nervous system during an active ongoing neuroinflammatory condition and extended her pioneering observations in defining the molecular events and mechanisms underlining cellular migration across the blood-brain barrier. She has authored more than 50 peer-reviewed publications, over 250 abstracts and numerous invited talks across United States and overseas. She has been bestowed with various honors and has served in several NIH study sections. She is currently a Member of AAI, ASM, SFN, ISNV, SNIP and a Life Member for the International Society for Dendritic Cell & Vaccine Science.

Abstract:

For last several years, our laboratory has placed tremendous efforts in understanding retroviral pathogenesis both in periphery and in CNS utilizing human T-cell leukemia virus (HTLV) as a model pathogen with prime focus on dendritic cells (DCs). HTLV-1 is not only a good model for human chronic viral infection but also of associated neurological complications. Therefore, through these studies we were able to provide new scientific insights and paradigms in the areas of neuroimmunology and neurovirology. Our long-standing research work with HTLV-1 helped in bridging two important fields of Neuroscience and Immunology while strengthening DCs’ presence and functions within CNS. This is by means of our original work providing direct evidence for the ability of circulating DCs to migrate across the inflamed blood-brain barrier during an active ongoing neuroinflammatory condition such as experimental autoimmune encephalitis (EAE) by live intravital video microscopy. This was further substantiated by a variety of non-invasive imaging tools such as NIR, SPECT-CT, MRI, PET, etc. These studies have identified lectins (i.e., CLEC12A) as key molecular targets for potentially new DC-based immunotherapeutic strategies against neuroinflammatory diseases such as MS. Fairly recently; we undertook similar approach toward HIV-1 CNS infection to investigate if follicular DCs (fDCs) within deep cerebral lymph nodes (CLNs) could be potential reservoir for HIV/SIV CNS infection. We are also interested in investigating novel means to inhibit HIV-fDC interactions as relate to the CNS pathogenesis. Taken together, our work on DC-CNS trafficking has helped changed the central dogma of CNS being the immune privileged site.

Biography:

Patricia Szot as a long-term member of the MIRECC research team at the VA Puget Sound Health care System has provided substantial information on the expression of receptors and transmitter-synthesizing enzymes in the human and rodent brain.  This has included autopsy brain material from Parkinson’s disease and Alzheimer’s or dementia patients.  Due to the in situ hybridization and slice autoradiography technical expertise he has worked on the localized quantitation of some important regulatory proteins.  These studies contribute to his understanding of the mechanisms of side effects and additional symptomatology observed, e.g., in Alzheimer’s disease and Parkinson’s disease- information which is of direct clinical relevance.

Abstract:

Neuroinflammation is proposed to be an important component in the development of several central nervous system (CNS) disorders including depression, Alzheimer’s disease (AD), Parkinson’s disease (PD), and traumatic brain injury (TBI).  The intra-peritoneal (ip) administration of lipopolysaccharide (LPS) induces peripheral inflammation and neuroinflammation as evident be elevations in blood and brain levels of cytokines.  However, the cellular and anatomical sources of these cytokines are not known. Here, we used in situ hybridization to examine in brain and spleen the sources of cytokine production after 3-injection regime previously shown to elevate cytokine levels in brain and blood.  Administration of LPS significantly increased mRNA expression of interleukin (IL)-6 and -10 in the spleen, an important organ for an immune response, consistent with increases in blood levels for these cytokines after LPS.  LPS significantly decreased IL-6 receptor (-6R) mRNA in the spleen, but had no effect on IL-7 or IL-7R mRNA.  In the CNS, IL-6 mRNA was expressed in neurons prior to LPS in regions that include the cortex, cerebellum and hippocampus.  After LPS, IL-6 mRNA expression in these neuronal populations was unchanged, but a diffuse non-neuronal pattern appeared throughout the brain.  IL-6R mRNA showed a pattern of expression similar to IL-6 mRNA and LPS significantly elevated all regions, except cerebellum, mainly in animals which expressed the non-neuronal IL-6 mRNA after LPS.  IL-10 mRNA was widely expressed in neurons in many discrete brain regions, with LPS tending to decrease expression in forebrain regions and increase it in hindbrain regions.  IL-7 and IL-7R had limited expression mainly to the cerebellum.  LPS had no effect on IL-7 or IL-7R mRNA in the CNS.  These studies indicate that LPS induced neuroinflammation has unique effects on regional and cellular patterns in the CNBS and splenic cytokine expression.  It is apparent that LPS can affect neuronal and non-neuronal cells in the brain, with IL-6 demonstrating the greatest change.

Biography:

Audrey D Lafrenaye is a Research Associate Faculty Member in the Department of Anatomy and Neurobiology at Virginia Commonwealth University. She has received her PhD in Anatomy. Following her graduate work she transitioned into the Trauma field. Her research focuses on evaluating the diffuse pathologies following traumatic brain injury. In the conduct of her studies she utilizes both rodent and micro pig models of diffuse traumatic brain injury and has been particularly interested in the effects of elevated intracranial pressure without hypoperfusion on subacute pathology and morbidity following TBI. For the past few years she has explored the pathological progression of diffuse axonal injury and acute neuro-inflammation following mild diffuse traumatic brain injury in the pig. 

