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First Multiple Sclerosis Summer College in Fukuoka (2–3 August 2014) Molecular targeted therapy in multiple sclerosis: Bench to bedside and bedside to bench

2014; Wiley; Volume: 5; Issue: s1 Linguagem: Inglês

10.1111/cen3.12169

1759-1961

Takuya Matsushita, Katsuhisa Masaki, Jun‐ichi Kira,

Macrophage Migration Inhibitory Factor

Day 1: 2 August 2014 Opening Remarks 13.00–13.05 Jun-ichi Kira (First MS Summer College President, Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Japan) (1) Opening Lecture 13.05–13.40 Chair: Jun-ichi Kira (Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Japan) 1. (L-1) MS diagnosis and disease classification using magnetic resonance imaging (MRI) Ernst-Wilhelm Radue (University Hospital Basel, Switzerland) (2) Workshop-1: Molecular targeted therapy in MS-1 13.40–15.16 Chair: Hirofumi Ochi (Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Japan) and Takayuki Kondo (Department of Community Network & Collaborative Medicine, Kyoto University, Japan) Commentator: Toshinari Nakane (Nagasaki Kawatana Medical Center, Japan) 2. (L-2) Keynote Lecture: Role of T cells and cytokines in the pathogenesis and therapy of multiple sclerosis and its experimental models Abdolmohamad Rostami (Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA) 3. (L-3) Effects of fingolimod in MS: From the neuroimaging standpoint of view Ernst-Wilhelm Radue (University Hospital Basel, Switzerland) 4. (O-1) Peripheral blood T-cell subset dynamics of oral fingolimod (FTY720)-treated multiple sclerosis patients Zi Ye Song1, Ryo Yamasaki2, Yuji Kawano1, Shinya Sato1, Katsuhisa Masaki1, Satoshi Yoshimura1, Dai Matsuse1, Hiroyuki Murai1, Takuya Matsushita2, Jun-ichi Kira1 (Departments of 1Neurology and 2Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Japan) 5. (O-2) Fingolimod prevents blood–brain barrier disruption Hideaki Nishihara, Fumitaka Shimizu, Yasuteru Sano, Masaaki Abe, Toshihiko Maeda, Mariko Ooishi, Hironori Sano, Takashi Kanda (Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan) (3) Workshop-2: Molecular targeted therapy in MS-2 15.30–17.00 Chair: Takashi Yamamura (National Center of Neurology and Psychiatry and Brain Research Institute, Niigata University, Japan) and Makoto Matsui (Department of Neurology, Kanazawa Medical University, Japan) Commentator: Wakiro Sato (National Center of Neurology and Psychiatry, Japan) 6. (L-4) Mechanism of MS based on the clinical trial results of molecular targeted therapy in MS Hirofumi Ochi (Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Japan) 7. (L-5) Molecular targeted therapy against B cells in MS Yusei Miyazaki and Masaaki Niino (Department of Neurology, Hokkaido Medical Center, Japan) 8. (L-6) Molecular targeted therapy against blood–brain barrier in MS Takashi Kanda (Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan) (4) Poster Presentation and Coffee Break 17.00–17.40 Chair: Masami Tanaka (Department of Neurology, NHO Utano Hospital, Japan) and Kazumasa Yokoyama (Department of Neurology, Juntendo University, Japan) 9. (P-1) Th1/Th2-related chemokine receptors in peripheral T cells in patients with multiple sclerosis treated with fingolimod Yuko Shimizu, Ryotaro Ikeguchi, Kohei Ota, Kazuo Kitagawa (Department of Neurology, Tokyo Women's Medical University School of Medicine, Japan) 10. (P-2) Fingolimod suppresses bone absorption marker in patients with multiple sclerosis Yusei Miyazaki1,2, Masaaki Niino1, Toshiyuki Fukazawa3, Seiji Kikuchi2 (Departments of 1Clinical Research and 2Neurology, Hokkaido Medical Center; 3Sapporo Neurology Clinic, Japan) 11. (P-3) Clinical features of the patients with multiple sclerosis-related disorder at Yokohama Rosai Hospital Takahiro Nakayama, Mizuki Kitamura, Ichiro Imafuku (Department of Neurology, Yokohama Rosai Hospital, Japan) 12. (P-4) Occurrence of multiple enhancing brain lesions shortly after discontinuation of fingolimod in a patient with multiple sclerosis Hiroki Masuda, Masahiro Mori, Akiyuki Uzawa, Saeko Masuda, Mayumi Muto, Tomohiko Uchida, Satoshi Kuwabara (Department of Neurology, Graduate School of Medicine, Chiba University, Japan) 