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Second German-Japanese Neuroimmunology Symposium Eibsee, Germany Thursday July 9 – Sunday July 12 2009 The talks in each session are arranged for a length of 15 minutes plus 5 minutes discussion. Please hand over your presentation on a USB stick or make sure your laptop is connected to the cpu switch in the meeting room before your session starts. Organizing committee: Reinhard Hohlfeld, Munich Edgar Meinl, Munich Hartmut Wekerle, Munich Takashi Yamamura, Tokyo Supported by Gabriele Boehlke, Jutta Marks, Stefanie Merker Second German-Japanese Neuroimmunology Symposium Eibsee, Thu 9th – Sun 12th July 2009 Overview Thursday, July 09 15.00 Reception, Welcome 18.00 Dinner 19.00 Welcome by Hartmut Wekerle Opening Lecture: Takashi Yamamura Friday, July 10 08.30 - 09.50 Session 1: Regulatory cells and basic neuroimmunology 10.10 - 12.00 Session 2: Migration and models of CNS inflammation 12.00 Lunch 13.00 Excursion to Neuschwanstein Castle and Wies-Church (UNESCO world heritage). Dinner in Oberammergau. Saturday, July 11 08.30 - 10.10 Session 3: Cytokines and neuroinflammation 10.30 - 12.10 Session 4: Neurobiology and pathology of MS 12.15 Lunch 14.00 - 16.40 Session 5: Therapy 17.30 Excursion to the Zugspitze with Dinner (Bayerischer Abend) Sunday, July 12 08.30 - 09.50 Session 6: Autoreactivity in MS 10.10 - 11.50 Session 7: NMO and others 12.00 Lunch and Farewell 3 Detailed program T HURSDAY 19.00 Opening remarks: Hartmut Wekerle Opening lecture: Takashi Yamamura FRIDAY 08.30 - 09.50 Session 1: Regulatory cells and basic neuroimmunology Chairs: Sachiko Miyake and Roland Martin 8.30 – 8.50 Sachiko Miyake National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo The role of regulatory cells in the regulation of EAE 8.50 – 9.10 Heinz Wiendl Julius Maximilians University of Würzburg Regulatory T cells in MS 9.10 – 9.30 Atsushi Kumanogoh Research Institute for Microbial Diseases, Osaka University Involvement of semaphorins, axonal guidance cues, in pathogenesis of EAE via regulating immune cell migration 9.30 – 9.50 Saburo Sakoda Osaka University Graduate School of Medicine The role of sema4A in multiple sclerosis 09.50 - 10.10 Coffee break 4 10.10 - 12.00 Session 2: Migration and models of CNS inflammation Chairs: Avi Ben-Nun and Takashi Kanda 10.10 – 10.30 Takashi Kanda Yamaguchi University Graduate School of Medicine, Ube A new model for studying blood nerve barrier 10.30 – 10.50 Britta Engelhardt Theodor Kocher Institute, University of Bern α4-integrins mediate the recruitment of immature dendritic cells across the blood-brain barrier during experimental autoimmune encephalomyelitis 10.50 – 11.10 Klaus-Armin Nave Max Planck Institute for Experimental Medicine, Göttingen The role of oligodendrocytes in maintaining white matter integrity 11.10 – 11.30 Guru Krishnamoorthy Max Planck Institute of Neurobiology, Martinsried Spontaneous EAE models 11.30 – 11.50 Naoto Kawakami Max Planck Institute of Neurobiology, Martinsried Migration patterns of autoreactive T cells 12.00 Lunch buffet 13.00 Excursion to Neuschwanstein Castle and Wies Church 13.00 – 13.15 Departure from the Eibsee Hotel 14.45 – 15.00 Arrival at the parking place of Neuschwanstein Castle, about 30 min. walk to the castle 5 15.30 – 16.00 Guided Tour (30 min.): Neuschwanstein Castle 30 min. walk back to the parking place 17.00 – 17.30 Departure and transfer to the Wies Church 17.30 Wies Church: Guided Tour (45 min.) 18.30 – 18.45 Departure to Oberammergau 19.15 Arrival at Oberammergau, Dinner in the restaurant "Ammergauer Maxbräu" (Hotel Maximilian) und return to the Eibsee Hotel. S AT U R D A Y 08.30 - 10.10 Session 3. Cytokines and neuroinflammation Chairs: Arthur Melms and Akio Suzumura 8.30 – 8.50 Burkhard Becher Department of Neurology, University Hospital, Zurich Th17 derived factors: the target organ matters 8.50 – 9.10 Thomas Korn Technical University Munich Th17 cells and EAE 9.10 – 9.30 Akio Suzumura Institute of Environmental Medicine, Nagoya University, Nagoya Production and functions of IL-25 in the CNS 9.30 – 9.50 Martin Kerschensteiner Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich In vivo pathogenesis of immune-mediated axon damage 9.50 – 10.10 Norbert Goebels Department of Neurology, University Hospitals Zurich/Basel Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss 6 10.10 - 10.30 Coffee break 10.30 - 12.10 Session 4: Neurobiology and Pathology of MS Chairs: Hans-Karl Müller-Hermelink and Takeshi Tabira 10.30 – 10.50 Christine Stadelmann-Nessler Georg August University Göttingen Grey matter damage in inflammatory demyelination 10.50 – 11.10 Zsolt Illes University of Pecs, Hungary Poly(ADP-ribose) polymerase (PARP) is activated in multiple sclerosis pattern III lesions and its inhibition prevents experimental demyelination and oligodendrocyte death 11.10 – 11.30 Jun-ichi Satoh Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo Molecular network of the comprehensive multiple sclerosis brain lesion proteome 11.30 – 11.50 Robert Weissert Division of Neurology, Geneva University Hospital Antigen presentation in the CNS in multiple sclerosis 11.50 – 12.10 Toshimasa Aranami National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo a-B crystalline as an immunomodulator in MS 7 12.15 Lunch 14.00 - 15.20 Session 5: Therapy Chairs: Ludwig Kappos and Jun-ichi Kira 14.00 – 14.20 Takeshi Tabira National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Tokyo Alzheimer’s disease vaccine 14.20 – 14.40 Yoh Matsumoto Tokyo Metropolitan Institute for Neuroscience Non-viral DNA vaccine therapy against Alzheimer's disease-effects, safety and mechanisms of Abeta clearance" 14.40 – 15.00 Ralph Gold Ruhr University Bochum Complications and monitoring of natalizumab therapy 15.00 - 15.40 Coffee break 15.40 - 16.40 Continuation of session 5 (Therapy) 15.40 – 16.00 Ludwig Kappos University Hospital Basel Oral treatments of MS 8 16.00 – 16.20 Matthias Meergans Novartis An update on fingolimod 16.20 – 16.40 Shinji Oki National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo Nuclear receptors as therapeutic target for multiple sclerosis 17.30 Bavarian Evening on Mount Zugspitze 17.30 Departure from the Eibsee Hotel 17:45 Eibsee station (1.000 m altitude), driving up-hill by the rack and pinion railway 18:25 Platt station (2.600 m altitude), arrival & terminal stop of the railway 18:30 Glacier railroad, driving up-hill by cable car; 3,5 min. to the peak. “Schnapps” reception on the peak terrace (2.955 m altitude) 19:00 Glacier railroad to „Sonn Alpin“ at 2.600 m altitude, followed by drinks and the opening of the snack buffet. 22:00 Platt station, driving down-hill by the rack and pinion railway (1 train for all of us) 22:40 Eibsee station, arrival 9 SUNDAY 08.30 - 09.50 Session 6. Autoreactivity in MS Chairs Toshimasa Aranami and Alexander Flügel 8.30 – 8.50 Roland Martin Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Hamburg CD4+ T cells in MS - Antigen recognition, phenotype and therapeutic implications 8.50 – 9.10 Klaus Dornmair Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich Reconstitution of functional autoaggressive T cells from biopsy samples 9.10 – 9.30 Bernhard Hemmer Technical University Munich Antibodies and biomarkers 9.30 – 9.50 Edgar Meinl Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich Novel axoglial autoantigens 09.50 - 10.10 Coffee break 10 10.10 - 11.50 Session 7: NMO and others Chairs: Reinhard Hohlfeld and Susumu Kusunoki 10.10 – 10.30 Susumu Kusunoki Kinki University School of Medicine, Osaka Gangliosides and ganglioside complexes as targets for neuroimmunological diseases 10.30 – 10.50 Jun-ichi Kira Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka AQP4 autoimmune syndrome and anti-AQP4 antibody-negative opticospinal MS in Japanese: neuroimmunological and genetical studies 10.50 – 11.10 Kazuo Fujihara Tohoku University Graduate School of Medicine, Sendai Neuromyelitis Optica: An Update 11.10 – 11.30 Monika Bradl Institute for Brain Research, Vienna Testing the pathogenicity of NMO IgG in vivo 11.30 – 11.50 Fujio Umehara Graduate School of Kagoshima University Recent progress of HTLV-I associated neurological disorders 12.00 Lunch and Farewell 11 Second German-Japanese Neuroimmunology Symposium ABSTRACTS 12 Second German-Japanese Neuroimmunology Symposium: Opening Lecture Multiple sclerosis research in Japan: past, present and future Takashi Yamamura Department of Immunology, National Institute of Neuroscience, NCNP It is widely accepted that development of multiple sclerosis (MS) is under control of both genetic and non-genetic factors. While recent whole genome analysis has revealed a number of gene polymorphisms linked with susceptibility to MS, knowledge about nongenetic factors in human MS is limited. Although Japan was known as a country where the prevalence rate of MS is very low, we have seen a remarkable increase of patients with MS in the last decades, allowing us to believe that improved hygiene status and/or adoption of western eating habits may play some role. With a mission to prevent the increase of MS in Japan, we are eager to clarify the mechanism of how non-genetic factors would influence on the development of autoimmune diseases. Our interests are particularly focused on the nongenetic factors that influence the function of Th17 cells and regulatory NKT cells and MAIT cells. In this line, I will discuss on the role of gut flora, helicobacter pylori, and vitamin A in the pathogenesis of MS. 13 Second German-Japanese Neuroimmunology Symposium: Session 1 The role of regulatory cells in the regulation of EAE Sachiko Miyake National Institute of Neuroscience, NCNP Sachiko Miyake, Hiroaki Yokote, Youwei Lin, Takashi Yamamura Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo The immuno-regulatory cells such as regulatory T (Treg) cells and invariant natural killer T (iNKT) cells are important in the regulation of autoimmune pathogenesis. We first demonstrate that iNKT cells are a sensitive detector for the environmental changes including intestinal flora. When we administered a mixture of non-absorbing antibiotics, kanamycin, colistin and vancomycin (KCV) orally to mice induced for EAE, the composition of gut flora was altered and the development of EAE was ameliorated. The suppression of EAE was associated with a reduced production of pro-inflammatory cytokines such as IL-17 from the draining lymph node cells and mesenteric lymph node cells. Moreover, we found that iNKT cells were required for maintaining the mesenteric Th17 cells and KCV-mediated suppression of EAE. Thus gut flora would influence the development of EAE in a way dependent of iNKT cells, which has significant implications for the prevention and treatment of autoimmune diseases. We next show that slight differences in the auto-antigen has different capacity to induce regulatory cells and autoimmune disease. Immunizing susceptible mice with proteolipid protein (PLP) peptide 139-151 (PLP139-151) induces relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) resembling MS. In contrast, immunization with a cross-reactive peptide PLP136-150 induces only a single EAE attack, and confers mice protection against RR-EAE. We found that the overlapping peptides sharing core peptide sequence PLP139-150 differentially induce most efficacious regulatory T cells (Foxp3+CD69+CD103+) in the draining lymph nodes. Furthermore, we revealed that Foxp3+CD69+CD103+ Tregs express RORgt, suggesting that these cells are the counterpart of active T regs recently reported in the human Treg popurations. These findings have implications for understanding the pathogenesis and the heterogeneity of clinical course of autoimmune diseases. 