Day 1 :
National Institutes of Health, USA
Time : 09:30-10:00
Chi-Chao Chan, M.D. is the chief of Immunopathology Section, Laboratory of Immunology and the Head of Histology Core at the National Eye Institute (NEI), National Institutes of Health (NIH). In 1967, Dr. Chan graduated from Chungzhan Medical College (now known as Sun Yat-sen University) in Guangzhou, China. She earned her A.B. in 1972 and M.D. in 1975 at Johns Hopkins University. Following medical school, she completed her medical internship at Maimonides Medical Center in New York and ophthalmology residency at Stanford University Medical Center. Continuing her educational enrichment, Dr. Chan completed two post-doctoral fellowships in ophthalmic pathology at the Wilmer Ophthalmological Institute in 1982, and clinical ocular immunology/uveitis at the NEI in 1985. She is a board certified ophthalmologist and obtained a license of Clinical Laboratory Improvement Act (CLIA), certifying her in clinical laboratory diagnostics in ophthalmic pathology and molecular pathology. Dr. Chan is a world expert in intraocular lymphoma, immunopathology of uveitis, molecular pathology of age-related macular degeneration (AMD), ocular lymphoma and von Hippel-Lindau disease.rn
Age-related macular degeneration (AMD), the leading cause of irreversible central blindness in the elderly, is characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium, which is sometimes accompanied by choroidal neovascularization. Development of AMD is contingent on both environmental and genetic risk factors, the strongest being advanced age. With normal aging, photoreceptors are steadily lost, Bruch’s membrane thickens, the choroid thins, and hard drusen may form in the periphery. The changes are characterized as kinetics between homeostasis and allostasis. In AMD, many of these changes are exacerbated (chronic allostatic overload leading to pathology and disease); additionally, there is development of disease-specific factors such as macular soft drusen, geographic atrophy, and choroidal neovascularization. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis and physiological allostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 macrophage populations and activation of retinal microglia are observed and potentially contribute to tissue degeneration. In the chronic stage of allostatic overload, including oxidative stress, inflammasomes, and inflammatory cytokines (e.g., IL-1β, IL-17 and IL-18) wax and wane; retinal pigment epithelium and photoreceptors degenerate leading to programed cell death via apoptosis, autophagy, pyrotosis and/or necroptosis. Neovascularization may also develop. Therefore, the underlying mechanism of AMD involves homeostasis, allostasis, and allostatic overload, which all depend primarily on aging, inflammation, degeneration, atrophy, and neovascularization.
Autism Research Institute, USA
Keynote: Brainstem hypothesis for autism
Time : 10:00-10:30
Woody R McGinnis was educated at Dartmouth College and the University of Colorado, USA. After volunteer work in rural Peru, his general practice in Arizona included treatment of many children with autism. McGinnis commenced full-time research in autism in 2001 under the auspices of the Autism Research Institute, San Diego. In 2009, the publication of ‘Neurotoxic Brainstem Impairment as Proposed Threshold Event in Autistic Regression’ by CRC Press as a chapter in Autism: Oxidative Stress, Inflammation and Immune Abnormalities established McGinnis as a leading thinker in brainstem and autism. He has worked closely with the Autism Tissue Program and the University of Maryland Brain and Tissue Bank to enhance the collection of brainstem, including preservation of midline structures such as NTS.
Site-specific impairment of a small brainstem structure, nucleus tractus solitarius (NTS), is a potential break-through finding in the understanding of autistic spectrum disorder (ASD). NTS serves as initial central synapse for most sensory information from the viscera, and a broad set of unusual physical findings that associate with the diagnostic behaviors of ASD are explicable on the basis of reduced visceral afference. An exaggerated inflammatory response in ASD associates significantly with aberrant behaviors, and parallels the observation of increased inflammation after experimental splenic deafferentation. Likewise, deafferentation of the laryngeal viscera of animals results in reduced glottal closing force, proposed mechanism for our finding of whisper in association with autistic vocal regression. Experimental impairment of NTS results in depressed motor and secretory function of the gastrointestinal tract, prominent in ASD. Hypoperfusion of extensive brain regions with \\\\\\\"global dysregulation\\\\\\\" of cerebral blood-flow (CBF) is well-documented in ASD, and might be expected to alter development and integrated function of higher regions of brain. Animal experiments show that NTS is important in autoregulation of CBF, and that artificial stimulation of NTS increases CBF. An unusual vascular microanatomy is seen to confer a dual vulnerability of NTS to injury via hypoxia but also to toxins from the bloodstream that tend to concentrate preferentially in regions of brainstem such as NTS that are unprotected by BBB. Hence, we consider specific hypoxic events and common toxic exposures that could act together or separately in order to trigger ASD at varied points in the neurodevelopmental sequence.