13. (P-5) Clinical phenotype of myelin oligodendrocyte glycoprotein (MOG) antibodies associated NMOSD patients Suguru Tanaka, Akihiro Kubota, Shoko Izaki, Hikoaki Fukaura (Neurology, Saitama Medical Center, Saitama Medical University, Japan) 14. (P-6) Anti-NMDAR+/anti-MOG+ multiphasic ADEM Kimihiko Kaneko, Douglas Sato, Kazuhiro Kurosawa, Tatsuro Misu, Ichiro Nakashima, Kazuo Fujihara, Masashi Aoki (Department of Neurology, Tohoku University Graduate School of Medicine, Japan) 15. (P-7) Callosal disconnection syndrome as an initial manifestation of NMOSD Hiroshi Kuroda, Junpei Kobayashi, Tatsuro Misu, Etsuro Mori, Kazuo Fujihara, Masashi Aoki (Department of Neurology, Tohoku University Graduate School of Medicine, Japan) (P-8) Effects of neuromyelitis optica IgG (NMO-IgG) at the blood–brain barrier Yukio Takeshita1, Birgit Obermeiert2, Anne Cotleur2, Simona Spampinato2, Fumitaka Shimizu2, Yasuteru Sano1, Kryzer Thomas3, Vanda Lennon3, Richard M. Ransohoff2, Takashi Kanda1 (1Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan, 2Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, USA, 3Department of Neurology, Immunology and Laboratory Medicine and Pathology, Mayo Clinic, Minnesota, USA) (5) Oral Session of Ordinary Submissions-1 17.40–18.32 Chair: Kazuo Fujihara (Department of Neurology, Tohoku University, Graduate School of Medicine, Japan) 16. (O-3) Peripheral atopy influences clinical and pathological manifestations of experimental autoimmune encephalomyelitis Mei Fang,1 Ryo Yamasaki,2 Jun-ichi Kira1 (Departments of 1Neurology and 2Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Japan) 17. (O-4) Effects of neuromyelitis optica IgG (NMO-IgG) at the blood–brain barrier Yukio Takeshita,1 Birgit Obermeiert,2 Anne Cotleur,2 Simona Spampinato,2 Fumitaka Shimizu,2 Yasuteru Sano,1 Kryzer Thomas,3 Vanda Lennon,3 Richard M Ransohoff,2 Takashi Kanda1 (1Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan, 2Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, USA, 3Department of Neurology, Immunology and Laboratory Medicine and Pathology, Mayo Clinic, Minnesota, USA) 18. (O-5) Blood–CSF barrier in MS, NMO and other neurological disorders Tetsuya Akaishi, Ichiro Nakashima, Koichi Narikawa, Hiroshi Kuroda, Yasushi Suzuki, Kazuo Fujihara (Department of Neurology, Tohoku University, Graduate School of Medicine, Japan) 19. (O-6) Anti-neurofascin antibody in inflammatory demyelinating diseases Hidenori Ogata,1 Dai Matsuse,1 Takuya Matsushita,2 Nobutoshi Kawamura,1 Ryo Yamasaki,2 Jun-ichi Kira1 (Department of 1Neurology, 2Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Japan) (6) Images in Demyelinating and Allied Disorders Session 18.32–18.58 Chair: Masaaki Niino (Hokkaido Medical Center, Japan) and Takuya Matsushita (Kyushu University, Japan) Commentator: Motohiro Yukitake (Saga Central Hospital, Japan) Commentator: Yoko Warabi (Tokyo Metropolitan Neurological Hospital, Japan) 20. (O-7) A case of 22-year-old male presenting with gadolinium enhanced bilateral longitudinal lesion along thoracic lateral funiculus suspected of neurosarcoidosis Kaori Sakuishi, Miho Kawabe, Jun Shimizu (The University of Tokyo Hospital, Japan) 21. (O-8) A case of intractable secondary progressive multiple sclerosis that turned around after recovery from multiple organ failure as a sequel of acute renal failure with massive white matter lesions Youwei Lin,1,3 Kazuma Tosaka,2 Miho Murata,1 Takashi Yamamura3 (1Department of Neurology, National Center Hospital, NCNP 2Section of Medical Engineering, National Center Hospital, NCNP 3Department of Immunology, National Institute of Neuroscience, NCNP NCNP: National Center of Neurology and Psychiatry, Japan) Day 2 (3 August 2014) (8) Neuroimmunology Education Symposium: How to manage molecular targeted therapy for MS in clinical practice 8:30–9:40 Chair: Takashi Kanda (Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Japan) and Kyoichi Nomura (Department of Neurology, Saitama Medical Center, Saitama Medical University, Japan) 22. (L-7) Molecular targeted therapy and infection Masaki Takao (Tokyo Metropolitan Institute of Gerontology, Japan) 23. (L-8) How to manage molecular targeted therapy for MS in