14 Second German-Japanese Neuroimmunology Symposium: Session 1 Regulatory T cells in MS Heinz Wiendl Julius Maximilians University of Würzburg The dysregulation of inflammatory responses and of immune self-tolerance is considered to be a key element in the autoreactive immune response in multiple sclerosis. Regulatory T cells (Treg) have emerged as crucial players in the pathogenetic scenario of CNS autoinflammation. Targeted deletion of Treg cells causes spontaneous autoimmune disease in mice, whereas augmentation of Treg cell function can prevent the development of or alleviate variants of experimental immune encephalomyelitis, the animal model of MS. Recent findings indicate that MS itself is also accompanied by dysfunction or impaired maturation of certain Treg populations. Conceptually, regulatory T cells could influence immune responses at the level of primary and secondary lymphoid organs during the initiation and perpetuation phase of autoimmune reactions. However, in addition Tregs might also play a key role in the parenchymal immune-regulation. A population of natural regulatory T cells characterized by the expression of the non-classical MHC class-1 molecule HLA-G was recently identified and characterized by our group. We provide data showing that these cells are specifically recruited to the central nervous system, in order to counterbalance inflammatory attacks. Finally, the use of regulatory T cells or the amplification of its function could be an achievable approach in the therapy of (auto)inflammatory disorders. 15 Second German-Japanese Neuroimmunology Symposium: Session 1 Involvement of semaphorins, axonal guidance cues, in pathogenesis of EAE via regulating immune cell migration Atsushi Kumanogoh Department of Immunopathology, Research Institute for Microbial Diseases, World Premier International Immunology Frontier Research Center, Osaka University, 3-1 Ymada-oka, Suita, Osaka 565-0871, Japan Semaphorins and their receptors have been identified as ‘repulsive’ axonal guidance cues that regulate direction and migration of neuronal cells during neuronal development. However, cumulative evidence indicates that they have diverse and important functions in other physiological processes, including heart development, vascular growth, tumor progression and immune responses. In particular, it is emerging that several semaphorins are critical for various phases of physiological and pathological immune responses, in which they exhibit co-stimulatory molecule-like activities to promote activation of B-cells, T-cells, dendritic cells (DCs) or macrophages through interactions between immune cells. Although the evidence highlights the importance of semaphorins in the immune system, their involvement in immune cell movement still remains unclear. We here present that plexin-A1, a primary receptor component for class III and class VI semaphroins, is crucially involved in trafficking of DCs and that plexin-A1-deficient mice are resistant to the development of experimental autoimmune encephalomyelitis (EAE). In addition, we show that Sema3A, not Sema6C or Sema6D, is required for transmigration of DCs across lymphatic endothelial cells. Collectively, these findings not only demonstrate the involvement of semaphorinsignals in DC trafficking but also provide a novel mechanism for DC-transmigration. 16 Second German-Japanese Neuroimmunology Symposium: Session 1 The role of sema4A in multiple sclerosis Saburo Sakoda Department of Neurology and Bio-medical Statistics, Osaka University Graduate School of Medicine Saburo Sakoda, Yuji Nakatsuji, Masayuki Moriya, Tatsusada Okuno, Makoto Kinoshita, Tomoyuki Sugimoto, Misa Nakano, Hitoshi Kikutani, Atsushi Kumanogoh, Department of Neurology and Bio-medical Statistics, Osaka University Graduate School of Medicine, Department of Immunopathology, Research Institute for Microbial Diseases, Osaka University, Toyonaka Municipal Hospital Background: While Semaphorins have been investigated mainly as axonal guidance molecules in the developing central nervous system (CNS), their significance in the immune system is emerging. Sema4A, a class 4 semaphorin, is important for the naïve T cell differentiation into Th1 cells and the treatment with anti-Sema4A antibody ameliorates experimental autoimmune encephalomyelitis (EAE). Objectives: Investigate the role of Sema4A in the pathogenesis of multiple sclerosis (MS). Methods: We generated monoclonal anti-Sema4A antibodies by immunizing Sema4Adeficient mice with recombinant human Sema4A protein, and established an ELISA system. Serum samples were collected from 69 patients with MS and 113 patients with other neurological diseases (OND). mRNA was prepared from CD4-positive, CD45RO-positive T cells of patients with MS, and quantitative RT-PCR for RORC and GATA3 was performed. Results: The serum Sema4A levels were significantly higher in patients with MS than OND. Receiver operating characteristic curve indicated that the disease sensitivity and the specificity were 36% and 90% respectively. Especially one third of patients with MS exhibited markedly high serum Sema4A levels. T cells obtained from MS patients with high Sema4A levels exhibited the character of Th17 cells compared to those with low Sema4A levels. Conclusions: 1) The level of serum Sema4A is significantly higher in patients with MS. 2) Sema4A participates in not only Th1 differentiation but also Th17 shift. These results suggest critical roles of Sema4A in the pathogenesis of MS. 17 Second German-Japanese Neuroimmunology Symposium: Session 2 A new model for studying blood nerve barrier Takashi Kanda Yamaguchi University Graduate School of Medicine, Ube To understand the migration mechanisms of inflammatory cells into the nervous system in various neuroimmunological disorders, human cells originating from blood-brain barrier (BBB) and blood-nerve barrier (BNB) are mandatory. In recent years cell lines of microvascular endothelial cells of human BBB origin (HBMEC) have been successfully established in some laboratories worldwide; however, very few studies have been directed to BNB and no adequate cell lines originating from BNB had been launched. In addition, no cell lines of pericyte, another key player composing BBB and BNB, had been established. In our laboratory, we successfully established human immortalized endothelial and pericyte cell lines originating from BBB and BNB using temperature-sensitive SV40 large T antigen and human telomerase gene. HBMEC cell line and human peripheral nerve microvascular endothelial cell (HPnMEC) line equally showed high transendothelial electrical resistance and most of the tight junction molecules and influx as well as efflux transporters were shared by these two cell lines. Human pericyte cell lines also possessed various tight junction proteins and secrete various cytokines and growth factors including bFGF, VEGF, GDNF, NGF, BDNF and angiopoietin-1. Co-culture with pericytes or pericyte-conditioned media strengthened barrier properties of HBMEC and HPnMEC. This result suggests that in addition to astrocytes, pericytes slso play key roles in maintaining the barrier function. This pericytic contribution is especially important in BNB, because BNB is considered to be functionally as effective as BBB despite absence of astrocytes. 18 Second German-Japanese Neuroimmunology Symposium: Session 2 α4-integrins mediate the recruitment of immature dendritic cells across the blood-brain barrier during experimental autoimmune encephalomyelitis Britta Engelhardt Theodor Kocher Institute, University of Bern, Bern, Switzerland Dendritic cells (DCs) within the central nervous system (CNS) are recognized to play an important role in the effector phase and propagation of the immune response in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. However, the mechanisms regulating DC trafficking into the CNS still need to be characterized. Here we show by performing intravital fluorescence videomicroscopy of the inflamed spinal cord white matter microvasculature in SJL mice with EAE that immature, but not LPS-matured, bone marrow-derived DCs efficiently interact with the CNS endothelium by rolling, capturing and firm adhesion. Immature, but not of LPS-matured DCs efficiently migrated across the inflamed microvascular wall into the CNS. Blocking α4-integrins interfered with the adhesion, but not rolling or capturing of immature and LPS-matured DCs to the CNS microvascular endothelium, preventing their migration across the vascular wall. Our study shows that during EAE especially immature DCs migrate into the CNS, where they may be crucial for the perpetuation of the CNS-targeted autoimmune response. Therapeutic targeting of α4integrins affects DC trafficking into the CNS and therefore may lead to the resolution of the CNS autoimmune inflammation by depleting the CNS of professional antigen presenting cells. 