Abstract:

Mild traumatic brain injury (mTBI) is a highly prevalent disease with devastating costs. While one of the major pathological hallmarks of TBI is diffuse axonal injury (DAI), neuroinflammation occurring chronically, weeks to months following injury, has also been implicated in a variety of detrimental as well as regenerative functions. Currently, little is known regarding acute neuroinflammation occurring within the first day following mTBI, particularly within the gyrencephalic brain. Therefore, we assessed acute neuroinflammation at 6h and 1d in a unique model of diffuse mTBI in the micro pig. Mild TBI did not precipitate systemic physiological abnormalities or overt histopathological damage; however, this micropig model generated substantial DAI in the thalamus, an area commonly affected in human mTBI, at both 6h and 1d following injury. Extensive acute neuroinflammation was also observed following mTBI within the thalamic domain. Importantly, the processes of activated microglia converged on axons sustaining DAI at both time points following mTBI. Contacts between activated microglia processes and swellings of injured axons increased two fold at 6h and nearly fourfold at 1d following mTBI compared to associations with uninjured myelinated axons in sham animals. While active phagocytosis was observed in association with wallerian degeneration following mTBI, the microglia that contacted swellings from diffusely injured axons were not ultra-structurally phagocytic. This study shows direct physical correlation between injured axonal swellings and non-phagocytic acute neuroinflammation in a higher order animal, finding that could lead to novel diagnostics based on a more complete understanding of acute neuroinflammation following mTBI. 

Biography:

Juan Pablo de Rivero Vaccari has received his Bachelor of Science degree in Biology in 2004 from Florida International University, where he graduated Summa Cum Laude and became a Member of Phi Beta Kappa Honor Society. In 2004, he joined the University of Miami as a graduate student in the Department of Physiology and Biophysics where he worked in the laboratory of Dr. Robert W. Keane. He has obtained his PhD in 2007 and joined the laboratory of Dr. W. Dalton Dietrich at the Miami Project to Cure Paralysis as a Postdoctoral Fellow where he continued his studies on innate immune responses after brain trauma. In 2010, he became a Research Assistant Professor in the Department of Neurological Surgery and the Miami Project to Cure Paralysis at the University of Miami. Currently, he works on identifying biomarkers and therapeutic targets in the innate immune response to improve outcomes after central nervous system injury and disease. In addition, his work has resulted in the filing of several patents with the United States Patent and Trademark Office and abroad. To move inventions forward, he co-founded InflamaCORE, LLC, a company dedicated to treating and diagnosing inflammatory injury and disease, as a spin-off company from the University of Miami.

Abstract:

The inflammasome plays a key role in the regulation of the innate immune inflammatory response in the central nervous system (CNS). The inflammasome regulates the activation of the inflammatory caspase; caspase-1 and the pro-inflammatory cytokines IL-1beta and IL-18. The inflammatory response is regulated differently at different stages of the aging cycle. This presentation will cover the regulation of the inflammasome in the brain as a result of naturally occurring aging in the brain of aged mice (18 months) when compared to younger mice (3 months). In addition, I will discuss the regulation of the inflammasome in the brain of reproductive senescent female rats when compared to the brain of young female rats. Taken together, our data indicate that the inflammasome is up-regulated in the brain as a result of aging. Importantly, inhibition of the inflammasome in the aging brain results in improvement in cognitive performance as determined by water maze testing in rats. In conclusion, our findings indicate that the inflammasome is a potential therapeutic target to inhibit inflammation in the aging brain, which could further protect from the development of neurodegenerative diseases associated with aging such as Parkinson's disease and Alzheimer's disease.

Biography:

Khanyisile Kgoadi is a Clinical Science and Immunology PhD student at the University of Cape Town, South Africa. She has completed her BSc in Biochemistry at the University of Johannesburg and MSc studies in Biochemistry at the University of Pretoria, South Africa. She has published a joint first authorship paper in the current metabolomics journal. She has won the South African Women in Science Award in 2015. She was awarded the Margaret McNamara Education Grant for her strong leadership qualities and empowerment of children and women through education.

Abstract:

Mycobacterium bovis BCG causes inflammation of the CNS referred to as central nervous system tuberculosis (CNS-TB). CNS-TB is a lethal form of tuberculosis that constitutes approximately 5-10% of extra-pulmonary tuberculosis cases. Pathogenesis of CNS-TB is initiated as a secondary infection during haematogenous dissemination of pulmonary infection to the brain parenchyma. CNS-TB is associated with high morbidity and 50% mortality. The mechanisms associated with CNS-TB infection and cells targeted for invasion is mostly unknown. The regulatory role of dendritic cells (DCs) in CNS-TB has been neglected because of their absence during homeostasis. This study investigated DC recruitment kinetics and phenotype in context to CNS-TB. C57BL/6 mice were intracerebrally infected with BCG and sacrificed at different time intervals. Bacterial loads of samples were determined by plating homogenates of organs and counting colony-forming units. Brain DCs were quantified and their phenotype determined using flow cytometry. Bacterial loads showed dissemination of BCG from the brain to the spleen and to a lesser extent to the lungs. A significant increase was observed in the amount of dendritic cells recruited to the brain at week 4 post BCG infections. At week 6, there was a significant drop in the mount of BCG present in the brain. Recruitment of T cells to the brain following BCG infection shows that DCS are successful in presenting antigens to T cells and eliciting an adaptive immune response in CNS-TB. This shows that the CNS is not immune privileged but CNS inflammation caused by mycobacteria is a highly regulated process that limits potential pathology damage.

Biography:

Rina Aharoni is currently a Senior Staff Scientist at the Department of Immunology, The Weizmann Institute of Science, Israel. She has completed her BSc in Biology, Hebrew University, Jerusalem, Israel and MSc and PhD in Life Sciences from The Weizmann Institute of Science, Rehovot, Israel. She did Postdoctoral Research at Stanford University, USA. Her main research interests include neuroimmunology, autoimmunity, pathology and therapy of multiple sclerosis (MS) and its model experimental autoimmune encephalomyelitis (EAE), immunomodulation, neuroprotection and repair processes in the central nervous system, inflammatory bowel diseases (IBD). She has published more than 60 papers and reviews on these subjects and she is also an Editorial Board Member of 20 journals.

