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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.
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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 RORt.
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
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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