19 Second German-Japanese Neuroimmunology Symposium: Session 2 The role of oligodendrocytes in maintaining white matter integrity Klaus-Armin Nave Max Planck Institute of Experimental Medicine, Göttingen MS lesions reveal a progressive loss of axons. This raises the question whether inflammation, demyelination, oligodendrocyte dysfunction, or any combination thereof is the underlying cause of axonal failure. We made the observation in mouse mutants of specific oligodendroglial genes (Plp1, Cnp1), originally created to study the mechanisms of myelination, that oligodendrocytes are critical for maintaining the long-term axonal integrity (Griffith et al., Science 1998; Lappe-Siefke et al., Nat Genet 2003). This novel function of oligodendrocytes emerged in the absence of inflammation, and is independent of demyelination, as these mouse mutants are well myelinated. A similar axon-supportive role is suggested for Schwann cells in the PNS by the progressive loss of axons in demyelinating neuropathies. The molecular mechanism by which oligodendrocytes and Schwann cells support axons are not yet understood. However, the phenotype of axonal swellings, specifically in the CNS, resemble those in MS and in patients with mitochondrial defects, suggesting that an axonal energy failure is involved. To study possible contributions of oligodendrocytes in maintaining the metabolism and normal energy balance of myelinated fibers in the brain, we genetically inactivated specific organell functions in glia (Kassmann et al., Nat Genet 2007). Loss of peroxisomal functions in oligodendrocytes not only causes marked axon loss, but also secondary invasion of B cells and activated CD8+ T cells into the white matter. The possible role of glial fatty acid metabolism in axonal preservation and neuroinflammation will be discussed. Supported by grants from the DFG, MS Society, EU-FP7, and BMBF. 20 Second German-Japanese Neuroimmunology Symposium: Session 2 Spontaneous EAE models Guru Krishnamoorthy Max Planck Institute of Neurobiology, Martinsried In the pathogenesis of many organ specific autoimmune diseases including Multiple sclerosis (MS), both T cells and B cells play important roles. Much of our current understanding about MS comes from actively induced or passive transfer EAE models, which are primarily mediated by CD4+ T cells. In addition to the T cells, B cells may act as an antigen presenting cells, produce potentially pathogenic autoantibodies or secrete cytokines shaping the local inflammatory milieu thus contributing actively to the disease pathogenesis. We have recently established two transgenic mouse models on C57BL/6 and SJL/J genetic background that develop spontaneous EAE at high frequency. In these models, development of spontaneous EAE critically depends on the co-operation between myelin-specific T and B cells. Clinical course of Spontaneous EAE and pathological manifestations differed drastically in these two strains representing Devic’s disease and relapsing remitting MS variants. B cells in SJL/J transgenic mice secreted pathogenic antibodies and enhanced demyelinating EAE episodes. B cell depletion completely prevented the spontaneous EAE development. The relative importance of various B cells functions in the pathogenic response in these models will be discussed. 21 Second German-Japanese Neuroimmunology Symposium: Session 2 Migration patterns of autoreactive T cells Naoto Kawakami Max Planck Institute of Neurobiology, Martinsried Naoto Kawakamia, Ingo Bartholomäusa, Christian Schlägera,b, Francesca Odoardia,b, Hartmut Wekerlea, and Alexander Flügela,b a Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany, b Depatment of Neuroimmunology, Institute for Multiple-Sclerosis-Research, Göttingen, Germany Experimental Autoimmune Encephalomyelitis (EAE) in Lewis rats was induced by adoptive transfer of myelin basic protein-reactive T cells genetically engineered to express green fluorescent protein (TMBP-GFP cells). Autoreactive T cells induce the CNS inflammation and severe paralytic disease after a disease free period of 3 days. Using two-photon microscopy we visualized the infiltration process of TMBP-GFP cells into CNS during EAE development. Intravital imaging was complemented by studies of the gene expression profiles of TMBP-GFP cells on their way into the CNS tissue. The first TMBP-GFP cells arrived at the CNS meninges within 24 h after T cell transfer (p.t.). Majority of T cells were in close contacts with leptomeningeal blood vessels. T cells crawled intraluminal surface of blood vessels, seemingly to find the place for extravasations. These crawling is integrin dependent because anti integrin α4 antibody infusion abolished T cell crawling. The number of intraluminal TMBP-GFP cells increased during the next 24 h. Thereafter T cells extravasated and scanned abluminal surface of the blood vessels. Extravasated T cells come in close to perivascular/meningeal macrophages. These macrophages are identified by intrathecal injection of dextran-fluorochrome conjugates or in chimeric rats grafted bone marrow cells from GFP transgenic rats and strategically located around vessels and distribute within the pia mater. TMBP-GFP cells showed short and long lasting contacts to these meningeal/perivascular macrophages. Following findings suggest these contacts have important role for activation and following recruitment of T cells into CNS. At first, phagocytes expressed MHC class II and could present antigen to T cells in vitro. Importantly, upon entry into the meningeal, TMBP-GFP cells were strongly activated and up-regulate pro-inflammatory cytokines genes. Thereafter the T cells infiltrated further to the parenchyma and within the next 24 h they diffusely distributed throughout the entire CNS tissue. Another evidence was shown by using OVA specific T cells (TOVA-GFP), which do not penetrate into CNS with high numbers. Intrathecal transfer of OVA pulsed meningeal/perivascular macrophages recruited considerable number of TOVA-GFP cells into CNS. In contrast, transfer of MBP pulsed meningeal/perivascular macrophages did not. Furthermore recruited TOVA-GFP cells show activated phenotype in antigen specific manner. In summary, T cells scan within the CNS with three steps. At first T cells crawl intraluminal then abluminal surface of pial vessels. During these scanning T cell get antigen specific activation after contacts with perivascular/meningeal macrophages. Thereafter T cells scan though meninges and finally infiltrate parenchyma. Any of the three stages of T cell scanning might be use for therapeutic targets for CNS autoimmune diseases . 22 Second German-Japanese Neuroimmunology Symposium: Session 3 Th17 derived factors: the target organ matters Burkhard Becher Inst. Exp. Immunology, Dept. Pathology, University Hospital of Zurich, Switzerland Over the past 20 years the importance of TH1 cells and TH1-inducing cytokines were studied in autoimmune disease and it was widely held that TH1 cells are the culprits behind the autoimmune attack against tissues. Even though the loss of major TH1 cytokines did not prevent the development of tissue inflammation, the central function of IL-12 and IL-18 in autoimmunity and their role as TH1-inducing cytokines kept the notion that TH1 cells are responsible for autoimmunity solidly in place. We and others provided the basis for a paradigm shift and the discovery that a close relative of IL-12, IL-23 is in fact the key player in EAE. IL-23 was subsequently found to drive the polarization of a new T helper cell subset coined TH17 cells. To study the actual impact of IL-17 on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to epithelial inflammation and granulocytosis, T cell–specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell–driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F–deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of auto-reactive T cells during disease. IL-22, another major TH17 cytokine also does not contribute to the development of EAE in gene-targeted mice. By systematically studying the role and function of TH17 signature cytokines in autoimmune disease in mice, we could demonstrate that they are powerful mediators of tissue inflammation in several organs, surprisingly however with the exception of the nervous system. Taken together with other recent reports which question the role of TH17 cells in autoimmune diseases, I will discuss the concept of TH1, TH17 cells and their produced factors as culprits behind autoimmune inflammation and the critical function of the target tissue of inflammation. 