Autism Research Institute, USA
Time : 10:45-11:30
WOODY R MCGINNIS was educated at Dartmouth College and the University of Colorado, USA. After volunteer work in rural Peru, his general practice in Arizona included treatment of many children with autism. McGinnis commenced full-time research in autism in 2001 under the auspices of the Autism Research Institute, San Diego. In 2009, the publication of ‘Neurotoxic Brainstem Impairment as Proposed Threshold Event in Autistic Regression’ by CRC Press as a chapter in Autism: Oxidative Stress, Inflammation and Immune Abnormalities established McGinnis as a leading thinker in brainstem and autism. He has worked closely with the Autism Tissue Program and the University of Maryland Brain and Tissue Bank to enhance the collection of brainstem, including preservation of midline structures such as NTS.
Site-specific impairment of the nucleus tractus solitarius (NTS), is a potential break-through finding in the understanding of autistic spectrum disorder (ASD). NTS serves as initial central synapse for most sensory information from the viscera, and a broad set of unusual physical findings that associate with the diagnostic behaviors of ASD are explicable on the basis of reduced visceral afference. An exaggerated inflammatory response in ASD associates significantly with aberrant behaviors, and parallels the observation of increased inflammation after experimental splenic deafferentation. Likewise, deafferentation of the laryngeal viscera of animals results in reduced glottal closing force, proposed mechanism for our finding of whisper in association with autistic vocal regression. Experimental impairment of NTS results in depressed motor and secretory function of the gastrointestinal tract, prominent in ASD. Hypoperfusion of extensive brain regions with \"global dysregulation\" of cerebral blood-flow (CBF) is well-documented in ASD , and might be expected to alter development and integrated function of higher regions of brain. Animal experiments show that NTS is important in autoregulation of CBF, and that artificial stimulation of NTS increases CBF. An unusual vascular microanatomy is seen to confer a dual vulnerability of NTS to injury via hypoxia but also to toxins from the bloodstream that tend to concentrate preferentially in regions of brainstem such as NTS that are unprotected by BBB. Hence, we consider specific hypoxic events and common toxic exposures that could act together or separately in order to trigger ASD at varied points in the neurodevelopmental sequence.
University of Texas Health, USA
Time : 11:45-12:05
Hanjing Emily Wu is a resident in the Department of Psychiatry and Behavioral Science at the University of Texas Health Science at Houston. She received her Doctor of Philosophy from University of Texas Health Science at Houston and Doctor of Medicine from St.Matthews University School of Medicine. She is currentlypursuing residency at Psychiatry Residency Program. Dr. Wu is interested in psycho-immunology. Her major interests include infl ammation in schizophrenia and its mechanism involved the pathophysiology of schizophrenia. She is passionate on developing novel treatments for schizophrenia. Dr. Wu has published over 20 peer-reviewed articles in immunology field as a young investigator.