daily clinical practice Katsuichi Miyamoto (Department of Neurology, Kinki University, Japan) (9) Basic Science Symposium: Novel Roles of Microglia in Maintenance, Repair and Inflammation of the Central Nervous System 9.55–11.10 Chair: Akio Suzumura (Research Institute of Environmental Medicine Nagoya University, Japan) and Yuji Nakatsuji (Department of Neurology, Osaka University, Japan) 24. (L-9) Novel roles of microglia Hiroshi Nakanishi (Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Japan) 25. (L-10) Distinct roles of microglia and macrophages in CNS inflammation and degeneration Ryo Yamasaki (Department of Neurological Therapeutics, Neurological Institute Graduate School of Medical Sciences, Kyushu University, Japan) (10) Farewell Lecture (Japanese) 11.10–11.55 Chair: Seiji Kikuchi (Department of Neurology, Hokkaido Medical Center, Japan) 26. (L-11) Glia and myself: Future glia-targeted therapy in MS Akio Suzumura (Research Institute of Environmental Medicine Nagoya University, Japan) Closing Remark 11.55–12.00 Hirofumi Ochi (Vice president, Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Japan) The First Annual Meeting of the Multiple Sclerosis (MS) Summer College was held at the MIRAI Hall and Conference, Fukuoka, Japan (Fig. 1), from 2 August (Saturday) to 3 August (Sunday) 2014. The main theme of the meeting was “Molecular Targeted Therapy in MS: Bench to Bedside and Bedside to Bench.” The meeting was dedicated to the promotion of interdisciplinary information exchange on the latest progress in MS and neuromyelitis optica (NMO) research among neuroimmunologists in Japan and overseas (Fig. 2). We would like to introduce some examples in this report. Professor Ernst-Wilhelm Radue, Medical Image Analysis Center, Basel, Switzerland, updated our knowledge of magnetic resonance imaging (MRI) for diagnosis and classification of MS as an opening lecture (Fig. 3). MS diagnosis is based on dissemination in space and dissemination in time of lesions in the central nervous system. A recent revision of the McDonald criteria simplified the requirements for dissemination in space and dissemination in time, and allowed for an earlier diagnosis of MS from a single baseline brain MRI. The interpretation of MRI is crucial for all MS practitioners, because the importance of early introduction of disease modifying therapy is stressed. Professor Radue presented many actual images, and pointed out the differences between MS and other diseases or artifacts that could be misleading. Following differential diagnosis by MRI, new methods were shown focusing on the neurodegenerative aspect of MS. Professor Radue showed the availability and limitation of double-inversion recovery to depict intracortical lesions, as well as quantitative magnetization transfer to clarify the neuropathological process in MS. He also mentioned the importance of thalamic volume and spinal cord atrophy as an index of disability progression. The volume of specific thalamic nuclei, together with normalized gray matter volume, explains a relatively large amount of variability within the expanded disability status scale.1 The upper cervical cord cross-sectional area inversely correlated with expanded disability status scale scores.2 In Workshop-1, Professor Abdolmohamad Rostami, Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA, delivered a keynote lecture entitled “Role of T cells and cytokines in the pathogenesis and therapy of multiple sclerosis and its experimental model.” In experimental autoimmune encephalomyelitis (EAE), a model for MS, Th1 and Th17 play a central role in the pathogenesis of central nervous system inflammation and demyelination. However, the exact cytokine networks, which regulate or exacerbate the response, are poorly understood. He presented the regulatory role of interleukin (IL)-27 and the critical function of Granulocyte macrophage colony-stimulating factor (GM-CFF) to induce EAE. IL-27 induces interferon-γ+/IL-10+ Tr1 cells, and the secreted IL-10 suppresses development of Th17 cells.3 Exogenous IL-27 reduces the severity of adoptively transferred EAE through a mechanism dependent on IL-10, but it shows limited efficacy in