23 Second German-Japanese Neuroimmunology Symposium: Session 3 Th17 cells in CNS autoimmunity Thomas Korn Technical University Munich Organ specific autoimmunity has been considered as a “Th1 disease” where autoreactive IFN-γ producing T cells drive immunopathology. However, more recently so-called Th17 cells that were named after their signature cytokine IL-17A were implicated in tissue inflammation during autoimmune reactions. Th17 cells are now established as independent lineage of helper T cells that have an interesting link to regulatory T cells that express Foxp3. Based on our investigations using Foxp3/GFP reporter mice in experimental autoimmune encephalomyelitis, it will here be asked what are the conditions of the development of Th17 cells in the peripheral immune compartment, to which extent they might be plastic in their functional phenotype and what their contribution might be to inducing tissue inflammation in the CNS. 24 Second German-Japanese Neuroimmunology Symposium: Session 3 Production and functions of IL-25 in the CNS Akio Suzumura Department of Neuroimmunology, RIEM, Institute of Environmental Medicine, Nagoya University, Nagoya Interleukin (IL)-25, a member of the IL-17 family of cytokines, is expressed in the brains of normal mice. However, the cellular source of IL-25 and its function in the brain remain to be elucidated. Here we show that IL-25 plays an important role in preventing infiltration of the inflammatory cells into the central nervous system. Brain capillary endothelial cells (BCECs) express IL-25. However, it is downregulated by inflammatory cytokines including tumor necrosis factor (TNF)-α,IL-17, interferon-γ, IL-1ß, and IL-6 in vitro, and is also reduced in active multiple sclerosis (MS) lesion and in the inflamed spinal cord of experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, IL-25 restores the reduced expression of tight junction proteins, occludin, junction adhesion molecule, and claudin-5, induced by TNF-α in BCECs and consequently repairs TNF-α-induced blood-brain barrier (BBB) permeability. IL-25 induces PKC ε phosphorylation and upregulation of claudin5 is suppressed by protein kinase Cε (PKCε) inhibitor peptide in the IL-25-stimulated BCECs. These results suggest that IL-25 is produced by BCECs and protects against inflammatory cytokine-induced excessive BBB collapse through a PKCε-dependent pathway. These novel functions of IL-25 in maintaining BBB integrity may help us understand the pathophysiology of inflammatory brain diseases such as MS. 25 Second German-Japanese Neuroimmunology Symposium: Session 3 In vivo pathogenesis of immune-mediated axon damage Martin Kerschensteiner Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich, Germany In my talk I want to summarize our recent insights into the pathogenesis of immune-mediated axon damage in vivo. Immune-mediated axon damage plays a crucial role in inflammatory diseases of the central nervous system (CNS) like multiple sclerosis (MS). In MS, immune cells infiltrate brain and spinal cord and attack axons and their surrounding myelin sheets. We know by now that the number of axons damaged by immune cells critically determines the clinical disability of MS patients, however we still understand very little about the process that leads to axon damage. We have used an in vivo imaging approach to investigate the pathogenesis of immunemediated axon damage in an animal model of multiple sclerosis. By time-lapse imaging of fluorescently labeled axons we could follow the slow and spatially restricted degeneration of axons in inflammatory CNS lesions. This “focal axonal degeneration” appears to be a novel type of axonal degeneration that can be differentiated from post-traumatic forms of axonal degeneration like Wallerian degeneration e.g. by its limited extension and slow speed of progression. We could further identify intermediate stages of “focal axonal degeneration” that can persist for several days and progress either to the degeneration or full recovery of the affected axons. The early stages of “focal axonal degeneration” are often associated with persistent macrophage contacts suggesting that macrophage-derived mediators play a crucial role for the induction of this process. The current aim of our studies is to identify the molecular mediators that induce the degeneration process and reveal the intra-axonal mechanism that leads to axon fragmentation. We hope that this work will improve our understanding of immune-mediated tissue damage in multiple sclerosis and pave the way towards the development of targeted neuroprotective therapies. 26 Second German-Japanese Neuroimmunology Symposium: Session 3 Collateral bystander damage by myelin-directed CD8+ T cells causes axonal loss Norbert Goebels Neurological Clinic and Polyclinic, University Hospitals Zurich/Basel, from 10-01-2009 Neurologische Klinik, Heinrich-Heine-Universität Düsseldorf Permanent disability of patients suffering from CNS inflammation such as multiple sclerosis (MS), the most common chronic inflammatory disorder of the central nervous system (CNS), originates mainly from demyelination and axonal damage. While many studies in the past focussed on the role of CD4+ T cells, several recent findings postulate the relevance of autoaggressive, cytotoxic CD8+ T cells in the effector phase of MS. Yet, it remains unresolved whether axonal injury is the result of a CD8+ T cell targeted hit against the axon itself or the consequence of an attack against the myelin structure. To address this issue of CD8mediated tissue damage in CNS inflammation, we performed continuous confocal imaging of auto-aggressive, cytotoxic CD8+ T cells in living organotypic cerebellar brain slices. We observed that loading brain slices with the cognate peptide antigen caused CD8-mediated damage of myelinated axons. To exclude the possibility that the cognate peptide loaded onto the brain slices was presented by axons directly, we restricted the cognate antigen expression exclusively to the cytosol of oligodendrocytes. Aside from vast myelin damage, extensive axonal bystander injury occurred. Using this model system of inflammatory CNS injury, we visualize that axonal loss can be the consequence from “collateral bystander damage” by auto-aggressive, cytotoxic CD8+ T cells, targeting their cognate antigen processed and presented by oligodendrocytes. 27 Second German-Japanese Neuroimmunology Symposium: Session 4 Grey matter damage in inflammatory demyelination Christine Stadelmann-Nessler Department of Neuropathology, Universitätsmedizin Göttingen, Germany Grey matter demyelination has recently been identified as an important feature of chronic multiple sclerosis (MS) patients. Similarly, neuronal loss in cortical and deep grey matter has been reported. However, it is a matter of debate whether local inflammatory demyelination or damage to the white matter tracts are the main culprits for neuronal damage. Our findings in MS autopsy spinal cord tissue indicate a remarkable early loss of ventral spinal neurons that does not progress with disease duration or histological lesion stage. Signs of neuronal stress and damage are detected early in lesion formation. In a model of selective grey matter experimental autoimmune encephalomyelitis without inflammatory damage to the white matter, no substantial early loss of neurons is observed. We thus hypothesize that damage to axons in the white matter is a major contributor to neuronal loss. 28 Second German-Japanese Neuroimmunology Symposium: Session 4 Poly(ADP-ribose) polymerase (PARP) is activated in multiple sclerosis pattern III lesions and its inhibition prevents experimental demyelination and oligodendrocyte death Zsolt Illes University of Pecs, Hungary Sara Veto1, Peter Acs2, Jan Bauer3, Hans Lassmann3, Zoltan Berente1, Balazs Sumegi1, Samuel Komoly2, Ferenc Gallyas Jr1, Zsolt Illes2 1 Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, Pecs, Hungary 2 Department of Neurology, University of Pecs Medical School, Pecs, Hungary 3 Center for Brain Research, Medical University of Vienna, Austria Background: Mitochondrial dysfunction has been indicated to play a role in loss of oligodendrocytes in MS. A nuclear-mitochondrial crosstalk dependent on poly(ADPribosyl)ation is critical in determining the fate of injured cells. Aim: We investigated activation of PARP in pattern III MS lesions, and examined the effect of PARP inhibition on experimental demyelination. Materials and Methods: Early, late active and NWM pathological samples from type III MS, type II MS/NMO and controls were analyzed by immunofluorescence or immunohistochemistry. Experimental demyelination was induced in vivo by cuprizone in C57BL/6 mice. Results: Strong PAR reactivity reflecting activation of PARP was observed in the nucleus and cytoplasm of apoptotic oligodendrocytes in pattern III MS lesions in contrast to pattern II MS/NMO and controls. Quantitative analysis confirmed that PAR reactive oligodendrocytes were enriched in areas of initial and active myelin breakdown. Apoptosis inducing factor (AIF) co-localized with increased anti-PAR staining in condensed nuclei, showing features of apoptosis. The same morphological and molecular pathology was observed in a primary demyelinating animal model induced by cuprizone: PARP activation in corpus callosum (CC); morphologic features of apoptosis with enlarged mitochondria in oligodendrocytes observed by electronmicroscopy; caspase-independent apoptosis with the nuclear translocation of AIF and strong nuclear anti-AIF immunostaining of oligodendrocytes in the CC. In addition, 4hydroxyquinazoline (4HQ), a potent inhibitor of the enzyme blocked both cuprizone induced and basal auto-poly(ADP-ribosyl)ation Inhibition of PARP attenuated oligodendrocyte depletion and decreased demyelination indicated by in vivo serial 9T MRI, and in vitro quantitative MBP immunoblotting/ immunohistochemistry. PARP inhibition suppressed JNK and p38 MAP kinase phosphorylation, increased the activation of the cytoprotective PI-3kinase-Akt pathway and prevented caspase-independent AIF-mediated apoptosis. Conclusion: PARP activation plays a crucial role in the pathogenesis of pattern III MS lesions. Inhibition of PARP effectively suppressed demyelination in an experimental model exhibiting similar morphological and molecular pathology to pattern III MS. Since PARP inhibition was also effective in EAE, the inflammatory model of MS, it may target all subtypes of MS: either by preventing oligodendrocyte death or attenuating autoimmune inflammation. 