Numerous studies report that abnormalities in both Brain-Derived Neurotrophic Factor (BDNF) and cytokines may be involved in the pathophysiology of schizophrenia. While recent studies have shown that immunocytokines interact with BDNF, however, the possible interaction between BDNF and cytokines; and their role in the psychopathology of schizophrenia have not been reported. We have analyzed serum BDNF, tumor necrosis factor-alpha (TNFα), Interleukin (IL)-2, IL-6 and IL-8 levels from the blood samples of 92 chronically medicated schizophrenia patients and 60 healthy controls. Th e symptoms of schizophrenia were assessed using the Positive and Negative Syndrome Scale (PANSS) with cognitive and depressive factors derived from the fi ve-factor model of the PANSS. Compared to the control group, the schizophrenia patients’ samples have signifi cantly decreased levels of BDNF and TNFα, but signifi cantly increased level of IL-2, IL-6 and IL-8. In patients, but not in controls, we observed a significant negative correlation between BDNF and IL-2; and between BDNF and IL-8. Furthermore, the negative correlation between BDNF and IL-8 was associated with the PANSS depressive factor, while decreased levels of BDNF and TNFα were associated with the PANSS cognitive factor. The decreased level of BDNF and change of immunocytokines level may be implicated in the pathophysiology of chronic schizophrenia. Moreover,immunocytokines may interact withBNDF in schizophrenia, which may contribute to the clinical symptoms and cognitive impairment of schizophrenia.
Dr. Hasbun has a clear research interest in central nervous system infections and have done pivotal studies in suspected meningitis, meningitis with a negative Gram stain and with bacterial meningitis. Most recently he has started to address HIV neurocognitive disorders at the Thomas Street Health Science Center in Houston.. He obtained funding from the Baylor UT CFAR to study HIV associated neurocognitive disorders to evaluated the MoCA as a screening tool and to evaluated the impact of neurocognition in retention in care. He is also a co-investigator of the U24 funded National Neuro AIDS Tissue Consortium.
HIV neurocognitive disorders range from asymptomatic neurocognitive impairment to CD8 encephalitis and AIDS dementia complex.. These disorders are seen in up to 50% of patients receiving highly active antiretroviral therapy and impair quality of life, activities of daily living and compliance with antiretroviral therapy.. Cerebrospinal fluid viral escape due to low central nervous system penetration of antiretrovirals could play a role for some of theses disorders and could be associated with discordant genotypes between the CSF and serum. We hereby describe the classification, screening of and potential therapies for this emerging syndrome.
University of Sherbrooke, Canada
Time : 13:25-13:45
Dr. Denis Gris is a head of neuroimmunology laboratory at the University of Sherbrooke QC Canada. He graduated from University of Western Ontario from Dr. Weaver’s laboratory where he studied inflammation after spinal cord injury. Dr. Gris moved to pursue his postdoctoral studies with Dr. Ting at university of North Carolina at Chapel Hills NC USA where he began to investigate role of NLRs in neurodegeneration. 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.
Many members of NLR family of proteins play an important role in human diseases including diabetes, Crohn’s disease, cancer, etc. We concentrated on the role of NLRs in neurodegenerative diseases. We postulate that Nlrs serve as sensors that detect intracellular stress. They can bind multiple proteins thus redirecting molecular signalling. In our work, we study mechanisms of neuroinflammatory responses and neuronal death. Using a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrate that Nlrx1 and Nlrp12 inhibit inflammation and improve biochemical and behavioural 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 secretion of cytokines including IL-1beta and TNF-alpha. Using N2A cell line, we demonstrated that Nlrx1 protects cells from rotenone toxicity. We demonstrated that Nlrx1 overexpressing cells were more viable and ration of apoptosis to necrosis was shifted to necrosis in cells that lacked Nlrx1. In conclusion, both Nlrx1 and Nlp12 decrease inflammatory responses in the CNS and, therefore, present as a target for treatments in neurodegenerative diseases
Uniformed Services University, USA
Time : 13:25-14:05
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. He obtained his MD in Binzhou Medical School, China, PhD in Hebrew University of Jerusalem, Israel, and Post-doc in the Children’s Hospital, Harvard Medical School. The major research interest in his 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.