ameliorating the ongoing disease. Th17 is indispensable in EAE, but the signature cytokine, IL-17, is not essential for EAE. GM-CSF is the most significant mediator of EAE and is produced by Th17 cells, and Professor Rostami showed that encephalitogenicity of both Th1 and Th17 cells depends on their GM-CSF production, because Th1/Th17 cells deficient in GM-CSF do not induce EAE. Additionally, a positive feedback loop was shown, in which IL-23 produced by antigen presenting cells induces GM-CSF production by Th17 cells, which in turn stimulates IL-23 production by antigen presenting cells.4 After the keynote lecture, Professor Radue presented the effects of fingolimod on MRI findings during the clinical trial of FREEDOMS. Fingolimod therapy reduces the number and volume of inflammatory lesions, as assessed by gadolinium-enhancing, as well as new or newly enlarged T2 lesions after 6, 12 and 24 months of therapy. Accumulation of T2-hyperintense and T1-hypointense lesion volume was also significantly reduced in patients with fingolimod compared with the placebo group. Fingolimod significantly reduces brain volume loss during months 0–6, 0–12, 12–24 and 0–24 versus placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence or absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status and disability level.5 In Workshop-2, three speakers, Dr Hirofumi Ochi, Department of Geriatric Medicine and Neurology, Ehime University Graduate School of Medicine, Ehime, Japan; Dr Yusei Miyazaki, Department of Neurology, Hokkaido Medical Center, Hokkaido, Japan; and Professor Takashi Kanda, Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan, reviewed molecular targeting therapy in MS, focusing on T cells, B cells and the blood–brain barrier, respectively. In an Oral Session of Ordinary Submissions, Dr Yukio Takeshita, Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan, constructed an ex vivo blood–brain barrier model using endothelial cell lines and astrocytes, with or without aquaporin-4, and observed a migration of mononuclear cells from the vascular side while applying NMO-immunoglobulin G to the brain parenchymal side. He showed that NMO-immunoglobulin G induces IL-6 in astrocytes with aquaporin-4, and IL-6 induces CCL2 and CXCL8 production in endothelial cells, thereby promoting mononuclear cell migration. In the Neuroimmunology Education Symposium, Dr Masaki Takao, Department of Neuropathology, the Brain Bank for Aging Research Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan, presented a comprehensive summary about progressive multifocal leukoencephalopathy (PML). Although PML has been considered a rare clinical condition, the number of PML cases has increased after the advent of the AIDS era. The association between PML and monoclonal antibody (MA) therapy has attracted attention. The number of PML cases attributed to natalizumab and rituximab has rapidly increased. As of 2014, approximately 500 cases of natalizumab-associated PML have been confirmed. More than 100 cases have been reported as rituximab-associated PML, and most of these patients had worse outcomes. In addition, several other MA were reported as causes of PML. Dr Takao also presented the clinical features of PML associated with MA, which might be different from classical PML. The use of MRI, in particular fluid-attenuated inversion recovery sequences, provides important information for diagnosing PML. PML neuropathology as a result of MA might be more severe than classical PML. In fact, once PML has been identified in an individual receiving MA therapy, the MA must be discontinued and immediately removed by plasmapheresis. Dr Katsuichi Miyamoto, Department of Neurology, Kinki University, Osaka, Japan, gave a very useful lecture about disease-modifying therapies currently used to treat MS. First, he showed, in detail, the effect–efficacy, adverse effects and pitfalls of fingolimod to treat MS. He also explained the unique effect on slowing brain atrophy by fingolimod. Several clinical trials using novel oral disease-modifying therapies, including ONO-4641 and BAF-312, have already started in Japan. In addition, he presented preliminary data from a nationwide