29 Second German-Japanese Neuroimmunology Symposium: Session 4 Molecular network of the comprehensive multiple sclerosis brain lesion proteome Jun-ichi Satoh Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo ([email protected]) Objective: To study molecular networks and pathways of multiple sclerosis (MS) lesionspecific proteome by focusing on the dataset of a recent proteomics study. Background: Following the completion of the Human Genome Project in 2003, the global analysis of transcriptome and proteome enables us to identify disease-specific molecular signatures. A recent MS brain proteomics study revealed a pivotal role of coagulation cascade proteins in chronic active demyelination (Han et al. Nature 451: 1076-81, 2008). However, nearly all of remaining proteins are left behind to be characterized in terms of their roles in MS brain lesion development. The integration of comprehensive proteome data of disease-affected tissues with underlying molecular networks would be the rational approach to identify disease-relevant pathways and the network-based effective drug targets. Methods: By using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the high-throughput proteome dataset derived from acute plaques (AP), chronic active plaques (CAP), and chronic plaques (CP) (Han et al). Results: The database search on KEGG and PANTHER indicated the relevance of extracellular matrix (ECM)-mediated focal adhesion and integrin signaling to CAP and CP proteome. KeyMolnet disclosed a complex interaction among diverse cytokine signaling pathways at all disease stages, as well as a key role of integrin signaling in CAP and CP. Ingenuity Pathway Analysis identified the network composed of a wide range of ECM components, such as COL1A1, COL1A2, COL6A2, COL6A3, FN1, FBLN2, LAMA1, VTN and HSPG2, as one of the networks highly relevant to CAP proteome. Although four distinct platforms achieved diverse results, they commonly suggested an important role of ECM and integrin signaling in development of chronic lesions of MS. Conclusions: The in silico observations suggest that the selective blockade of the interaction between ECM proteins and integrins in brain lesions in situ would be an effective therapeutic intervention in MS (Satoh et al. Mult Scler. 15:531-41, 2009). 30 Second German-Japanese Neuroimmunology Symposium: Session 4 Antigen presentation in the CNS in multiple sclerosis Robert Weissert Division of Neurology, Geneva University Hospital, Geneva, Switzerland MHC molecules display antigens as short peptides to T cells. So far, there is limited experimental proof of the MHC I and II ligandome in the central nervous system of multiple sclerosis patients. I will present the methodological approach and demonstrate the MHC ligandome in patients with MS. 31 Second German-Japanese Neuroimmunology Symposium: Session 4 αB crystalline as an immunomodulator in MS Toshimasa Aranami National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo Toshimasa Aranami, Wakiro Sato and Takashi Yamamura Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which activation of autoreactive CD4+ T cells targeting myelin antigens and differentiation into Th1 or Th17 effector cells are presumed to play a pathogenic role. It was reported that CD4+ T cells lacking costimulatory molecule CD28 expression (CD28null T cells) are expanded in a part of MS patients probably due to repeated stimulation. However, the specific antigen and the pathogenic role for these T cells in MS have been unclear. Here we report that CD28null T cells from MS patients are enriched in T cells reactive to small heat shock protein (HSP) αBcrystallin (CRYAB), which is the most abundant transcript in the MS lesion. We also show a novel function of CRYAB, which stimulates antigen-presenting cells (APC) to produce proinflammatory cytokines. Age and sex-matched forty untreated MS patients in the remission state and nine healthy subjects (HS) were enrolled in this study. We analyzed the frequencies of T cells responding to ovalbumin (OVA), myelin basic protein (MBP) or CRYAB in CD28+ or CD28null T cells, and found that the frequencies responding to CRYAB but not to OVA nor MBP in CD28null T cells from MS patients were significantly higher than those from HS. CD28+ T cells from MS and HS responded to none of those antigens. Since several HSPs bind to toll-like receptors and activate APC, we analyzed the immunostimulatory function of CRYAB. We found that CRYAB stimulated APC to produce IL-6, TFN-a, IL-10 and IL-12, and these responses were not attributed to LPS contamination. CRYAB augmented IFN-g but not IL-17 production from PHA-stimulated PBMC. Furthermore, we found that the frequencies of CD28null T cells were inversely correlated with anti-EBNA-1 antibody titers. Since CRYAB expression is induced upon EB virus infection, these results suggest that CRYAB might be induced upon EB virus reactivation and activate CD28null T cells repeatedly. Moreover, CRYAB might aggravate the inflammation by promoting Th1 response in the MS lesion. 32 Second German-Japanese Neuroimmunology Symposium: Session 5 Alzheimer's disease vaccine Takeshi Tabira Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo, Hongo, Bunkyou-ku, Tokyo Schenk et al. (1999) have shown that immunization of APP transgenic mice with Abeta resulted in prevention and reduction of beta amyloid deposits in the brain. This immunization therapy was tested in Alzheimer's disease (AD) patients parenterally with adjuvant. Although the trial was halted because of autoimmune meningoencephalitis as a serious side effect, autopsy cases suggested clearance of senile plaques in humans. Moreover, patients who had high titers of antibodies to beta amyloid plaques showed slower decline of cognitive functions than those who had low titers of the antibodies. Recently Holmes et al. described that cognitive functions of patients who had received AN-1792 vaccine declined similarly to controls. Therefore, vaccination seems to be better if it is used for for prevention than treatment of Alzheimer disease. In this sense, active immunization seems to be better than passive immunization , if it is safe. We developed an oral A-beta vaccine using Adeno-associated virus vector and A-beta1-43 cDNA with a signal peptide sequence of APP. When this vaccine was given once orally in APP transgenic mice tg2576 at different ages, all mice showed significant reduction of A-beta burden without showing any side effects. Vaccinated mice showed significant improvement of cognitive functions. Aged monkeys who received the same vaccine also showed significant reduction of amyloid deposits without any side effects . Thus, amyloid vaccine using viral vectors seems to be useful for prevention of Alzheimer disease. (Supported by grants from Ministry of Health, Welfare and Labor) Reference Hara H et al. J Alzheim Dis 6(5): 483-8, 2004 (Alzheimer Award 2005).; Mouri A et al. FASEB J 21(9): 2135-48, 2007. 33 Second German-Japanese Neuroimmunology Symposium: Session 5 Non-viral DNA vaccine therapy against Alzheimer's disease - effects, safety and mechanisms of Aβ clearance Yoh Matsumoto Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience We recently demonstrated that newly developed non-viral Aβ DNA vaccines are safe and effective in Aβ reduction in the cerebral cortex and hippocampus of Alzheimer’s disease model mice (APP23 mice) (PNAS, 2006). In the present study, we performed several examinations to elucidate the mechanism of the plaque reduction and to confirm the efficacy and safety of the DNA vaccines in aged monkey. DNA vaccines (100 µg/mouse or 3 mg/monkey) were injected intramuscularly on a biweekly basis. The brains of treated and control animals were sampled 2-15 months after the first vaccination and brain sections were stained with Iba-1 for microglia and with 6F3D for Aβ depositions. DNA vaccination reduced Aβ burden to approximately 50% of that found in untreated mice at 18 months of age. A large number of activated microglia encased amyloid plaques and their processes entered the plaques. Furthermore, phagocytosed Aβ fragments by microglia were found more frequently in the treated group than in untreated controls. Western blot analysis showed significant reduction of Aβ oligomers in the treated group. The level of Aβ in plasma of treated mice was not significantly different from that of untreated controls, suggesting that the sink effects by anti-Aβ antibodies in blood are not marked in Aβ DNA vaccination (JNEN, 2008). Aged rhesus monkeys (15-18 y. o.) were also treated with the DNA vaccines and their safety and efficacy were assessed in a similar way. Consequently, it was found that DNA vaccination significantly reduced Aβ burden without obvious adverse effects (ICAD, 2009). The present study demonstrates the efficacy and safety of non-viral Aβ DNA vaccination. Based on these findings, we have started the preclinical trial and plan to finish it by the end of 2010. 34 Second German-Japanese Neuroimmunology Symposium: Session 5 Complications and monitoring of natalizumab therapy Ralph Gold Ruhr University Bochum Ralf Gold, Andrew Chan and Aiden Haghikia, Dept of Neurology, Ruhr Univ. Bochum Natalizumab seems to be a telling example of translational medicine. Within 12 years this humanized monoclonal antibody directed against alpha4beta1 integrin made its way from the laboratory to treatment of multiple sclerosis. Yet unexpectedly, and still poorly understood up to now 7 patients developed progressive multifocal leukoencephalopathy (PML) after a minimum of 12 months of natalizumab monotherapy. Here we describe the detailed clinical and therapeutic course of a 52-year-old multiple sclerosis (MS)-patient who survived PML by elimination of natalizumab by plasma exchange and immunoadsorption, and also became critically ill during subsequent apparent immune reconstitution inflammatory syndrome (IRIS). Steroid-pulse therapy led to stabilization and rehabilitation has achieved significant clinical recovery. These cases emphasize the need for careful clinical vigilance during natalizumab therapy. Prompt recognition and treatment can avert death with severe natalizumab-associated PML. In the future bioenergetic parameters such as intracellular ATP-production may help and reflect cellular immunocompetence. We correlated intracellular ATP-concentrations in PHAstimulated immunoselected CD4+-cells from more than 200 MS patients under different immuntherapies with flow cytometry of mitochondrial transmembrane potential (∆Ψm) and microarray expression analyses of genes involved in ATP-production. Such measures of cellular immunocompetence may have implications for risk stratification and individualized monitoring strategies for opportunistic infections under specific immunotherapies. 