Alpha/beta-hydrolase domain 6 (ABHD6) is a novel 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, that can fine-tune the endocannabinoid signaling in the central nervous system. Recently we and others have demonstrated the protective effect of ABHD6 inhibition in the animal models of traumatic brain injury and epileptic seizures. In this study, we investigated the role of targeting ABHD6 in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Post-symptom treatment with a selective ABHD6 inhibitor WWL70 dramatically ameliorated the clinical signs of EAE, T cells infiltration, microglia activation and the expression of activated leukocyte cell adhesion molecules which implicates the increased monocyte adhesion and migration in EAE mouse spinal cord. The production of iNOS, COX-2, TNF-α and IL-1β and the phosphorylation of NF-κB were also significantly reduced by WWL70 treatment. The neuroprotective effect of WWL70 was clearly demonstrated by increased mature oligodendrocytes, reduced demyelination and axonal loss in WWL70 treated EAE mouse spinal cord. Interestingly, the therapeutic effect of WWL70 on EAE was remarkably reversed by co-administration of CB2 receptor antagonist, but not CB1 receptor antagonist. Consistently, WWL70 did not have any protective effect in CB2 receptor knockout mice after EAE induction. Given the increased expression of ABHD6 in microglia/macrophages, but not in T cells, we speculated that inhibition of ABHD6 might enhance 2-AG signaling particularly in microglia/macrophages to exert anti-inflammatory effects via activation of CB2 receptors. These results suggest that inhibition of ABHD6 might be used as an ideal strategy for the treatment of MS and other neurodegenerative diseases.
Presbyterian College School of Pharmacy, USA
Title: Modulation of neuroimmune interactions using nanotechnology to prevent the development of chronic pain
Time : 14:05-14:25
E Alfonso Romero-Sandoval is originally from Guatemala, and received his MD from Universidad de San Carlos de Guatemala in 1999 and his PhD in Neuroscience from Universidad de Alcalá, Alcalá de Henares, Spain, in 2003. He did a postdoctoral training at Wake Forest University, Winston Salem, NC (2003-2006) and at Geisel Dartmouth Medical School, Lebanon, NH (2006-2007). He was Instructor (2007-2009) and Assistant Professor (2009-2012) at Geisel Dartmouth Medical School, Lebanon, NH. Currently (2012-present) he is Associate Professor and Director of Research at Presbyterian College School of Pharmacy, Clinton, SC. Romero-Sandoval is studying the molecular mechanisms of spinal cannabinoid receptor 2 activation for induction of analgesia, the role of endocannabinoids in postoperative pain, the function of phosphatases and kinases in spinal cord in the transition from acute to chronic pain, the use of nanotechnology to promote surgical wound healing and to prevent the development of chronic postoperative pain.
The interactions of glial cells (spinal cord) or macrophages (periphery) and neurons have been demonstrated to be signifi cant players in the mechanisms underlying chronic pain. We have identifi ed novel signaling pathways that physiologically regulate mitogen activated-protein kinases (MAPKs), namely MAP kinase phosphatases (MKPs) and CD163. We uncovered that both molecules seem to play signifi cant roles in microglial cells in the spinal cord, and in macrophages at the periphery in regulating the resolution of infl ammatory processes. We have observed that the lack of MKP-3 (KO mice) in spinal cord or the periphery results in the development of chronic pain following a surgical model of acute pain. Likewise, we have observed that the induction of MKPs or CD163 using nanotechnology in microglia or macrophages prevent the development of chronic pain,and induces an anti-infl ammatory phenotype by reducing the expression of p-p38 and p-ERK MAPKs. Our data uncovered that MKPs or CD163 molecules are suitable targets for gene therapies directed to prevent the development of chronic pain. Furthermore, we have demonstrated that specifi c nanoparticles with proven clinical relevance could be implemented to develop an innovative cell-directed gene therapy for chronic pain conditions.
Brunel University, UK
Time : 14:25-14:45
Uday Kishore completed his PhD from University of Delhi and did post-doctoral training at the Salk Institute (California) and University of Oxford. He is currently the Director of Centre for Infection, Immunity and Disease Mechanisms at Brunel University London. Prof Kishore’s research interests include understanding role of innate immunity in human health and disease. He is a receipient of fellowships from NASA, Wellcome Trust, Medical Research Council UK, and Humboldt Foundation. He was recently awarded the prestigious Mother Teresa Excellence Award in 2014.