Abstract:

Multiple sclerosis (MS) is currently recognized as complex diseases in which inflammatory autoimmune reactivity in the central nervous system (CNS) results in demyelination, axonal and neuronal pathology. Treatment strategies thus aim to reduce the detrimental inflammation and induce neuroprotective repair processes. The synthetic copolymer Copaxone (Glatiramer acetate, GA), an approved drug for the treatment of MS, is the first and so far the only therapeutic agent to have a copolymer as its active ingredient. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the mechanism of action of GA was elucidated. These studies indicated that GA treatment generates immunomodulatory shift from the inflammatory towards the anti-inflammatory pathways, such as Th2-cells that cross the blood brain barrier (BBB) and secrete in situ anti-inflammatory cytokines as well as T-regulatory cells (Tregs) that suppress the disease. The consequences of GA treatment on the CNS injury inflicted by the disease were studied using immunohistochemistry, electron microscopy and magnetic resonance imaging. These analyses revealed reduced demyelination and neuro-axonal damages as well as neuroprotective repair processes such as neurotrophic factors secretion, remyelination and neurogenesis. These combined findings indicate that immunomodulatory treatment can counteract the neurodegenerative disease course, supporting linkage between immunomodulation, neuroprotection and therapeutic activity in the CNS.

Biography:

S Ghosh is currently pursuing his Postdoctoral research at Washington School of Medicine, St. Louis, USA. His research interest lies in understanding the neuro-immune signaling pathways that are disrupted during neurodegenerative diseases and autoimmune disorders in the brain. He/ has received his Bachelor’s degree in Technology in Genetic Engineering from SRM University, India. He has pursued his PhD at Purdue University, USA in kinase signaling examining the role of different kinases such as CDK5 in neuronal cell death, Aurora A kinase in breast and ovarian cancer and spleen tyrosine kinase in microglial cell activation.

Abstract:

Microglial cell is the primary immune cell of the central nervous system and maintains the brain homeostasis. In Alzheimer’s disease brain, microglial cell are recruited to amyloid beta (Aβ) plaques and exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. To explore the molecular basis for these phenomena, we hypothesized that defect in the functions of the protein-tyrosine kinase SYK, which is important both for macrophage activation and phagocytosis, might underlie much of this observation. Recent evidence from our lab indicates that SYK can associate with stress granules, ribonucleoprotein particles that form in stressed cells and contain inactive translation initiation complexes. In our study, we found that microglial cell line and primary mouse brain microglia, when stressed by exposure to sodium arsenite or Aβ(1-42) peptides or fibrils, form extensive stress granules to which SYK is recruited. SYK enhances the formation of stress granules as evidenced by the inhibition of stress granule formation by small molecule inhibitors, knockdown of SYK expression by shRNA and SYK haplo-insufficiency in mouse microglial cells. SYK is active within the resulting stress granules where it catalyzes the phosphorylation of stress granule-associated proteins on tyrosine. SYK-dependent stress granule formation stimulates the production of reactive oxygen and nitrogen species. These are toxic to neuronal cells as demonstrated by a co-culture assay using stressed microglial cells and HT22 neuronal cells. The ability of microglial cells to phagocytose E. coli is blocked by SYK inhibitors. The sequestration of SYK into stress granules inhibits the ability of microglial cells to phagocytose either E. coli or Aβ fibrils. Microglial cells from aged mice are more susceptible to the formation of stress granules than are cells from young animals. Stress granules containing SYK and phosphotyrosine are prevalent in the brains of patients with severe Alzheimer’s disease, suggesting that the sequestration of SYK into stress granules is part of the pathology of the disease. Phagocytic activity can be restored to stress microglial cells by treatment with IgG independent of the epitope specificity, suggesting a mechanism to explain the therapeutic efficacy of intravenous IgG.

Biography:

Abstract:

Persistent cognitive sequelae occur following neuro-invasive infection with neurotropic flaviviruses, including Japanese encephalitis virus, Saint Louis encephalitis virus, and West Nile virus (WNV). We used an established murine model of recovery from WNV in which animals display spatial learning defects and loss of presynaptic termini within the hippocampal CA3. Transcriptional profiling of the hippocampi of mice with poor learning revealed decreased expression of genes involved in adult neurogenesis and increased expression of innate immune molecules known to inhibit this process, including interleukin (IL)-1. WNV-infected adult mice exhibited decreased numbers of proliferating neuroblasts, which are not directly targeted by virus, and increased generation of astroblasts, within neurogenic zones, with limited recovery of neurogenesis in the sub-granular zone at 30 days. Accordingly, IL-1R1-deficient, WNV-infected mice exhibited normal neurogenesis, rapid recovery of presynaptic termini, and resistance to WNV-mediated impairment in spatial learning and memory compared with wild type mice. Our results reveal that alterations to neuronal progenitor cell homeostasis during adult neurogenesis may underlie long-term cognitive consequences of WNV infection and provide a therapeutic intervention to prevent these deficits.

Biography:

Dianne Lorton has completed her PhD in Neurosciences from Indiana State University in affiliation with Indiana University School of Medicine. She has completed her Post-doctoral training in Pharmacology from Duke University and in Neuroimmunology from the University of Rochester. She is currently an Assistant Professor at Kent State University in the College of Arts and Sciences. She has published over 70 papers (manuscripts, reviews, and book chapters) on neuroimmunology focusing on sympathetic nervous system regulation of immunity. 

Abstract:

Statement of the Problem: In 80% of patients, major life stressors precede onset of autoimmune diseases, including rheumatoid arthritis (RA) linking stress pathway activation to disease onset. We examined the contribution of high sympathetic nervous system activity to RA onset using the adjuvant-induced (AA) arthritis model in Lewis rats.

Methodology: Rats were immunized with complete Freund’s adjuvant to induce AA. From day (D) 12 (disease onset) through D28, rats were treated with vehicle or 2 mg/kg/day moxonidine, an imidazoline receptor-1 agonist that acts centrally to reduce SNS tone. Disease outcome was assessed using dorsoplantar widths and X-ray analysis. Cytokines critical for inflammation and CD4+ Th cell development (interleukin (IL)-1beta, IL-10, tumor necrosis factor (TNF)-alpha, IL-6, IL-2, IL-4, IFN-gamma, and tumor growth factor (TGF)-beta) were assessed in spleen, draining lymph node (DLN) and peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunoassays. 