35 Second German-Japanese Neuroimmunology Symposium: Session 5 Oral treatments of MS Ludwig Kappos Neurology and Department of Biomedicine, University Hospital Basel Three IFNB preparations and glatiramer acetate are now widely available “first line” diseasemodifying treatments (DMT) for MS. Partial efficacy on relapse rates, relapse-related disability and magnetic resonance imaging (MRI) measures has been shown in numerous clinical studies for these agents. Their effects seem to be better early in the course of the disease, are long lasting and there is good tolerability with no evidence of rebound effects. Nevertheless, since efficacy of these first line agents is limited, there is a need for modified treatment regimens and the development of novel therapies. The therapeutic rationale, current evidence from clinical studies and the emerging role of new oral treatments in MS in our therapeutic armamentarium will be reviewed. Teriflunomide is a de novo pyrimidine synthesis inhibitor with antiproliferative activity. It is the active metabolite of leflunomide, which is used in the treatment of rheumatoid arthritis. Evidence from studies of (EAE) and more recently, a phase II clinical trial suggest that Teriflunomide acts as an immunomodulator in MS and has been the starting point for a large phase II/III program that currently explores the potential of this compound both as a monotherapy and as an add on treatment to currently available “first line” agents (IFN Beta and Glatiramer acetate) Cladribine is a chlorinated purine analog, (2-chloro-2’-deoxyadenosine; 2-CdA) that differs in structure from the naturally occurring nucleoside, deoxyadenosine, by the substitution of chlorine for hydrogen in the 2-position of the purine ring. This substitution renders Cladribine resistant to deamination by adenosine deaminase. Cells with high levels of deoxycytidine kinase and low levels of deoxynucleotidase activity (e.g., lymphocytes and monocytes), phosphorylate cladribine to the triphosphate form, impairing deoxyribonucleic acid (DNA) synthesis and cellular metabolism and causing death in dividing and quiescent cells. Recently, results of a large 96 week Phase III study comparing Cladribine with placebo in relapsing remitting MS were presented (Giovannoni G, AAN 2009) and have shown efficacy on annualized relapse rates (appr. 50% reduction), other relapse related and MRI outcomes and also on the rate of confirmed increase of disability / impairment. Short term tolerability of this oral immunosuppressive treatment was good. Ongoing follow up studies will hopefully inform about the longer term risk –benefit balance of this promising approach. FTY720 is one of a new class of immunomodulators with a unique mode of action that act by binding to sphingosine 1-phosphate G-protein-coupled receptors (GPCR). Besides inhibiting T-cell recirculation, experimental and in vitro studies suggest that FTY720 may also have direct effects on remyelination and neuroprotection. 36 Second German-Japanese Neuroimmunology Symposium: Session 5 BG0012, an oral fumarate, has also passed into Phase III after a successful Phase II proof of concept study. Fumarates that have been used for several years in the treatment of severe psoriasis may have a dual mode of action in MS: They may dampen inflammation and promote its resolution by interfering with NfkB-dependent inflammatory signalling. In addition, experimental evidence suggests that they may “protect” oligodendrocytes and neurons from inflammatory and metabolic damage via activation of Nrf2 and of anti-oxidant and metabolic defense mechanisms Laquinimod is a novel synthetic oral compound which is related to a predecessor compound, roquinimex that was shown to inhibit the development of a variety of autoimmune diseases in animal models as well as to suppress the appearance of new active lesions on magnetic resonance imaging (MRI) in clinical phase II and phase III studies in MS. However due to toxicity issues the development of roquinimex had to be discontinued. Laquinimod has a significantly improved therapeutic index and – after demonstrating anti-inflammatory activity in 2 Phase II studies in RR MS is now also in Phase III with 2 ongoing large studies comparing Laquinimod with Placebo and weekly IFNB1a. Several Oral VLA4 antagonists are currently in Phase II studies as putative more convenient and probably better manageable alternatives to natalizumab. Just recently premature discontinuation of a trial with one of these agents, CDP323, has dampened enthousiasm about this group of compounds. 37 Second German-Japanese Neuroimmunology Symposium: Session 5 An update on fingolimod Matthias Meergans Novartis Oral fingolimod (FTY720) – a sphingosine 1-phosphate receptor modulator1 – is the lead compound in a novel class of drugs for the treatment of multiple sclerosis.2 The efficacy, safety and tolerability of oral fingolimod are currently being assessed in a large worldwide phase III clinical trial program in MS with more than 4000 patients. Sphingosine 1-phosphate receptors are widely expressed on a variety of cells including lymphocytes, as well as on neural cells.3-5 These receptors play a key role in the normal egress of lymphocytes from the lymph nodes.6 Fingolimod reduces the number of activated lymphocytes circulating in the bloodstream, but a proportion of memory and effector lymphocytes remain in the circulation and are available to migrate to peripheral tissues. Oral fingolimod significantly reduced both the annualized relapse rate and inflammatory activity on MRI scans at 6 and up to 48 months compared with placebo in patients with relapsing MS. It was generally well tolerated up to 48 months of treatment. There was no evidence for effects on heart rate with chronic therapy, pulmonary function and mean arterial blood pressure remained stable during the extension phase.7,8 A risk minimization plan is under development for later use of fingolimod. Literature 1. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1phosphate receptors. J Biol Chem 2002;277(24):21453-21457. 2. Adachi K, Chiba K. FTY720 Story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology. Perspectives in Medicinal Chemistry 2007;1:11–23. 3. Baumruker T, Billich A, Brinkmann V. FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis. Expert Opin Investig Drugs 2007;16(3):283-289. 4. Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 2007;115(1):84-105. 5. Dev KK, Mullershausen F, Mattes H, et al. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol Ther 2008;117(1):77-93. 6. Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005;23:127-159. 7. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355(11):1124-1140. 8. Montalban X, O'Connor P, Antel J. et al. Oral Fingolimod (FTY720) Shows Sustained Low Rates of Clinical and MRI Disease Activity in Patients with Relapsing Multiple Sclerosis: 4-year Results from a Phase II Extension. In: 19th Meeting of the European Neurological Society (ENS); 2009 20–24 April; Milan, Italy: Oral Presentation, 2009. 38 Second German-Japanese Neuroimmunology Symposium: Session 5 Nuclear receptors as therapeutic target for multiple sclerosis Shinji Oki Dept. of Immunology, National Institute of Neuroscience, NCNP, Tokyo, Japan Nuclear receptors are molecular regulators that play versatile roles, not only in physiological processes such as development, differentiation and homeostasis, but also in pathological processes including cancer, metabolic syndrome, and autoimmunity. We have performed functional analysis of two nuclear receptors as possible therapeutic targets for the treatment of multiple sclerosis (MS). Orphan nuclear receptor NR4A2 is shown to be selectively upregulated in peripheral blood T cells from MS patients and is functionally involved in production of inflammatory cytokines such as IL-17 and IFN-. NR4A2 upregulation was also observed during experimental autoimmune encecephalomyelitis (EAE), the murine model of MS, amongst peripheral blood T cells and leukocytes infiltrating the central nervous system (CNS). NR4A2 was shown to influence the production of inflammatory effector cytokines: NR4A2 overexpression in splenic T cells resulted in enhanced IL-17 and IFN- production, whilst RNAi-based downregulation of NR4A2 expression in T cells elaborated reduced levels of IL-17 and IFN-. Furthermore, NR4A2-specific siRNA-treated encephalitogenic T cells transfered less severe EAE in recipient mice. All-trans retinoic acid (ATRA) has recently been demonstrated to suppress Th17 differentiation and promote the generation of Foxp3+ regulatory T cells via retinoic acid receptor signals. We investigated the effect of a synthetic retinoid AM80 on Th17 differentiation and function and evaluated its therapeutic potential in EAE. AM80 treatment is more effective than ATRA in inhibiting the differentiation of Th17 cells. Oral administration with AM80 is protective for the early development of EAE with an apparent suppression of Th17 cells. AM80 inhibits IL-17 production by memory T cells, in vitro-differentiated Th17 cells, and CNS-infiltrating T cells. Accordingly, AM80 is effective as a treatment when administered after the onset of EAE. Intriguingly, despite a sustained suppression of Th17 phenotype in CNS-infiltrating T cells, continuous AM80 treatment is not effective at inhibiting late EAE symptoms, possibly due to the concomitant suppression of IL-10, which is produced by a distinct regulatory T cell subset expressing both Foxp3 and RORt. Our findings suggest that these nuclear receptors and their modulator ligands can be considered as a possible therapeutic intervention for the treatment of MS. References (1) Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines Proc. Natl. Acad. Sci. USA 105, 8381-8386 (2008) (2) Synthetic retinoid AM80 inhibits Th17 cells and ameliorates EAE Am. J. Pathol. 174, 2234-45 (2009) 39 Second German-Japanese Neuroimmunology Symposium: Session 6 CD4+ T cells in MS - Antigen recognition, phenotype and therapeutic implications Roland Martin Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Hamburg 40 Second German-Japanese Neuroimmunology Symposium: Session 6 Reconstitution of functional autoaggressive T cells from biopsy samples Klaus Dornmair Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich Antigen-specific immune responses in multiple sclerosis have been studied for decades, but the target antigens of the putatively autoaggressive B- and T-cells still remain elusive. We have developed a strategy that is based on the direct analysis of biopsy or autopsy specimens from patients. Since this material is extremely scarce, the experimental methods need to be exceptionally sensitive. Our technology distinguishes (auto)aggressive T-cells from irrelevant bystander lymphocytes by analyzing clonal expansions in relation to the morphological location of the cells in the tissue lesions. We isolate single T cells by laser microdissection from frozen brain biopsy samples and clone matching α- and β-chains of the antigen-specific T cell receptor molecules. This is necessary because usually several clones are expanded and are diluted by many irrelevant cells. The matching TCR chains from individual T-cells can be resurrected in hybridoma cells which may then be used for antigen searches. 