C1q is the first subcomponent of the complement classical pathway. Classically, it is known to bind to immune complexes containing IgG and IgM and trigger the complement cascade leading up to the generation of membrane attack complex and C3a and C5a fragments that cause cellular infiltration. In addition, C1q is also known as a charge pattern recognition molecule which is involved in the clearance of non-self and altered self. It has become increasingly evident that C1q (and other complement proteins) can be made locally by microglia, neurons and atrocytes within the central nervous system. Thus, C1q can bind beta amyloid aggregates and precipitate neuroinflammation and neurodegeneration in Alzheimer’s Disease (AD) via classical pathway as well as microglia activation. It turns out that developmental expression of C1q is essential for synaptic prunning and C1q deficiency can have aberrant neuropathogical consequences. Therefore, under pathological conditions, regulating C1q expression and its target binding can have therapeutic benefits. We have identified two recombinant inhibitors of the classical pathway that interfere at the C1q function level. We have also immunologically characterised a natural model of AD, a Chilean rodent called Octodon degus, and found a direct link between complement activation (via C1q upregulation) and burrowing behaviour.
Cedars-Sinai Medical Center , USA
Title: The therapeutic roles of ACE-overexpressing macrophages and resistance to structurally defined Aβ1-42 forms
Time : 14:45-15:05
Maya Koronyo-Hamaoui, Ph.D., Assistant Professor in the Department of Neurosurgery and the Department of Biomedical Sciences at Cedars Sinai Medical Center, is head of the Neuroimmunology and Retinal Imaging Laboratory in the Department of Neurosurgery. She has held research positions at the Danek Gertner Institute of Human Genetics at The Chaim Sheba Medical Center at Tel Hashomer and was a faculty adjunct lecturer at The Sackler School of Medicine at Tel Aviv University, in Israel. She earned her bachelor’s degree cum laude and her master’s magna cum laude at Tel Aviv University before receiving her Ph.D. in human molecular genetics and psychiatric genetics at the university’s Sackler School of Medicine. She completed her postdoctoral fellowship in neuroimmunology at one of the world’s leading neuroimmunology laboratories at the Weizmann Institute of Science, Rehovot. Dr. Koronyo-Hamaoui’s laboratory focuses on various models of acute and chronic CNS-degeneration, with a great emphasis on Alzheimer’s disease: retinal pathology, retinal imaging and immune-based therapies. Her pioneering work on imaging of beta-amyloid retinal pathology created the basis for translating this novel approach to the clinic for early detection of Alzheimer’s disease through a non-invasive eye scanning; her team is committed to developing a definitive diagnosis early, when the disease is most likely to be treatable. Her other main focus is on immune-based mechanisms of repair and regeneration in the brain and developing immune-modulation therapies for Alzheimer's disease. In addition to the BrightFocus award, she has received the George S. Wise Faculty of Life Sciences recognition, the Wolf Fund and Sackler School of Medicine Faculty Dean's Honor & Prize for Best Achievements, a Pioneer in Medicine Award from the Brain Mapping Foundation, and the primary research award from the Coins for Alzheimer’s Research Trust (CART) Fund.
Introduction: Previously, a fundamental role for monocyte-derived macrophages (Mo/MΦ) was implicated for the clearance of amyloid β-protein (Aβ) that is tightly associated with Alzheimer’s disease (AD) pathology. Angiotensin-converting enzyme (ACE) can degrade neurotoxic Aβ1-42 and mice overexpressing ACE in myelomonocytic cells (i.e. microglia, Mo, and MΦ; termed ACE10) have enhanced innate immune responses. We further demonstrated that targeted ACE-overexpression in myelomonocytes in APPSWE/PS1ΔE9 transgenic mice modeling AD (AD+) markedly attenuated AD-associated pathology and cognitive decline via enhanced recruitment of Mo/MΦ. Aims: To further investigate the therapeutic potential of ACE-overexpressing (ACE10)-Mo/MΦ and their ability to eradicate and resist structurally defined forms of Aβ. Methods: Peripheral blood enrichment with bone marrow (BM)-derived ACE10-Mo was achieved through BM transplantation (irradiation with head shielding) or adoptive transfer into the tail vein of AD+ mice. In vitro studies were utilizing primary cultures of ACE10- vs. WT-MΦ to evaluate phagocytosis capacity, cell morphology, intracellular Aβ processing, and enzymatic degradation in response to structurally defined forms of Aβ1-42. Results: Peripheral blood enrichment of ACE10-Mo alleviated disease progression in AD+ mice. We revealed that BM-ACE10 as compared to BM-WT or BM-AD+ resulted in reduction of soluble and fibrillar Aβ as well as GFAP+ reactive astrocytes. Transplantation of GFP-labeled BM cells allowed us to track the cells in the brain and characterize them around Aβ plaques. We found increased infiltration of ACE10- vs. WT-Mo/MΦ and their reduced TNF production. Adoptive transfer of ACE10-Mo derived from young donor mice into symptomatic AD+ mice markedly attenuated cognitive decline assessed by the Barnes maze test and cerebral Aβ and hippocampal GFAP+ levels. Our in vitro studies indicated the high capacity of BM-derived ACE10- vs. WT-MΦ to bind and uptake fibrillar (f) and oligomeric (o) Aβ1-42, especially at early time points (5-15 minutes). Accelerated rates of extracellular fAβ1-42 degradation by ACE10-MΦ were detected after 18, 20, and 23 hours. Both cellular uptake and extracellular degradation of fAβ1-42 were significantly reduced by inhibition of ACE catalytic domains (Lisinopril). Moreover, we discovered a unique, potentially ‘protective’, cell morphology associated with ACE10- as compared to WT-MΦ in response to fAβ1-42, along with increased scavenger receptors’ expression. Conclusions: These studies provide evidence to support powerful therapeutic effects to the genetically modified Mo/MΦ (ACE10) in curbing Aβ-induced toxicity and controlling neuroinflammation associated with AD.
University of Alabama, USA
Time : 15:05--15:25
Tara DeSilva, Assistant Professor, recently joined the faculty at the University of Alabama at Birmingham after her postdoctoral fellowship at Harvard Medical School and Children’s Hospital Boston. The research in Dr. DeSilva’s laboratory focuses on understanding demyelinating diseases such as Multiple Sclerosis and Transverse Myelitis. Dr. DeSilva’s research has been awarded grants from the National Multiple Sclerosis Society, National Science Foundation, and the National Institutes of Health. The goal of Dr. DeSilva’s research is to understand 1) how activity-dependent mechanisms stimulate glutamatergic signaling between axons and oligodendrocyte progenitor cells (OPCs) to turn on transcriptional programs necessary for myelination; and 2) how immune cell infl ammatory mediators prevent newly proliferated OPCs, as a consequence of neuroinfl ammation, from forming normal mature myelin. The goal of these studies is to understand how to reprogram newly proliferated OPCs to remyelinate, which has important implications in neural regeneration in demyelinating diseases like multiple sclerosis as well as neurodegenerative diseases. To elucidate these mechanisms Dr. DeSilva’s laboratory uses conditional knockout mice in developmental models of myelination, animal models of experimental autoimmune encephalomyelitis, and co-culture models of immune cells and glia cells.
T cell infi ltration into the central nervous system (CNS) is a signifi cant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infi ltration in neuroinfl ammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc- transporter, however, this mechanism has not been tested in animal models of autoimmune infl ammatory demyelination. We fi nd that pharmacological and genetic inhibition of system Xc- attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc- seven days aft er induction of EAE attenuated T cell infi ltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system Xc- were resistant to EAE, corroborating a central role for system Xc- in mediating immune cell infi ltration. We next examined the role of the system Xc- transporter in the CNS aft er immune cell infiltration .Pharmacological inhibitors of the system Xc- transporter administered during the fi rst relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, infl ammation, and myelin loss. Primary co-culture studies demonstrate that myelin-specifi c CD4+ T helper type 1 (Th 1) cells provoke microglia to release glutamate via the system Xc- transporter causing excitotoxic death to mature myelin-producing OLs. Taken together these studies support a novel role for the system Xc- transporter in mediating T cell infi ltration into the CNS as well as promoting myelin destruction aft er immune cell infi ltration in EAE.
University of Warsaw, Poland
Title: The infl uence of glucocorticoids on the day/night changes of thymus-deriving natural regulatory T cells development and function
Time : 15:25-15:45
Ewelina Kiernozek has completed individual PhD studies on the Faculty of Biology at the University of Warsaw. She manages the Laboratory of Cytometry in Department of Immunology at Faculty of Biology UW. She co-operates with other scientifi c units, for example Department of Organic Food Faculty of Human Nutrition and Consumer Science SGGW (Warsaw), Department of Biochemistry (Medical University of Warsaw) or Department of Molecular Biology (Centre of Oncology in Warsaw). She also works in Institute of Genetic Analysis – INAGEN which deals with analysis of selected fragments of the genome of the athletes that determine innate predisposition to the development of physical characteristics relevant in professional sports.
Natural CD4+CD25+Foxp3+ regulatory T (nTreg) cells develop in the thymus and migrate in the periphery as a mature population of T lymphocytes with suppressive activity. They play a crucial role in the maintenance self-tolerance and immune homeostasis. Furthermore, nTregs have signifi cant therapeutic potential in suppressing autoreactive T cells and protecting from autoimmune diseases and chronic infl ammation. Currently, the mechanisms regulating nTregs development are still unclear. One of the factors, but still little explored, aff ecting their development and regulation of immune function are glucocorticoids. It is known that glucocorticoids are produced mainly by the adrenal cortex under the control of HPA axis. The treatment of mice with a synthetic glucocorticoid hormone, dexamethasone (Dex) induces the increase of Foxp3 expression in CD4+CD25+ thymocytes and their suppressive function. Considering the important role of HPA axis and glucocorticoids as effector molecules in the regulation of the immune response we aimed to determine the content and function of thymic nTregs in males and females C57BL/6 mice aft er treatment with Dex (25mg/kg/body weight) in a day/night dependent fashion. Results indicated that glucocorticoids play a role in the survival and development of thymocytes, thus, infl uencing the distribution of thymocyte subsets. Their concentration in the thymus deriving from endogenous synthesis and exogenous supplementation in accordance with the circadian rhythm of their synthesis correlate with the content and function of CD4+CD25+Foxp3+ cells.
Tsukuba University, Japan
Title: Pathophysiological roles of the prostaglandin D2 system in the central and peripheral nervous system
Time : 16:00-16:20
Yoshihiro Urade has completed his PhD at the age of 29 years from Kyoto University in 1983 and postdoctoral studies from ERATO project of Japan Science and Technology Agency. He was the visiting professor of Roche Institute of Molecular Biology in 1988, the senior scientist of International Laboratories of CIBA-GEIGY Japan in 1990, and the vise-head of Department of Molecular Behavioral Biology of Osaka Bioscience Institute in 1993, and the head of this department in 1998 to 2014. In 2014, he became a principal investigator of a newly established institute in Tsukuba University. He has published more than 300 papers in reputed journals and has been serving as an editorial board member of Prostaglandins, Leukotriens and Essential Fatty Acids and as the secretary general of Asian Society of Sleep Medicine (ASSM).
Prostaglandin (PG) D2 is a major prostanoid produced in the CNS of various mammals including humans and acts as an endogeneous sleep-promoting substance and an infl ammatory lipid mediator. PGD2 is produced by two distinct synthases, i.e., lipocalin-type PGD synthase (L-PGDS) and hematopoietic PGD synthase (H-PGDS), and stimulates two distinct G-proteincoupled receptors, Gs-coupled DP1 receptor and Gi-coupled DP2 (CRTH-2/GPR-44) receptor. (1) In the CNS, L-PGDS is dominantly expressed in the leptomeninges, choroid plexus and oligodendrocytes, and secreted into the cerebrospinal fluid (CSF) as beta-trace protein, a major human CSF protein, whereas H-PGDS is localized in microglia and mast cells. DP1 receptor is localized in subpopulation of cells within the leptoneninges and glial limitance and upregulated in hypertrophied astrocytes in various neuro-infl ammatory circumstances. DP2 receptor is expressed in various infl ammatory cells including activated microglia and invaded macrophages aft er brain damages. By using gene-knockout mice and pharmacological blockades with enzyme inhibitors or receptor antagonists, we revealed that the L-PGDS/DP1 receptor system is involved in the regulation of sleep; (2) the L-PGDS/DP2 system, in myelination of Schwann cells; (3) the H-PGDS/DP1 system, in the suppression of epilepsy; (4) and the H-PGDS/DP2 system, in the chemotaxis of infl ammatory cells during neuroinfl ammation. We reported that L-PGDS/beta-trace protein secreted into the human CSF is upregulated aft er subarachnoid hemorrhage and acts as a scavenger for biliverdin, a harmful heme-degrading product.(5) We recently found that L-PGDS/beta-trace protein binds PGD2 at a high affi nity with Kd value in a submicromoler range and also covalently binds PGJ2 derivatives, nonenzymic dehydration products of PGD2. Th ese results are useful to develop new drugs targeting the PGD2 system and diagnostic kits for various neuroinfl ammatory and neuroimmunological diseases.
University of Western Ontario, Canada
Title: Physiological stress results in potent suppression of iNKT cells following alpha-galactosylceramide mediated activation
Time : 16:20-16:40
Christopher Shaler completed his Ph.D in 2014 at McMaster University, Ontario, Canada. During his tenure as a graduate student he was the recipient of various awards, including numerous awards for graduate student excellence as well as the prestigious, Canadian Institutes of Health Research, Banting and Best’s Doctoral scholarship award. Christopher Shaler has published 14 peer-reviewed publications, with 2 first author primary research papers and 2 first author reviews. Currently, Christopher is entering his second year as a postdoctoral researcher at the University of Western Ontario.
It has long been recognized that physiological stress is associated with an increased risk of infection. Despite these observations it is incompletely understood as to how physiological stress infl uences the immune system resulting in this increased susceptible to infection. While it is known that the production of cortisol and its ensuing eff ects can potently suppress many facets of the immune response, cortisol alone cannot completely explain the impaired functionality seen following physiological stress. Indeed, stress is known to induce the release of various catecholamines with demonstrable immune modulatory eff ects. In our current study, we utilized a murine model of restraint stress to evaluate the impact of physiological stress on the function of a unique population of invariant Natural Killer T cells (iNKT cells). Highly enriched in mice, iNKT cells play a key role in initiating the immune response to various infections. Utilizing a potent and selective activator of iNKT cells,alpha-galactosylceramide, we have demonstrated in vivo that physiological stress blunts iNKT cell activated preventing the secretion of pro -inflammatory cytokines following in vivo activation. Further, we have demonstrated that it is the production of norepinephrine, rather than cortisol, that is responsible for this impaired functionality. Our work for the fi rst time begins to evaluate the impact of physiological stress and its impact on the functionality of critical innate immune initiators, giving insight into the mechanisms by which stress leaves an individual highly susceptible to infection.
Khon Kaen University, Thailand
Title: Physiological stress results in potent suppression of inkt cells following alpha-galactosylceramide mediated activation
Time : 16:40-17:00
Chantana Boonyarat has completed her PhD from Mahidol University, Bangkok, Thailand. She is the lecturer at the faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand. She has published more than 15 papers in reputed journals.
Beta-amyloid (Aβ) is a major pathogenic peptide for Alzheimer’s disease (AD). Th e Aβ monomers aggregate into oligomeric and fi brillar forms which have been implicated as the toxic species inducing the neuronal dysfunction. Chalcone is known for its anti-oxidant and anti-infl ammatory functions. Th erefore, we investigated the eff ects of fi ve chalcones extracted from Dorris intica on aggregation of Aβ peptides and neuroprotection. Five chalcones extracted from the fruit of Dorris intica included obovatachalcone, tunicatachalcone, ovalichalcone, pongamol, derrischalcone. Th e results exhibited that almost compounds except pongamol showed an ability to inhibit Aβ1-42 aggregation assessed by Th iofl vin T assay. Ovalichalcone exhibited the highest activity with inhibitory percentage of 75.1 at 50 μM. Molecular modeling studies revealed that these compounds interacted with Aβ1-42 side chain at salt bridge (Asp23 – Lys28) and hydrophobic region (residue 17 - 21) which are important for amyloid aggregation. For neuroprotection assessed by cell culture model, our results showed that all of these compounds could reduce neuronal death induced by Aβ1-42 toxicity. Th e overall results indicated that the chalcones extracted from Dorris intica possess amyloid aggregation inhibitory action and neuroprotection. Th us, these compounds canbe considered as a promising candidate for further pharmacological development in Alzheimer’s therapy.