Biography:

Born 1929 in Shanghai in an intellectual family. My father held the idea of “Save our country with medicine”, which determined my live as a student of medical school and a scientist in medical field.

In 1953 I was recruited by People’s Liberation Army to be a teacher in Dept. of Anatomy of the Fourth Military Medical University, a school just established and located in Xi’an, a very back-woods city. The university had little, if any, research facilities. In the Dept. of Anatomy there was only one old Zeiss bronze monocular microscope, probably a little better than the one Cajal had used. I was the only one in Dept. of Anatomy who knew Neuroanatomy. Hodology is an important research field in Neuroanatomy , the best tracing technique was Nauta’s staining invented in mid-50’s. I am the first one in China who mastered this technique and published a paper in early 90’s in Journal of Anatomy (Chinese), then the best journal in China available. Then came a national turmoil of so called “Cultural Revolution”which revolved all cultures away. We were forbidden to do scientific research, even not allowed to go to libraries. The “Cultural Revolution” was finally proved a conspiracy and was crushed down in 1986. It spoiled 20 of by best years.

Abstract:

Throughout my life I have been focused my research on three fields:

1. Direct neural regulation of mammalian anterior pituitary. A student of mine accidentally found many nerve fibers in the anterior pituitary of a monkey”. Since beside the gland cells there are abundant blood vessels in the anterior pituitary, therefore, the first thing is to clarified what do the nerve fibers innervate in the gland. It turned to be that the nerve fibers innervate both of them, but mainly the gland cell. A series of studies were then followed. To make the story short, the golden criterion was that our electron microscopic study found typical synapses between the terminals of the nerve fibers and the gland cells. We then put forth a hypothesis: Neuro-humoral dual regulation of mammalian anterior pituitary.

2. Brain control of immunity

3. Early neural surgery of spinal cord contusion, a surgery I myself designed. The operations were followed by rehabilitation of three months. The outcome was beyond imagination. In 30 ASIA grade-A patients, the optimal operation time window was 4-14 days. There were13 cases in the window, 85% were able to walk with a pair of crunchers, or a stick, or without any support.

4. A small but very popular staining technique. The glucose oxidase-DAB-nickel method in peroxidase histochemistriry of the nervous system. 1988. It has been cited more than 1,000 times and is still popular today.

Biography:

Zhihai Lei is a Professor working at Nanjing Agricultural University (NAU), Nanjing, Jiangsu, China. His research fields are nueroanatomy and neuroendocrine of domestic animals and pay more attention to roles of newly discovered neuropeptides in reproduction and immune regulations. 

Abstract:

Statement of the Problem: Neuromedin U (NMU) is a conserved mammalian neuropeptide discovered in the 1980s and found in two forms, NMU-25 and NMU-8. Wide distribution of NMU in animal organs suggests that NMU is involved in multiple physiological functions, including immune regulation. However, the role of NMU in pig immune regulation has not been reported.

Methodology & Theoretical Orientation: To study the effect of NMU on pig immune regulation, we cloned and detected the expression of NMU and its receptors in pig lymphatic organs and immune cells. We also investigated the effect of NMU on cytokine secretion after injection of (0, 5, 15, 45 nmol) NMU into the intracerebral ventricle (i.c.v) of 16 pigs (n=4 for each group) and the effect of (0.1~1000 nM) NMU on cytokine secretion in cultured dendritic cells and natural kill (NK) cells using ELISA and RIA methods.

Findings: NMU and its receptors were expressed in lymphatic organs, cultured dendritic cells and NK cells. NMU stimulated IL-1β, IL-6, IL-8, TNF-α and IL-10 secretion (P<0.05) post-injection in a time- and dose-dependent manner, compared with the control group. NMU increased IL-8, IL-6 and IL-13 secretion and reduced IL-10 secretion (P<0.05) in cultured dendritic cells. NMU enhanced the killing activity of cultured NK cells, stimulated IFN-γ secretion via PLC, PI3K and MEK signal pathways and inhibited IL-10 secretion (P<0.05) in NK cells in atime- and dose-dependent manner.

Conclusion & Significance: This study suggests that NMU has the role in pig immune regulation through its effect on cytokine secretion and increasing killing activity of NK cells.

Biography:

Grace Y Sun has completed her BS in Chemistry from Seattle Pacific University and PhD in Biochemistry from Oregon State University. After holding a Research Scientist position in Cleveland, she was recruited to the Biochemistry Department in University of Missouri. As a Neuroscientist, she is recognized for research on brain lipids and signaling pathways related to neuro-inflammation and aging. Her research experience included serving as Program Project Director of the MU Alzheimer’s disease research program and as a Project Leader in the MU Center for Phytonutrient and Phytochemistry. Besides training a large number of graduate students and post doctorates, she is also experienced in organizing national and international symposia and meetings. She has published over 300 articles in highly regarded journals. Among the many awards, the most notable one is the MU System President’s Award for Sustained Excellence in 2012, which was the highest award recognizing faculty achievement at the university.