41 Second German-Japanese Neuroimmunology Symposium: Session 6 Antibodies and biomarkers Bernhard Hemmer Technical University Munich Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, de- and remyelination, neurodegeneration and astrogliosis. While the cause of MS has remained obscure, many findings support the concept of an autoimmune pathogenesis on the background of a complex interaction between multiple genes and environmental factors. B cells and antibodies seem to play an important role in the inflammatory process underlying MS. The role of antibodies in the inflammatory lesion is supported by the occurrence of a local antibody synthesis - predominantly IgG - in the CSF of the majority of MS patients. These antibodies are produced by a subset of memory B cells and plasmablasts, which are recruited to lesions and CSF. B cells in CSF and lesion are of oligoclonal origin and express B-cell receptor genes, which underwent somatic mutation compatible with an antigen driven expansion and recruitment of these cells to the CNS. Antibody deposits and activated complement components are found in the lesions of most MS patients and in all likelihood are the cause of frank demyelination in at least a fraction of MS patients. Accordingly antibody and B cell directed therapies have been successfully applied to MS and related diseases. While we are now confident that B cells and antibodies contribute to inflammation and damage it has been difficult to pinpoint the targets of the B cell response in the CNS. However, the data suggest that B cell responses similar to T cells are driven by antigens expressed on the surface of glia or neuronal cells in the CNS. In a rare autoimmune disease of the CNS, Neuromyelitis optica, diagnostic autoantibodies to Aquaporin-4 were discovered. Also, antibodies to Myelin-Oligodendrocyte Glycoprotein were found in MS and acute disseminated encephalomyelitis, although the significance of these antibodies remains controversial. The presentation will address the current state of antibody biomarker research in MS and related diseases. 42 Second German-Japanese Neuroimmunology Symposium: Session 6 Novel axoglial autoantigens Edgar Meinl Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) involving T cells, B cells and antibodies. In recent years it has become clear that axonal damage and gray matter injury are frequent in MS and linked to disability development. We set out to identify novel targets of the autoimmune response in MS patients. To this end, we prepared lentil lectin binding glycoproteins from human myelin containing purely myelin proteins and proteins shared by myelin and axons. This approach allowed us to investigate autoreactivity to quantitatively minor glycoproteins that may be exposed at the membrane surface. Our glycoprotein preparation was separated by 2-D gel electrophoresis and subsequently screened by Western blotting using Ig preparations from MS patients. Thereby we identified neurofascin and contactin-2/TAG-1 as novel targets of autoantibodies. Neurofascin exists in two isoforms: NF155 is a myelin protein at the paranode, while NF186 is a neuronal protein linked to the Nodes of Ranvier. Contactin-2 and its rat homologue TAG1 (transiently-expressed axonal glycoprotein 1) are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin side. Contatin-2/TAG-1 was also recognized by Th1/17 T cells. Having identified these targets, we studied the pathogenic significance of such an autoimmune responses in experimental autoimmune encephalitis (EAE) models in the rat. Thereby we found that contactin-2/TAG-1 specific T cells induced a CNS inflammation preferentially in the grey matter and pave the way for cortical demyelination. To evaluate possible effects of circulating Abs to neurofascin, a mAb to neurofascin was co-transferred with encephalitogenic T cells that breach the blood-brain barrier. In this model, the antineurofascin Abs specifically targeted the Nodes of Ranvier and induced an axonal injury. Together, we identify two axo-glial antigens (contactin-2/TAG-1 and neurofascin) as novel targets of the autoimmune response in MS. Animal experiments suggest that contactin2/TAG-1 specific T cell response contribute to the development of gray matter pathology and antibodies to neurofascin to axonal injury. 43 Second German-Japanese Neuroimmunology Symposium: Session 7 Gangliosides and ganglioside complexes as targets for neuroimmunological diseases Susumu Kusunoki Department of Neurology, Kinki Univeristy School of Medicine, Osaka, Japan Anti-ganglioside antibodies are frequently present in some autoimmune peripheral neuropathies. In particular, they are present in about 60% of the acute-phase sera of Guillain-Barré syndrome (GBS). Some of them may be directly involved in the pathogenetic mechanisms by biding to the regions where the respective target ganglioside is localized. We have recently found the presence of the IgG antibody that specifically recognizes a new conformational epitope formed by two gangliosides (ganglioside complex, GSC) in the acutephase sera from some GBS patients. The IgG antibodies against GD1a/GD1b complexes are associated with severe GBS requiring artificial ventilation. In contrast, the binding activity of the antibody highly specific to GD1b should be weaker towards GSC comprising GD1b than to GD1b alone because GD1b undergoes conformational change in that GSC. GD1b is localized in large sensory neurons in dorsal root ganglia. Monospecific anti-GD1b IgG has been shown as a causative factor of sensory ataxic neuropathy. We investigated GBS sera with anti-GD1b IgG antibodies and found that the antibody titers to GD1b mixed with GD1a, GT1b, GQ1b and GalNAc-GD1a were significantly more reduced in ataxic patients than in non-ataxic patients (p<0.001). It suggests that the IgG antibodies associated with ataxia are highly specific to GD1b. Thus, highly specific antiGD1b IgG may bind to GD1b tightly to cause ataxia in GBS. Most of the patients with Miller Fisher syndrome (MFS) have anti-GQ1b IgG antibody. Our recent investigation showed that some MFS patients have antibodies with higher titer against GSCs including GQ1b; such as GQ1b/GM1 and GQ1b/GD1a. In contrast, patients with Bickerstaff’s brainstem encephalitis (BBE) have antibodies specific to GQ1b but not to GSCs. Gangliosides along with other components as cholesterol are known to form lipid rafts, in which the carbohydrate portions of two different gangliosides may form a new conformational epitope. Within the rafts, gangliosides are considered to interact with important receptors or signal transducers. More study is needed to elucidate the mechanisms how the antibodies against gangliosides or ganglioside complexes cause nerve dysfunction. 44 Second German-Japanese Neuroimmunology Symposium: Session 7 AQP4 autoimmune syndrome and anti-AQP4 antibody-negative opticospinal MS in Japanese: neuroimmunological and genetical studies Jun-ichi Kira Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Objective: To clarify immunological and pathological differences between aquaporin (AQP) 4 autoimmunity-related and -unrelated opticospinal multiple sclerosis (OSMS) patients in Japanese, and to clarify the immunogenetic background of Japanese MS with regards to HLA-DRB1 haplotypic and genotypic effects. Methods: We measured serum antibody titres against AQP4 and CSF cytokine profiles in 191 patients with idiopathic CNS demyelinating diseases. We pathologically studied autopsy specimens from 11 OSMS (10 fulfilled the neuromyelitis optica (NMO) criteria) and 4 conventional MS (CMS) cases. In addition, HLA-DRB1 was genotyped in 108 MS patients (27 positive and 81 negative) and 127 healthy controls (HC). Results: In CSF, IL-17, IFN-gamma, granulocyte-colony stimulating factor, and IL-8 were markedly upregulated in OSMS patients, irrespective of the presence or absence of the antiAQP4 antibody. Pathologically, 6 OSMS and 1 CMS cases showed more exaggerated losses of AQP4 than of GFAP or myelin, while 5 OSMS and 3 CMS cases demonstrated preservation of AQP4, even in acute necrotic lesions. Three OSMS cases had both pathological patterns. HLA-DRB1*09 and HLA-DRB1*01 decreased the incidence of antiAQP4 antibody-negative MS. By contrast, HLA-DRB1*12 increased the risk of anti-AQP4 antibody-positive MS while HLA-DRB1*09 decreased the risk of anti-AQP4 antibody-positive MS. Individuals with HLA-DRB1*09/15 had a decreased risk of anti-AQP4 antibody-negative MS, while those with HLA-DRB1*12/15 had an increased risk of anti-AQP4 antibody-positive MS. Conclusions: Both anti-AQP4 autoimmunity-related and -unrelated OSMS occur in Japanese. Th17/Th1 cells are involved in both conditions, while additional humoral factors also act in the former. HLA-DRB1*09 significantly reduces the risk of MS in Japanese, irrespective of the presence or absence of anti-AQP4 antibody. The ability of HLA-DRB1*09 to reduce the risk of anti-AQP4 antibody-negative MS may arise from an interaction with HLA-DRB1*15, whereas HLA-DRB1*12 increases susceptibility to anti-AQP4 antibodypositive MS, possibly via an interaction of HLA-DRB1*12 with HLA-DRB1*15. 