NMO survey in Japan, which helped to estimate approximately 4500 patients with NMO in Japan. In the Basic Science Symposium, Professor Hiroshi Nakanishi, Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan, gave a great lecture about the novel role of microglia. He showed very interesting data demonstrating that microglia contain an intrinsic molecular clock and exhibit a circadian expression of cathepsin S (CatS).6 CatS deficiency causes mice to exhibit hyperlocomotor activity, and inhibits diurnal variations in synaptic activity and spine density, which are significantly higher during the dark-phase compared with the light-phase. Dr Nakanishi concluded that CatS, secreted by microglia during the dark-phase, decreases spine density of cortical neurons by modifying the perisynaptic environment. This further leads to downscaling of synaptic strength during the subsequent light-phase.6 In addition, he found that peripheral CatS is involved in neuropathic pain. CatS-deficiency, or systemic administration of a specific CatS inhibitor, significantly attenuated maintenance of tactile allodynia and activation of splenic CD4 + -T cells after peripheral nerve injury.7 Peripherally active selective CatS inhibitors could be a novel therapeutic option for the pharmacological treatment of neuropathic pain. Dr Ryo Yamasaki, Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, presented distinct roles of microglia and macrophages in central nervous system inflammation and degeneration. He developed red–green mice, which enable one to distinguish between monocytes and microglia that express Red fluorescence protein (RFP) and Green fluorescence protein (GFP), respectively. He showed for the first time in EAE mice, histologically and genetically distinct characteristics between monocytes and microglia.8 In addition, he recently observed interesting characteristics of monocytes and microglia in Amyotrophic lateral sclerosis (ALS) model mice. A clear distinction and visualization of monocytes and microglia in central nervous system lesions is important for elucidating disease mechanisms and to develop novel therapeutic options. In the Farewell Lecture, Professor Akio Suzumura, from the Department of Neuroimmunology, RIEM, Nagoya University, Nagoya, Japan, gave us a very nice comprehensive and historical review, entitled “Glia and myself: Future glia-targeted therapy in MS.” In the late 1980s, Professor Suzumura established for the first time the “shaking off” method to obtain pure microglial cultures.9 His subsequent pioneering research in the field revealed many in vitro and in vivo microglial functions. In particular, microglia play critical roles in MS pathogenesis, functioning as antigen presenting cells, effector cells for tissue damage including demyelination, and regulators to orchestrate immune cells and/or neural cells. Microglia produce both inflammatory and neurotrophic factors, and Professor Suzumura explained that these factors could play a role in neuronal and/or oligodendrocyte damage, as well as play protective and reparative roles by inducing neuroinflammation. In recent years, he and his colleagues have shown the significance of cell-to-cell communication through connexin gap junctions and hemichannels in neuroinflammation and neurodegeneration.10 Finally, he emphasized that studies on these interactions could provide clues to better understanding the pathophysiology of MS, and also to establish novel strategies to treat MS. Author T.M. has received research support from Bayer Schering Pharma, Biogen Idec, Novartis Pharma, and Mitsubishi Tanabe Pharma. T.M. has received speaker honoraria from Mitsubishi Tanabe Pharma. Author K.M. declares no conflict of Interest for this article. Author J.K. serves as an editorial board member of Clinical and Experimental Neuroimmunology, Multiple Sclerosis Journal, Multiple Sclerosis and Related Disorders, BMC Medicine, PLOS ONE, Expert Review of Neurotherapeutics, Intractable and Rare Diseases Research, The Scientific World Journal, and Journal of the Neurological Sciences. He has received honoraria from Biogen Idec Japan, Novartis Pharma Japan and Mitsubishi Tanabe Pharma Corporation.