Abstract:

Microglia is the major immune active cell in the brain, are known to play multiple functional roles for maintaining brain health. Besides ability to migrate to sites of injury and scavenge cellular debris, these cells also become activated in response to stimuli, including cytokines, chemokines and toxins. Upon activation, these cells release pro-inflammatory and neurotrophic factors, this can alter the environment of neighboring cells. Microglia activation has been implicated in the acute and chronic inflammation in a number of neurological diseases, including Alzheimer’s disease, stroke and traumatic brain injury. Some noted pro-inflammatory events include activation of cytosolic phospholipase A2 (cPLA2) and stimulation of the NF-kB transcriptional pathway. In our studies, we have used the bacteria endotoxins (lipopolysaccharides, LPS) to stimulate the Toll-like receptors in microglia and activate both cPLA2 and the NF-kB pathway, leading to the release of prostaglandins, pro-inflammatory cytokines, reactive oxygen species (ROS), and nitric oxide (NO). A number of botanical polyphenols have been shown to inhibit the oxidative/inflammatory responses elicited by LPS. Interestingly, some phytochemicals not only can mitigate the NF-kB responses but also stimulate the anti-oxidant pathway involving the Nrf2 and activation of the Antioxidant Response Element (ARE). The Nrf2/ARE transcription pathway is known to play an important role in the synthesis of a large number of antioxidant enzymes including heme oxygenase-1 (HO-1). Although more studies are needed, there is evidence that activation of MAPKs may play an important role in mediating the cross-talk between the NF-kB and Nrf2 pathways. Future studies to uncover regulation of these pathways in microglia will be important in the development of novel therapeutic strategies to fight against neurological diseases and aging.

Biography:

D Gris is a Head of Neuroimmunology Laboratory at the University of Sherbrooke, Canada. He has graduated from Dr. Weaver’s Laboratory in University of Western Ontario where he studied inflammation after spinal cord injury. He has completed his Post-doctoral studies from the University of North Carolina at Chapel Hills, NC, USA where he began to investigate role of NLRs in neurodegeneration. He is investigating novel computerized methods of evaluating behavioral outcomes of neuro-inflammation. His main interest is to discover novel anti-inflammatory pathways within the central nervous system and use this knowledge to design therapies for neurological diseases including multiple sclerosis amyotrophic lateral sclerosis autism and epilepsy.

Abstract:

Many members of NLR family of proteins play an important role in human diseases including diabetes, Crohn’s disease, cancer, etc. NLRs bind multiple proteins inside cells, thus redirecting molecular signaling. We concentrated on the role of anti-inflammatory NLRs in multiple sclerosis. Using state-of the art automated behavioral platform we demonstrate that NLRX1 and NLRP12 inhibit progression of the diseases in a mouse model of MS. We observed reduced inflammation and improve biochemical and behavioral outcomes of the disease. Furthermore, NLRX1 acts at the level of mitochondria promoting DRP1 dependent mitochondrial fission. In inflammatory cells such as microglia and astrocytes, this results in inhibition of assembly of proinflammatory pathways including type I interferon and NFkB. Accordingly; we observed reduction in the expression of iNOS, cytokines including IL-1beta and TNF-alpha during microglial activation. In neurons, NLRX1 effect results in inhibition of necrosis and increased viability. Using N2A cell line, we demonstrated that NLRX1 protects cells from rotenone toxicity. We demonstrated that NLRX1 over-expressing cells were more viable and the ration of apoptosis to necrosis was shifted to necrosis in cells that lacked NLRX1. We confirmed profound role of NLRs by generating mice that spontaneously develop multiple sclerosis-like disease. In conclusion, both NLRX1 and NLP12 decrease inflammatory responses in the CNS and, therefore, present as a target for treatments in neurodegenerative diseases.

Biography:

Biswadev Bishayi has completed his BSc in Physiology in 1990 from Midnapore College and MSc in Human Physiology from Vidyasagar University West Bengal, India in 1992. After qualifying NET-CSIR examination he joined Indian Institute of Chemical Biology as JRF and completed his PhD from Jadavpore University, West Bengal, India in 1999. He has joined as Lecturer in the Department of Physiology, University of Calcutta in 1997 and promoted to Professor in 2012. After being awarded the Biotechnology Overseas Associateship from the DBT he did his Postdoctoral research in Boston University Medical School, USA. The main focus of his research is host-pathogen interaction, role of cytokines in inflammatory diseases as well as neuro-endocrine immune interactions in relation to Staphylococcus aureus infection. He has regularly published papers in national and international reputed journals.

Abstract:

A reciprocal regulation exists between the central nervous and immune systems where the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The hypothalamic pituitary adrenal (HPA) axis regulates the immune system via glucocorticoid hormones (GC). Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate inflammatory disease. Glucocorticoids have multiple effects on immune cells but insensitivity of immune cells to this hormone during chronic stress and persistent inflammation has been the cause of several neuroimmunological disorders. In a mouse model of restraint stress and infection with Gram negative (E. coli) or Gram positive (S. aureus) or injection of bacterial endotoxin (LPS) several inflammatory parameters and behavioral changes were studied. Increased resistance of mice to infections that correlated with their behavioral changes in an open field test (OFT) and on an elevated plus maze (EPM) has been observed. Reduced acetyl cholinesterase (AChE) activity in the hypothalamus indirectly suggested that more acetylcholine molecules must be playing their anti-inflammatory role to modulate the activity of the HPA axis. Exogenous administration of pro-inflammatory cytokine (IL-6) or an anti-inflammatory cytokine (IL-10) along with ciprofloxacin (an antibiotic having secondary anti-inflammatory role apart from its primary anti-bacterial effect) to stressed and infected mice, down regulated the inflammatory mediators and also effectively helped in bacterial killing. Thus this work provides new insight into the therapeutic strategy that can be adopted when considering treatment against chronic stress and infection induced neuroimmunological disorders.

Biography:

Monique F Stins has her expertise in Blood Brain Barrier research and is seeking to dissect underlying molecular relations between Blood brain barrier activation and neurological damage. This may lead to identification of pharmacologic targets for therapeutic intervention to improve neurological outcomes of infections with neurotropic microbes. She is using various models of the blood brain barrier in microbial disease to target these pathogenic mechanisms. She has experience teaching students at levels ranging from middle and high school to undergraduate college and upper level college courses.