45 Second German-Japanese Neuroimmunology Symposium: Session 7 Neuromyelitis Optica (NMO): An Update Kazuo Fujihara Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan Neuromyelitis optica (NMO) is characterized by severe optic neuritis and transverse myelitis. Since the discovery of disease-specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on foot processes of astrocytes, clinical features, MRI and other laboratory findings in NMO have been clarified. AQP4 antibody is now recognized as the most important finding for the diagnosis of NMO. However, studies of AQP4 antibody-positive patients have revealed that brain lesions are not uncommon in NMO, and some of them appear to be unique to NMO. Moreover, manifestations associated with brain lesions can develop as the onset events in some patients without previous history of optic neuritis or myelitis. Thus, the term NMO is no longer appropriate to represent the whole spectrum. The disease is now defined by AQP4 antibody. Pathological studies demonstrated an extensive loss of immunoreactivities to AQP4 and glial fibrillary acidic protein (GFAP) with relative preservation of the staining of myelin basic protein in NMO lesions. In fact, the GFAP levels in the cerebrospinal fluid during acute exacerbation of NMO are remarkably elevated. In addition, recent experimental studies conducted in vitro and in vivo have shown that AQP4 antibody is pathogenic, although AQP4 antibody alone cannot cause the disease as shown by a recent report on a case seropositive for AQP4 antibody years before the onset of NMO. All these findings strongly suggest that severe astrocytic damage probably mediated by AQP4 antibody is a unique finding of NMO. Further analyses of this pathological process are expected to help develop effective therapies for the devastating disease. Recent clinical findings of NMO and AQP4 antibody will be reviewed in the presentation. 46 Second German-Japanese Neuroimmunology Symposium: Session 7 Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo Monika Bradl Institute for Brain Research, Vienna Monika Bradl1, Tatsuro Misu2,3, Toshiyuki Takahashi3,4, Mitsutoshi Watanabe5, Simone Mader6, Markus Reindl6, Milena Adzemovic1, Jan Bauer1, Thomas Berger6, Kazuo Fujihara2,3, Yasuto Itoyama3 & Hans Lassmann1 1 Medical University Vienna, Center for Brain Research, Dept. Neuroimmunology, Spitalgasse 4, A-1090 Vienna, Austria; 2,3Departments of 2Multiple Sclerosis Therapeutics and 3 Neurology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574, Japan; 4Department of Neurology, National Yonezawa Hospital, Yonezawa 982-1202, Japan; 5Therapeutic Protein Product Research Department, The Chemo-Sero-Therapeutic Research Institute, KAKETSUKEN, 1-6-1 Okubo, Kumamoto, 8608568, Japan, 6Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020, Innsbruck, Austria Severe inflammation and astrocyte loss along with profound demyelination in spinal cord and optic nerves are typical features of neuromyelitis optica (NMO), a disease of the central nervous system. Diagnostic hallmark of this disease is the presence of serum autoantibodies against the water channel aquaporin 4 (AQP-4) on astrocytes. We induced acute T-cell mediated experimental autoimmune encephalomyelitis in Lewis rats and confronted the animals with an additional application of immunoglobulins from AQP-4 antibody positive and negative NMO patients, multiple sclerosis patients and controls. We found that immunoglobulins from NMO patients with AQP-4 autoantibodies are pathogenic. When they reach serum titers in the experimental animals comparable to those seen in patients with NMO, the patient-derived antibodies augment clinical disease and induce lesions in the central nervous system which are closely similar in structure and distribution to those seen in patients with NMO, consisting of AQP-4 and astrocyte loss, of granulocytic infiltrates, T cells and activated macrophages and microglia cells, and an extensive immunoglobulin and complement deposition on astrocyte processes of the perivascular and superficial glia limitans. AQP-4 antibody containing NMO immunoglobulin injected into naïve rats, young rats with leaky blood brain barrier or after transfer of a nonencephalitogenic T-cell line did not induce disease or neuropathological alterations in the central nervous system. Our data suggest that human anti-AQP-4 antibodies are not only important in the diagnosis of NMO, but also augment disease and induce NMO like lesions in animals with T-cell mediated brain inflammation. 47 Second German-Japanese Neuroimmunology Symposium: Session 7 Recent progress in HTLV-I associated neurological disorders: Inclusion body myositis with human T-lymphotropic virus-type I infection Fujio Umehara Department of Neurology and Geriatrics, Graduate School of Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, Japan, TEL: 81-99-275-5332, FAX: 81-99-265-7164, E-mail: [email protected] Human T-lymphotropic virus-type I (HTLV-I) is an human retrovirus that infects 10-20 million people worldwide. The majority of infected individuals remain healthy lifelong asymptomatic carriers, while 0.25-3 % develop inflammatory disease of the central nervous system termed HTLV-I-associated myelopathy /tropical spastic paraparesis (HAM/TSP). HAM/TSP is considered to be an immune-mediated disease. HTLV-I is also the etiologic agent in adult T cell leukemia and other inflammatory diseases including uveitis, arthritis, polymyositis, Sjögren syndrome and alveolitis. The objective of this study was to investigate the role of HTLV-I infection in patients with sporadic inclusion body myositis (sIBM) from endemic area in Japan. Anti-HTLV-I antibodies were present in the serum of all the patients. The muscle biopsies showed endomysial T cell infiltration with rimmed vacuoles, deposits of phosphorylated tau, abnormal filaments in the nuclei and cytoplasm of the muscle fibers, all diagnostic of IBM. The muscle fibers expressed MHC class-I antigens and were invaded by CD8+ cells and CD4+ cells. In situ HLA-A*0201 / Tax11-19-pentamer staining showed the pentamer-positive cells surrounding the muscle fibers. Double staining of immuno-gold silver staining and polymerase chain reaction in situ hybridization revealed that HTLV-I proviral DNA was localized on helper-inducer T cells, but not on muscle fibers. HTLV-I proviral loads in peripheral blood mononuclear cell from each patient were comparable to those seen in HAMTSP. This study suggests that HTLV-I infection may be one of the causes of sIBM, as has been reported in human immunodeficiency virus type 1 (HIV-1) infection. Reference Matsuura E, Umehara F, et al. J Neuropathol Exp Neurol. 2008; 67:41-9. 48 Second German-Japanese Neuroimmunology Symposium: Support T his Symposi um was s upported b y: Deutsche Forschungsgemeinschaft SFB 571 Autoimmune reactions: From manifestations to therapy Japanese MS Society Novartis TEVA Asahi Kasei Boehringer Ingelheim 49 Second German-Japanese Neuroimmunology Symposium: Participants Al p h a b e t i c a l l i s t o f p a r t i c i p a n t s Name Institute Email Aranami, Toshimasa Becher, Burkhard Ben-Nun Avraham Bradl, Monika Chiba, Asako Dornmair, Klaus Engelhardt, Britta Flügel, Alexander Fujihara, Kazuo Goebels, Norbert National Institute of Neuroscience, NCNP, Tokyo Institute of Experimental Immunology, University Hospital, Zürich Max Planck Institute of Neurobiology, Martinsried HIFO Institute for Brain Research, Wien National Institute of Neuroscience, NCNP, Tokyo Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich Theodor Kocher Institute, University of Bern Max Planck Institute of Neurobiology, Martinsried Tohoku University Graduate School of Medicine, Sendai Neurological Clinic and Polyclinic, University Hospitals, Zurich/Basel, from 10-01-2009 Neurologische Klinik, Heinrich-Heine-Universität Düsseldorf St. Josef Hospital / Ruhr University, Bochum Clinic of Neurology and Polyclinic, Technical University, Munich Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich University of Pecs, Pecs [email protected] Yamaguchi University, Graduate School of Medicine, Ube Kantonsspital University Hospitals, Basel Max Planck Institute of Neurobiology, Martinsried Institute of Clinical Neuroimmunology, University Hospital, Munich [email protected] Neurological Institute, Kyushu University, Fukuoka Neurological University Clinic, Technical University, Munich Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich International Immunology Frontier Research Center (iFReC), Osaka International Immunology Frontier Research Center (iFReC), Osaka [email protected] Gold, Ralph Hemmer, Bernhard Hohlfeld, Reinhard Illes, Zsolt Kanda, Takashi Kappos, Ludwig Kawakami, Naoto Kerschensteiner, Martin [email protected]. ch [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] c.jp [email protected], [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] -muenchen.de Krishnamoorty Kira, Jun-ichi Korn, Thomas Krumbholz, Markus Kumanogoh, Atsushi Kusunoki, Susumu [email protected] [email protected] [email protected] [email protected] 50 Second German-Japanese Neuroimmunology Symposium: Participants Martin, Roland Matsumoto, Yoh Meergans, Matthias Meinl, Edgar Melms, Arthur Miyake, Sachiko Müller-Hermelink, Hans-Konrad Nave, Klaus-Armin Oki, Shinji Sakoda, Saburo Sato, Wakiro Satoh, Jun-ichi Stadelmann-Nessler, Christine Suzumura, Akio Tabira, Takeshi Umehara, Fujio Weissert, Robert Wekerle, Hartmut Wiendl, Heinz Yamamura, Takashi Institute for Neuroimmunology and Clinical MS Research, Hamburg Tokyo Metropolitan Institute of Neuroscience, Tokyo Novartis Pharma GmbH, Nürnberg [email protected] [email protected] Institute of Clinical Neuroimmunology, Ludwig Maximilians University Munich Center for Neurology, Tübingen [email protected] National Institute of Neuroscience, NCNP, Tokyo Pathology Institute Julius-Maximilians University, Würzburg Max Planck Institute for Experimental Medicine, Göttingen National Institute of Neuroscience, NCNP, Tokyo Osaka University Graduate School of Medicine, Osaka Max Planck Institute of Neurobiology, Martinsried Meiji Pharmaceutical University, Tokyo Institute of Neuropathology, GeorgAugust University, Göttingen RIEM, Nagoya University [email protected] National Institute for Longevity Sciences, Aichi Graduate School of Kagoshima University Geneva Research Center, Merck Serono Int. SA, Geneva Max Planck Institute of Neurobiology, Martinsried Clinical Research Group for MS and Neuroimmunol., University Würzburg National Institute of Neuroscience, NCNP, Tokyo [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] 51 Second German-Japanese Neuroimmunology Symposium: Your notes 52 Second German-Japanese Neuroimmunology Symposium: Your notes 53