Abstract:

Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection, especially in young children, but also in non-immune travelers and military personnel visiting or sent out to malaria endemic regions. Clinically, CM features symptoms such as seizures and reversible coma. Without proper supportive care often leads to death, despite anti-malarial chemotherapy.  Upon clearance of the infection, patients are often left with neurologic sequelae, such as seizures, learning and behavioral disorders such as ADHD in African children. Post malaria syndromes can also include psychotic or acute confusional episodes and tremors. Sequestration of Plasmodium infected erythrocytes (PRBC) in high endothelial venules is a hallmark of CM. It is unclear as to how these intracellular parasites, while confined to the lumen of the brains vasculature induce neurological dysfunction.  In CM, the blood brain barrier (BBB) lies at the interface of the events occurring in blood and brain. The BBB is part of the neurovascular unit (NVU), a concept that emphasizes homeostatic interactions between its components to ensure optimal functioning of the central nervous system. It is hypothesized that activation of the BBB endothelium disturbs the homeostasis between the astroglial and neuronal components of the NVU leading to neurological dysfunction. Using in vitro models for the human BBB, PRBC increase ICAM-1 expression and decrease the barrier function of monolayers in a dose dependent manner. Microarray and gene ontology (GO) analysis indicated a predominance of the NFB mediated pro-inflammatory responses among the host signaling pathways. RT-PCR and protein analysis confirmed the increase in transcripts and directional release of both cytokines and chemokines in various in vitro models. Basal directed BBB secretions caused dose-dependent abnormal astroneuronal morphology and cell death. Determination of the underlying pathogenesis of observed BBB activation and astroneuronal effects may lead to development of adjunctive neurotherapeutics to ameliorate neurologic sequelae.

Biography:

Abstract:

Background: Aggression has been recognized as a near-universal behavior with substantial influence on and implications for human and animal social systems. It can be a significant problem since escalated aggression may result in serious damage to others and can reveal itself as a symptom of psycho- pathologies. It is often considered to be the product of environmental stressors, health problems, pain, psychiatric morbidity or behavioral stressors. Psychopharmacology is a one of field of medicine that addresses the use of medications to correct or alleviate common mental illnesses. It is a scientific discipline that utilizes drugs to increase our knowledge and understanding of the workings of the mind.

Objective: The objective of this study is to review and discuss the advancements of neural mechanisms and neuropharmacological agents related to aggression.

Methods: Systematic review method was used for this study.

Results & Discussion: An imbalance in neurochemicals is thought to be the primary reason for psychological problems and seizure activity. The understanding of each neurotransmitter's functions and responsibilities explains why a decrease or increase in normal levels would cause elevated aggression. Psychopharmacology emphasizes drug induced changes in mood, thinking and behavior. Among its aim is the utilization of medicinal substances for the restoration and maintenance of mental health, the prevention of mental breakdowns, and the exploration of the reaches of the mind. Its basic purpose is to help disease, but to change the personality, improve human nature, or cure bad habits. Developing novel therapies to reduce or prevent violent outbursts is a key objective of psychopharmacological research on aggression.

Conclusion & Recommendation: Despite considerable progress, therapeutic possibilities for controlling or coping with, pathological aggressive behavior remain far from being satisfactory. Consequently, studying both the fundamental causes of aggression and dysfunctions and the modification of behavior by pharmacologic interventions is surmountable.

Biography:

Luis Venegas S has completed his under graduation from Universidad de Antofagasta and has completed his PhD from Universidad Andres Bello in 2016. His Doctoral thesis was on the thyroid hormones during the gestation in the development and function of blood brain barrier. Currently, he is pursuing his Post-doctoral studies from Pontificia Universidad Catolica de Chile.

Abstract:

Hypothyroidism is a thyroid hormone deficiency condition. Around the world, 7% of pregnant women suffer maternal hypothyroidism. It causes low intellectual quotient (IQ), and mental retardation in the offspring. Gestational hypothyroidism increases the intensity of experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Given that the immune system is important for learning, we propose the following hypothesis: “The offspring gestated in hypothyroidism will affect the pattern of inflammatory cytokines in the serum that will alter learning, the BBB permeability and the migration of the immune system to the CNS”. To evaluate this maternal hypothyroidism was induced to pregnant mice. The learning capacity was analyzed and the serum levels of cytokines were analyzed by ELISA and multiplex in the offspring. The permeability of BBB was analyzed by Evans Blue (EB) extravasation in the CNS and the integrity of BBB was analyzed by immunofluorescence. The migration of immune cells to the CNS was analyzed by FACS. We found that the offspring gestated in hypothyroidism has impaired learning and low levels of IL-4, high basal levels of TNFα and IL-17, high EB extravasation and a higher number of CD4+ T cells in the CNS with an altered expression of BBB proteins. In conclusion, our data support that maternal hypothyroidism have altered cognition, BBB permeability and the presence of the immune system in the CNS. Together with an altered pattern of cytokines in the serum that are important for learning and for altering the BBB.

Biography:

Yeon Sun Lee is an Expert in peptide drug discovery area like novel peptide and peptidomimetic ligands for the treatment of pain and neuronal disease. She has been conducting research in identifying key structural features for target receptors including opioid receptors. The goal of her research is to develop new class of ligands modulating serious side effects that are caused by long term administration of opioids to treat chronic pain states, while retaining their high efficacies. Her studies represent a new approach: Drug design for pathological conditions and multifunctional ligands.

Abstract:

Statement of the Problem: Dynorphin A is an endogenous ligand showing neuro-inhibitory effects via opioid related mechanism. However, chronic pain, nerve injury, and inflammation often result in the up regulation of dynorphin A in the spinal column neurotransmitter pathway to the brain and cause neuroexcitatory effects such as motor impairments and hypersensitivity via non-opioid mechanism. The purpose of this research is to develop dynorphin A antagonists to modulate the adverse neuroexcitatory effects under pathological conditions.

Methodology & Theoretical Orientation: Systematic structure-activity relationship studies on the non-opioid dynorphin A fragment, dyn A-(2-13) were performed to identify the key structural features for the interaction with the bradykinin receptors, and then structures were refined by examining the effects of different substituents to obtain an antagonist activity. Lead ligands showing a high affinity at the bradykinin receptors were advanced to test their metabolic stability in plasma and anti-hyperalgesic effects in animals.

Findings: Our studies have discovered a novel mechanism of neurotransmission related to pain in which the bradykinin receptors are upregulated and dynorphin A peptides have neuroexcitatory effects that result in hyperalgesia. Our studies have also shown that lead ligand LYS1044 blocks dynorphin A-induced hyperalgesia and motor impairments in naïve animals and inhibits thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured animals. Importantly, the ability of LYS1044 is limited to the CNS and thus can avoid serious cardiovascular effects caused by blocking peripheral bradykinin receptors. However, the ligand showed low metabolic stability in plasma and thus, to improve the stability various modifications were performed. As the result, we could identify a highly stable ligand with retained high affinity at the bradykinin receptors.

Conclusion & Significance: This study presents a new class of ligands based on the unanticipated pathophysiological interaction between the endogenous opioid ligand dynorphin A and bradykinin receptors for the treatment of chronic pain without the toxicities associated with current treatments for these maladies (Figure 1).

Biography:

Dr. Oz is a scientist with expertise in inflammatory and infectious disease, immune-modulations, pathogenesis, innate and mucosal Immunity, cytokines, chemokines and receptors’ modifications, inflammatory and neuropathic pain and behavioral modifications, ROS, micronutrient,  gastrointestinal complications and drug discoveries.

Guest and lead Editor for Special Issues in journals: Nutrients (infectious and inflammatory Diseases); Antioxidants (Antioxidants, Microbiome and Gut Health), Canadian J Infectious Diseases and Medical Microbiology (Environmental Health – How Does It Relate to Parasites?); Gastroenterology Research and Practice (Gastrointestinal Inflammation and Repair: Role of Microbiome, Infection, and Nutrition), Mediators of Inflammation (Inflammatory, Infectious and Nutrition 

Abstract:

Statement of the Problem: Toxoplasma a ubiquitous organism is one of the most important sources of congenital infection and foodborne diseases. An estimated 1.5 billion people are globally infected frequently with unknown lifelong health complications. Organisms cause severe immune-inflammatory reaction in vital organs with the surge of chemokines and cytokines. Following acute phase, the organisms lodge in cyst forms predominantly in brain and muscles for the life pending to become reactivated by immunosuppression.  Organisms are transmitted mainly by consumption of contaminated animal products (meat, milk and dairy) with cysts, congenital and breast feed from actively infected mom, organ transplantation or by sexual transmission.  Cats are only definitive host which can release environmental resistance forms (oocysts) in feces which contaminate vegetations and water and orally taken to infect humans and animals.  Toxoplasmosis in congenital infection or immunodeficient individuals is manifested with growth retardation, encephalomyelitis, intracranial calcifications, hydrocephalus, neurological, mental illnesses, and seizures, retinochoroiditis, visual and auditory inflammatory disorders, cardiovascular abnormalities, gastroenteritis, myositis and pain.  Toxoplasma is a neurotropic organism which bypasses brain barrier to infect neurons and glial cells and to cause mild to severe behavioral modifications.  Recent studies reveal a mind alteration and sexual attraction in Toxoplasma infected subjects including schizophrenic behaviors in animals as well as humans.  As, fearless infected rodents seek cats are eaten up to keep the sexual life cycle continued. Toxoplasma impairs the limbic brain neurons responsible for instinct defensive behavior and judgment activity adjacent to limbic regions of sexual desire. Yet there is no safe and effective approved therapy for congenital and chronic infection or a vaccine available to prevent toxoplasmosis. Different aspects of maternal and fetal toxoplasmosis will be discussed including neuroinflammatory and behavioral alteration.  

Biography:

Xiaoming Hu has her expertise in neuroinflammatory responses after ischemic brain injury and neurodegeneration. Her core research interests are to explore the immune-related mechanisms and to identify novel immunotherapies for stroke. One of her research directions is to explore the effect of regulatory T cell on stroke and to elucidate the underlying mechanisms. She is among the first who demonstrated neuroprotective effects of this specialized T cell subpopulation in cerebral ischemia (Li et al., Ann Neurol 2013; 74:458; Li et al., Stroke 2013; 44: 3509; Li et al., Stroke 2014; 45: 857). Dr. Hu also investigates the mechanism for microglia/macrophage polarization and explores the exogenous signals that induce the phenotype shift. The identification of these critical signaling molecules brings hope to therapies that promote healthy microglia/macrophage responses even under pathological conditions. Dr. Hu has published more than 50 peer-reviewed manuscripts in this research area.

Abstract:

Delayed thrombolytic treatment with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier (BBB) breakdown after ischemic stroke and lead to lethal hemorrhagic transformation (HT). This study assessed the protective effect of regulatory T cell (Treg) transfer on tPA-induced HT and investigated the underlying mechanisms of protection. We used murine suture and embolic middle cerebral artery occlusion models of stroke to investigate the therapeutic potential of adoptive Treg transfer against tPA-induced HT. The results showed that delayed administration of tPA (10mg/kg) reproducibly resulted in hemorrhage in the ischemic territory 1d after MCAO. Intravenous administration of Tregs (2×10⁶/mouse) immediately after tPA treatment almost completely abolished this hemorrhage and improved sensorimotor deficits after stroke. Tregs dramatically reduced BBB disruption in tPA-infused stroke mice, as measured by Evans blue or fluorescent tracer (cadaverine) leakage and IgG extravasation. Consistent with these observations, Treg treatment mitigated tight junction damage in tPA-treated stroke mice, as revealed by Western immunoblotting and electron microscopy. Mechanistic studies demonstrated that Tregs almost completely abolished the tPA-induced elevation of matrix metalloproteinase 9 (MMP9) and CCL2 after stroke. Using MMP9 and CCL2 knockout mice, we discovered that both molecules partially contributed to the protective actions of Tregs. In an in vitro endothelial cell-based model of the blood-brain barrier, we confirmed that Tregs inhibited tPA-induced endothelial expression of CCL2 and preserved blood-brain barrier integrity after an ischemic challenge. Lentivirus-mediated CCL2 knockdown in endothelial cells completely abolished the blood-brain barrier protective effect of Tregs. Altogether, our data suggest that Treg adoptive transfer after thrombolytic treatment alleviates hemorrhage in stroke victims. Treg-afforded protection in the tPA-treated stroke model may be mediated by two inhibitory mechanisms involving CCL2 and MMP9. Thus, Treg adoptive transfer may be useful as a cell-based therapy to improve the efficacy and safety of thrombolytic treatment for ischemic stroke

Biography:

Dr. Bielekova received an M.D. degree in 1993 from Comenius University in Bratislava, Slovakia. After a medical internship at SUNY Downstate, Medical Center in Brooklyn and a neurology residency at Boston University, she did a 3 year postdoctoral research fellowship at the NIH/NINDS/Neuroimmunology Branch (NIB). She remained at NIB for additional 5 years as a staff physician, focusing on development of novel therapies for multiple sclerosis (MS). In 2005, she became associate professor of neurology with tenure and director of the Waddell Center for MS at University of Cincinnati. In 2008, she moved back to NINDS as an investigator. Her laboratory is studying mechanisms of immunoregulation and immune-mediated central nervous system (CNS) tissue injury in MS and other neuroimmunological diseases with a long-term goal of developing effective therapies. In addition, Dr. Bielekova is a principal investigator on several innovative protocols including adaptively-designed Phase I/II clinical trials.

Abstract:

Because of inadequate efficacy of immunomodulatory treatments, primary- (PPMS) and secondary-progressive multiple sclerosis (SPMS) were thought to have significantly less intrathecal inflammation than relapsing-remitting (RRMS) MS.  Using functional assays and innovative combinatorial cerebrospinal fluid (CSF) biomarkers, we demonstrated that both progressive MS subgroups have on average identical amount of intrathecal inflammation to RRMS. Instead, significantly greater level of compartmentalization of immune responses to central nervous system (CNS) tissue and greater terminal differentiation of intrathecal immune responses were characteristic of progressive MS. This makes progressive MS inflammation inaccessible to systemically-administered large molecules (e.g. monoclonal antibodies; mAb), while small molecules that may penetrate CNS are ineffective, because they predominantly target cells in proliferation cycle. Thus, in the placebo-controlled, Phase II clinical trial (RIVITALISE trial, clinicaltrials.gov identifier NCT01212094) we investigated whether intrathecal (IT) administration of mAb, such as rituximab can effectively inhibit intrathecal inflammation in SPMS. The trial was stopped for futility, after prospectively-acquired CSF biomarkers convincingly demonstrated that IT-administered rituximab decreased intrathecal inflammation only by approximately 10%. Mechanistic studies revealed following reasons for decreased efficacy of rituximab in the intrathecal, as compared to systemic compartments: 1. Due to active transport of antibodies from CSF to blood, achievable CSF concentrations of rituximab did not fully saturate CD20 on intrathecal B cells. 2. CSF lacks lytic complement, which results in decreased complement-dependent cytotoxicity (CDC). 3. The predominant cellular subtype of natural killer (NK) cells in CSF are CD56bright NK cells, which have low expression of Fc receptor and thus decreased levels of antibody-dependent cellular cytotoxicity (ADCC).

In conclusion, novel immunomodulatory agents with high CNS penetrance, not dependent on CDC or ADCC and effective on proliferation-quiescent immune cells will be necessary to successfully inhibit intrathecal inflammation in progressive MS.

Biography:

Interest in the medical use of cannabinoids has greatly increased in the last few years. Our previous studies have shown that inhibition of the minor endocannabinoid 2-AG hydrolytic enzyme alpha, beta-hydrolase domain 6 (ABHD6) significantly reduces neuroinflammation and exerts neuroprotection in animal models of traumatic brain injury and multiple sclerosis. Unlike inhibition of the principle 2-AG hydrolytic enzyme, monoacylglycerol lipase (MAGL), which leads to 2-AG overload and cannabinoid receptor desensitization, selective inhibition of ABHD6 is thought to provide therapeutic benefits without producing cannabimimetic side effects.  Accumulating evidence suggests that neuroinflammation is a major contributing factor to the pathogenesis of neuropathic pain. In this study we sought to determine the potential therapeutic effect of a selective ABHD6 inhibitor WWL70 in the management of neuropathic pain. In the murine model of neuropathic pain induced by chronic constriction (CCI) of the sciatic nerve, we found that WWL70 treatment significantly alleviated CCI-induced thermal hyperalgesia and mechanical allodynia in the ipsilateral paw at 3 and 7 days post-injury. Treatment with WWL70 also significantly attenuated the increased inflammatory response characterized by the downregulation of TNF-α, IL-6, IL-1β, MCP-1 in the ipsilateral sciatic nerve, DRG and spinal cord of CCI mice. Co-administration of cannabinoid receptor antagonists did not affect the effect of WWL70, suggesting that WWL70’s anti-nociceptive effect is independent on cannabinoid signaling pathways. Treatment with WWL70 reduced the expression of COX-2 and PGES₂ and the production of PGE₂ in the injured sciatic nerve. This result suggested that interference with the eicosanoid signaling pathway contributes, at least in part, to the therapeutic mechanisms of WWL70 on CCI induced neuropathic pain.  

Abstract: