BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
We thank the following sponsors for their generous support:
CELL COMMUNICATION
IN HEALTH AND DISEASE
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Greetings from the Rector of the Medical University – Wolfgang Schütz
Dear Colleagues,
The Medical University of Vienna is one of the world’s most
renowned medical schools. Around 7,500 students are currently
studying the diploma course in human or dental medicine. One
important element of learning at the Medical University of Vienna is
the PhD course delivered in English.
The excellent quality of this postgraduate education, which complies with the most rigorous
of standards, has earned the PhD courses at the MedUni Vienna tremendous international
acclaim. This is also highlighted by the high proportion of PhD students who are from outside
Austria, accounting for 38 per cent of the students on these courses.
Some of the key areas of research at the MedUni Vienna are Immunology, Inflammation,
Vascular biology and Neurobiology. This year, for the first time two PhD programmes of the
MedUni Vienna – CCHD and IAI – present a joint symposium. The 7th international PhD
workshop entitled “Bridging the Gap” is therefore the ideal complement to this research.
I wish the event every success, and would like to thank the people who have organised it and
worked behind the scenes for their tremendous commitment. I hope that everyone who
participates will have the opportunity to enjoy stimulating debate and gain new experiences.
Wolfgang Schütz, Rector Medical University of Vienna
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Greetings from the Head of the CCHD Program – Stefan Böhm
At the Medical University of Vienna, which also runs the Vienna
General Hospital, we believe that by schooling students in medicine
they will learn to provide effective relief to patients, but by
additionally training them in science, they might move on to discover
cures. To this end, we study the underlying causes for disease by
focusing on how cells exchange vital information. Our doctoral
training program “Cell Communication in Health and Disease” (CCHD)
provides students with challenging research projects that range from
basic biomedical sciences to translation into clinical application. CCHD gives students the
opportunity to acquire skills that can be employed in highly divergent areas, by exposing them within a single multidisciplinary framework - to
four research themes that deal with organ-independent ubiquitous regulatory systems:
neurobiology; vascular biology; immunology; and inflammation research.
CCHD being in its eighth year gives us the opportunity to have our 7th international “Bridging the
Gap”-workshop. In accordance with scientific multidisciplinarity as the major asset of CCHD, this
workshop brings together experts in the four CCHD research topics with the aim of bridging the gap.
I would like to thank the students for putting together this program and our guests for accepting the
students’ invitations in order to share their results and expertise with us. I look forward to
illuminative seminars and lively discussions and I do hope that not only the CCHD students, but also
all other participants will keep this CCHD workshop in mind as unforgettable event.
Stefan Böhm (CCHD PhD program coordinator)
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Greetings from the Head of the IAI Program – Maria Sibilia
The IAI program runs as an educational excellence platform in basic
medical research at the Medical University of Vienna (MUW) which as a
major European Center of biomedical research and education provides
the infrastructure for students from all over the world. Our aim is to
strengthen the research interactions and to extend our collaborative
network beyond laboratory wallsand different research disciplines, as
well as language gaps and cultural differences. Each year the IAI PhD
students organize an international workshop which should contribute to
facilitate our endeavors.
The topics chosen by our students for the 7th international “Bridging the Gap”-workshop are
medically extremely important to accelerate the process from basic discoveries to new therapeutic
strategies for the cure of many disorders such as cancer, allergy, and infections. The students have
invited internationally well-known experts and world leading scientists in the field and we are looking
forward to an active exchange of opinions, stimulating discussions and exciting scientific interactions
for the next two days.
In the name of all faculty members I would like to thank the students for putting together such an
exciting program and to all the speakers for accepting the invitation and traveling to Vienna to make
this event possible. I wish all the IAI students and all participants of the workshop two exciting days.
Finally, we would like to express our gratitude towards the Austrian Science Fund (FWF) and the
MUW for financing and supporting our PhD program and to all companies for co-sponsoring this
workshop.
Maria Sibilia (IAI PhD program coordinator)
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Greetings from the CCHD and IAI students
Dear participants,
Once again it is our – the student organizing committee’s – pleasure to invite you to our annual
Bridging the Gap (BTG) symposium. This year, for the first time we are holding a Joint Symposium of
the Cell Communication in Health and Disease (CCHD) and the Inflammation and Immunity (IAI) PhD
programs.
In line with the interdisciplinary philosophy of our Ph.D. programs, we sought to compile an up-todate program, covering important developments and hot topics from neurobiology, vascular biology,
immunology and inflammation research. To this effect, we are proud to present you with 14
international top scientists from Europe and overseas who have made – and continue to make –
important contributions to these fields. This year’s program features such seemingly diverse topics as
virotherapy, neuronal signaling and control of infectious diseases. However, in a biological system all
of these aspects of molecular research are interconnected with each other – something we want to
reemphasize in today’s highly specialized science business.
Being in its seventh year, the BTG symposium is now a regular feature of Vienna’s varied conference
schedule. This is not only due to the outstanding presentations and diligent preparation of speakers
and organizers of the past. Essentially, our workshop depends on the active participation of the
audience. We encourage all of you to take part in the discussions during (as well as in between) the
scientific sessions. Thus we hope to bridge the gap – not only between different disciplines of
research, but also between the representatives of said disciplines, professors and students alike.
We warmly welcome you to our workshop here in Vienna and wish you a scientifically inspiring time!
Having said this, we hope you enjoy the selection of talks assorted for 2014. In addition, do not
hesitate to address us during the meeting to comment and give us your feedback.
Also at this year’s BTG workshop, life is all about communication.
Karin Komposch, Carol-Ann Eberle, Hend Gafar, Nicole Amberg
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Program CCHD-IAI Joint Symposium
12th-14th February 2014
12th February
Program
09:15-09:45
Registration + Coffee
09:45-10:00
Opening
Session I
Chairs: Giulio Superti-Furga, Mathias Müller
10:00-11:00
Grant McFadden
Exploiting oncolytic virotherapy to treat cancer
11:00-12:00
Annette Oxenius
Regulation of T-cell responses during viral infection
12:00-13:30
Lunch
Poster Session – IAI PhD Program
Session II
Chairs: Maria Sibilia, Robert Eferl
13:30-14:30
Joel Weinstock
Helminths control autoimmunity through regulation of innate immunity
14:30-15:30
Federica Sallusto
Diversity of the human T cell repertoire to pathogens and vaccines
15:30-16:00
Coffee
16:00-17:00
Session III
Chair: Monika Bradl
Don Mahad
Mitochondria and progressive MS
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
13th February
Program
09.00-09:30
Registration + Coffee
Session IV
Chairs: Irene Lang, Brigitte Hantusch
09:30-10:30
Paul Kubes
NETs and platelets in infections
10:30-11:30
Mihaela Skobe
Mechanisms and significance of lymphatic metastasis
11:30-12:00
Coffee
Session V
Chairs: Stefan Böhm, Thomas Klausberger, Michael Freissmuth
12:00-13:00
Thomas Euler
What the mouse eye tells the mouse brain: Recording the entire visual
representation along the vertical pathway in the retina
13:00-14:30
Lunch
Poster Session – CCHD PhD Program
14:30-15:30
Hannah Monyer
GABAergic neurones – their role for synchronous network activity
15:30-16:30
Ron de Kloet
Stress in the brain: from adaptation to disease
15:30-17:00
Coffee
17:00-18:00
Session VI
Chair: Barbara Bohle
Alan Sher
Self-regulation of CD4+ T cell effector function in the immune response
to Toxoplasma gondii
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
14th February
Program
09.30-10:00
Registration + Coffee
Session VII
Chairs: Sylvia Knapp, Veronika Sexl
10:00-11:00
Matteo Iannacone
Determinants of intrahepatic effector CD8+ T cell trafficking and antigen
recognition
11:00-11:30
Coffee
11:30-12:30
Florence MargottinGoguet
How the SAMHD1 restriction factor counteracts HIV in non-dividing cells
12:30-13:30
Stefan Rose-John
The biology of Interleukin-6 and novel strategies of blockade
13:30-14:00
Closing Remarks
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
ABSTRACTS
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Grant McFadden
College of Medicine, University of Florida, Gainesville, Florida, USA
Exploiting Oncolytic Virotherapy to Treat Cancer
Myxoma virus (MYXV) is a host-restricted leporipoxvirus that causes an acute lethal infection
specifically in European rabbits. Although MYXV normally is pathogenic only to rabbits, it also has the
innate capacity to infect and kill a wide spectrum of human cancer cells. We are currently developing
MYXV as an oncolytic virotherapeutic to treat a spectrum of human cancers that exhibit defective
antiviral responses. We have recently shown that MYXV can selectively infect and kill primary human
cancer cells that contaminate bone marrow samples from patients with acute myeloid leukemia or
multiple myeloma but the virus spares the normal CD34+ hematopoetic stem and progenitor cells
within the sample needed to reconstitute the immune system following autologous bone marrow
transplantation. Using flourescently-tagged MYXV virions, we have shown that the virus fails to bind
CD34+ hematopoetic stem and progenitor cells from primary human bone marrow samples, which
explains why these cells are uniquely unable to be infected with this virus. Unexpectedly, the
identical ex vivo treatment of allogeneic bone marrow transplant samples from normal cancer-free
donors was found to suppress the development of graft-vs-host-disease (GVHD) in recipient NSG
mice. Our recent studies in collaboration with the lab of Dr. Chris Cogle (U Florida) indicate that
tagged MYXV virions can efficiently bind naive human T cells ex vivo but the virus does not infect
these T cells until after they have become activated. Thus, the fundamental study of a rabbit-specific
poxvirus pathogen has revealed unexpected applications for improving the clinical outcomes of both
autologous and allogeneic stem cell transplantation therapy for cancer.
Dr. McFadden is a Professor in the Department of Molecular Genetics
and Microbiology at the University of Florida, College of Medicine, who
has pioneered the field of viral immunomodulation. He received a B.Sc.
degree in 1970 and a Ph.D. degree in 1975, both from McGill University
in Montreal, Canada. In 2001, he was named Canada Research Chair in
Molecular Virology and in 2002, he received the Hellmuth Prize. He was
inducted as a Fellow of the Royal Society of Canada in 2004 and as a
Fellow of the American Academy of Microbiology in 2007. McFadden is
a co-founder of Viron Therapeutics, Inc. to develop the use of viral
proteins for therapeutic purposes against systemic inflammatory
diseases. He is a member of the WHO research oversight Committee on
Variola Virus research and is often consulted internationally about
issues related to bioterrorism and biosecurity. Currently, he is the
Deputy Editor-in-Chief for PLoS Pathogens, a senior Editor for Journal
of Virology, and he also serves on the Editorial Boards of a variety of other scholarly journals. For the
past 30 years, his lab has been investigating how viruses, particularly poxviruses, evade the immune
system. In 2006, Brett Finlay and Dr. McFadden coined the term “anti-immunology” to describe this
growing field of research. Currently, his lab is focusing on the molecular basis for the host and
cellular tropism specificity of poxviruses, using the myxoma virus model system as a novel platform
for replication-restricted vaccine vectors and as an oncolytic virus. To date, he has published over
300 peer-reviewed papers and reviews, filed nearly two dozen US patents, presented over 100 times
at international, national and regional meetings, trained over 120 students, postdocs or fellows, and
has given over 100 invited lectures at various Institutions and Universities around the world.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Annette Oxenius
Swiss Federal Institute of Technology, Zurich, Switzerland
Regulation of T-cell responses during viral infection
Direct type-I IFN signaling on T cells is necessary for the proper expansion, differentiation and
survival of responding T cells following infection with viruses prominently inducing type-I IFN. The
reasons for the abortive response of T cells lacking type-I IFN receptor (IFNAR-/-) remain unclear. We
discuss here that IFNAR-/- T cells are highly susceptible to NK cell mediated killing in a perforin
dependent manner. Depletion of NK cells prior to LCMV infection completely restored the early
expansion of IFNAR-/- T cells. IFNAR-/- T cells expressed elevated levels of NCR1 ligands upon infection,
rendering them targets for NCR1 mediated NK cell attack. Thus, direct sensing of type-I IFNs by T cells
protects them from NK cell killing by regulating the expression of NCR1 ligands, thereby revealing a
new mechanism by which T cells can evade the potent cytotoxic activity of NK cells that are activated
in a type-I IFN dominated environment.
Anette Oxenius obtained her PhD in 1997 at the
ETH, Institute for Experimental Immunology, in the
laboratory of Prof. Hans Hengartner and Prof. Rolf
Zinkernagel, generating TCR transgenic mice to
study virus-specific CD4+ T cell responses in vivo.
She continued with a postdoctoral position in the
laboratory of Prof. Hans Hengartner and Prof. Rolf
Zinkernagel. In 1999 she moved to the laboratory
of Prof. Rodney Phillips at the Nuffield Department
of Medicine, John Radcliffe Hospital in Oxford, UK,
as a postdoctoral fellow. By 2002, she went back to
the ETH in Zurich as an Assistant Professor for
Immunology at the Institute of Microbiology. In
2007, she became Associate Professor and in 2012 Full Professor for Immunology at the Institute of
Microbiology, ETH Zurich. To mention only some, she is member of the steering committee of the
Swiss Society of Allergology and Immunology (SGAI), of the American Association of Immunologists,
board member of the Novartis Foundation and member of the Scientific Advisory Board of the
Heinrich Pette Institute (Hamburg, Germany). Furthermore, she is Co-director of the Microbiology
and Immunology (MIM) PhD program Zurich and already directly supervised 23 PhD theses. So far,
she published 135 peer-reviewed publications and 4 book chapters.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Federica Sallusto
Università della Svizzera Italiana, Bellinzona, Switzerland
Diversity of the human T cell repertoire to pathogens and vaccines
It is becoming increasingly appreciated that the human T cell response to pathogens and vaccines is
heterogeneous and comprises different types of effector and memory cells. The cellular basis for this
heterogeneity is not clear. It may result from multiple T cell clones, each instructed to perform a
given function, or from the descendants of clones that have acquired multiple functions due a
process of intraclonal diversification. To discriminate between these possibilities, we study the T cell
response to microbes and vaccines at the clonal level using a combination of high throughput cellular
screenings and next generation TCR V sequencing. Functionally distinct T cell subsets are isolated
according to the expression of surface markers, labeled with CFSE and stimulated in vitro with
antigen-pulsed monocytes. Proliferating CFSE– cells are sorted and used to perform TCR V CDR3
clonotypic analysis and to isolate T cell clones. By performing deep sequencing analysis of TCR V
CDR3 on genomic DNA obtained from the different samples, we can estimate the number of
individual clones present in each subset and identify immunodominant clonotypes. This analysis
revealed that the response to pathogens, such as C. albicans, and vaccines, such as tetanus toxoid,
comprises several expanded T cell clones that are present in different T cell subsets, thus
demonstrating intraclonal diversification in vivo. These results indicate that the human T cell
response can comprise immunodominant clones that, in spite of identical antigenic specificity,
display different, sometimes divergent, types of effector function.
Federica Sallusto received the degree of Doctor in Biology from the
University of Rome, worked at the Istituto Superiore di Sanità in Rome
and at the Basel Institute for Immunology, and since 2000 she is a group
leader at the Institute for Research in Biomedicine in Bellinzona,
Switzerland. She is an expert in the field human cellular immunology. Her
research has focused on dendritic cell and T cell traffic, mechanisms of T
cell differentiation and immunological memory. Her studies revealed a
differential expression of chemokine receptors in human Th1 and Th2
cells and led to the characterization of “central memory” and “effector
memory” T cells as memory subsets with distinct migratory capacity and
effector function. Among her recent contributions are the discovery of
Th22 cells, the identification of surface markers of human Th17 cells, and
the characterization of two distinct types of pathogen-specific human Th17 cells that produce IFN-γ
or IL-10. In the mouse system her work has focused on leukocyte traffic in lymph nodes and brain.
She showed that NK cells, T helper cells, and cytotoxic T cells can migrate to inflamed lymph nodes,
where they profoundly modulate T cell responses, and that pioneer CCR6-positive Th17 cells enter
the CNS through the choroid plexus, which in turn allows other cells to enter and cause
autoimmunity. Recently, her lab showed that in mice persistent antigen and germinal centre B cells
sustain Tfh cell responses and phenotype. For her scientific achievements, she received the
Pharmacia Allergy Research Foundation Award in 1999, the Behring Lecture Prize in 2009, and was
elected member of the German Academy of Science Leopoldina in 2009 and of EMBO in 2011. She is
currently President of the Swiss Society for Allergology and Immunology.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Joel V. Weinstock
Tufts University School of Medicine, Boston, USA
Helminths control autoimmunity through regulation of innate immunity
Lack of early childhood exposure to helminthic parasites and some symbiotic microorganisms many
increase susceptibility to immune mediated diseases like inflammatory bowel disease (IBD).
Helminths powerfully influence host immunity, which probably accounts for their protective effect.
Their mechanisms of action likely involve induction of several independent immune regulatory
pathways. At least part of the protection depends on parasite induction of regulatory-type cytokines
and interactions with cells of the innate immune system. They activate specific pathways in Foxp3+ T
cells making them highly regulatory. They also induce regulatory dendritic cells. They alter how
dendritic cells sense their external environment by changing their display of pattern recognition
receptors. These changes limit the capacity of intestinal dendritic cells to activate T cell responses
near the mucosal surface. This action is likely to help control IBD, since aberrant T cell immunity
likely contributes greatly to the development of this disease. How intestinal helminths control
dendritic cell functions remains unknown. Research in progress is attempting to identify the
molecules secreted by helminths that mediate their immune modulatory effects. This effort could
lead to development of novel therapeutics that modulate host immunity and perhaps stop the
progression of immune mediated diseases.
Joel V. Weinstock received his medical training at the University
of Michigan. He was Chief of the Center for Digestive Disease at
the University of Iowa prior coming to his appointment at Tufts.
Dr. Weinstock is a world authority on inflammatory conditions of
the intestine. His clinical specialty is in inflammatory bowel
diseases such as ulcerative colitis and Crohn's disease. He has
active research programs both in clinical studies related to
inflammatory bowel disease as well as in basic mechanisms of
immune regulation. He has been Member of the Scientific
Advisory Board of Asphelia Pharmaceuticals, Inc. since
September 2008. Dr. Weinstock serves as the Chief of the
Division of Gastroenterology/Hepatology at Tufts New England
Medical Center, and is a professor at Tufts University School of
Medicine. Dr. Weinstock is board certified in Gastroenterology
and Internal Medicine.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Don Mahad
College of Medicine and Veterinary Medicine at the University of Edinburgh
Mitochondria and progressive MS
Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system with
neurodegeneration. Over the past two decades there has been an impressive gathering of disease
modifying agents for the so called relapsing phase of MS characterized by bouts of neurological
impairment that recovers to a variable extent. These agents are effecting for preventing the stepwise
accumulation of permanent neurological deficit, which is due to incomplete recovery of relapses. They
are, however, ineffective for the gradual decline in neurological function, which encompass the
progressive forms of MS. Pathological studies indicate a profound loss of axons and damage to neuronal
cell bodies, particular in lesions where inflammation and demyelination are most prominent. How this
inflammatory demyelination conspires with neurodegeneration is much less well understood. There is a
gathering body of evidence implicating mitochondria in the pathogenesis of MS. Mitochondria are the
most efficient producers of cellular energy and they contain the only non-nuclear DNA, mitochondrial
DNA (mtDNA). MtDNA is much more susceptible to oxidative injury than nuclear DNA. The resulting
mtDNA mutations can ultimately compromise the biochemical activity of the mitochondrial respiratory
chain complexes (complex I-complex V, except complex II which is entirely encoded by nuclear DNA).
We and others have identified a plethora of mitochondrial abnormalities all resulting in the deficiency of
various mitochondrial respiratory chain complexes. The high level mtDNA deletions abolished the activity
of complex IV while a decrease in nuclear DNA encoded transcripts impaired the activity of complex I and
complex III. Furthermore, immunohistochemical data indicated the loss of subunits of ATP synthase or
complex V. The majority of these abnormalities were evident within different neuronal compartments
(axons and neuronal cell bodies).
Based on detailed neuropathological findings, we present a novel three step hypothesis for axonal energy
failure and subsequent degeneration in patients with progressive MS. First, inflammatory mediators and
reactive oxygen species damage mitochondria including mtDNA in the white matter and grey matter,
leading to the formation of mtDNA mutations (formation step). These mitochondrial abnormalities
accumulate through amplification processes such as clonal expansion of mtDNA deletions and deposition
of iron leading to additional oxidative injury (amplification step). The resulting neuronal cell bodies
abundant in dysfunctional mitochondria then act as a reservoir of abnormal mitochondria which displaces
to the axon causing axonal energy failure (displacement step). The limitations of the established models
of MS will be discussed in the context of the above converging hypothesis for axon degeneration in
progressive MS.
Don Mahad was born on the 6th August 1969. He graduated at the Medical
School at the University of Sheffield (UK) in 1994. In 1997, he received his
Diploma in Pediatrics in London. From 1999 to 2001, he was research
fellow in Neurology at the University of Sheffield in Newcastle (UK). From
2001 to 2004, he was a research fellow in neuroscience and joined Prof.
Richard Ransohoff and Prof. Bruce Trapp at the Cleveland Clinic Foundation
in Ohio. In 2004, he received his PhD degree from the University of
Sheffield. From 2004 to 2006, he was specialist in Neurology in Newcastle.
From 2006 to 2011, he was intermediate clinical fellow of the Wellcome
Trust at Newcastle University with Prof. Doug Turnbull. After his, he was
physician fellow of the National Multiple Sclerosis Society Clinical Care. From 2011 to 2012, he was
senior clinical research fellow at the University of Edinburgh with Prof. Peter Brophy. Since 1.1.2012
he is Honorary Consultant Neurologist in Edinburgh. In March 2012, he completed his specialist
training in Neurology. Since 1.11.2013, he is Scottish senior clinical fellow at the University of
Edinburgh.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Paul Kubes
University of Calgary, Canada
NETs and Platelets in Infections
Although it is possible to see the formation of NETs in vitro and much important molecular
information has been derived from such experiments, the conditions in vivo under which NETs might
be released has been poorly studied due to the challenges of visualizing these events. We have
developed a spinning disk microscopy technique that allows us to begin to explore the mechanisms
by which NETs are formed in vivo. Tremendous neutrophil-platelet interactions occur in the
vasculature during a systemic blood borne infection leading to NET formation. While macrophage in
the liver and spleen are thought to trap bacteria from blood, they are often overwhelmed by
systemic infections. Neutrophils are directed to places like liver and lung where they release NETs to
increase the catching capacity of the immune system 4 fold. The NETs attach to the vessel walls
potentially via anchors that involve the histones, and getting rid of the DNA with DNase often leaves
remnant proteins attached to the vessel wall. A better therapeutic approach in vivo appears to be
preventing the formation of NETs. Outside the vasculature NETs can also be formed presumably
without the need for platelets. S.aureus appears to be an excellent stimulator of NETs. Rather than
dying the neutrophils release their DNA in a programmed fashion of vesicular release independent of
cell death. In this case NETs limit dissemination.
Dr. Paul Kubes is professor of Physiology and Pharmacology at
the University of Calgary. He is also the director of the Calvin,
Phoebe and Joan Snyder Institute for Chronic Diseases and Chair
of the Critical Care Research at the Snyder Institute. Dr. Paul
Kubes studied Biology and received his PhD in Physiology from
the Queen´s University at Kingston, Canada, in 1988. He has
focused his career in the study of the immune system and the
mechanisms of inflammation. Currently his lab concentrates in
the use of imagining approaches to understand the immune
responses in the microcirculation. His lab is leading the way in
directly imaging the immune system using cutting edge technology, including spinning-disk confocal
and multi-photon microscopy. His group has contributed significantly to the current leukocyte
recruitment paradigm, as well as uncovered novel roles of known adhesion molecules in leukocyte
behaviors such as intravascular crawling. They have defined a novel means by which neutrophils in
vitro and in vivo release DNA in large mesh structures (neutrophil extracellular traps, NETs) in order
to trap bacteria at focal sites like skin. By imaging complex cellular behaviors in real time, both in
vitro and in vivo, we can now begin to understand how immune cells, such as neutrophils,
monocytes, NKT cells and Kupffer cells function under physiological and pathological disease states.
Dr. Kubes has received numerous honors and awards, including the CIHR Researcher of the Year
award in 2011, one of Canada´s top awards for medical research.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Mihaela Skobe
Icahn School of Medicine at Mount Sinai, USA
Mechanisms and significance of lymphatic metastasis
The lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation
system. It is widely believed that tumor cells enter lymph nodes passively, with the flow of lymph.
We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node. In
vitro, tumor migration to lymphatic endothelium (LECs) was inhibited by blocking chemokine CCL1 or
its receptor CCR8. Recombinant CCL1 promoted migration of CCR8+ tumor cells. Pro-inflammatory
mediators TNF-, IL-1β and LPS increased CCL1 production by LECs as well as tumor cell migration to
LECs. Blocking studies showed that CCL1 is a key molecule mediating tumor cell chemotaxis to
inflamed lymphatic endothelium. In mouse and human tissues CCL1 protein was detected in lymph
node lymphatic sinuses, but not in the skin or tumor lymphatics. In addition, CCR8 was strongly
expressed by human malignant melanoma. In a mouse model, blocking CCR8 function decreased
lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting
lymphatic vessels at the junction with the lymph node subcapsular sinus. Furthermore, intravital
multiphoton imaging revealed active migration of tumor cells within the sinus. These data identify a
novel function for CCL1/CCR8 in metastasis and lymph node LECs as a critical check-point for entry of
metastases into the lymph nodes.
Dr. Skobe received her bachelor’s degree in Molecular
Biology from the University of Zagreb, Croatia. In 1996 she
obtained PhD in Cell Biology from the University of
Darmstadt, Germany and the German Cancer Research
Center in Heidelberg. She performed her postdoctoral work
at the Massachusetts General Hospital and Harvard Medical
School, and has joined Icahn School of Medicine at Mount
Sinai, New York City, in 2001, where she is now an Associate
Professor. Dr. Skobe is an internationally recognized cancer
biologist whose main research interest is in cancer
metastasis and tumor microenvironment. Dr. Skobe has
pioneered the field of tumor lymphangiogenesis and has
made a number of important contributions to the fields of cancer and lymphatic vascular biology.
She serves on many advisory committees and review boards nationally and internationally. Dr. Skobe
is the recipient of several prestigious awards and she was recently honored by the Lymphatic
Research Foundation for her seminal contributions to the field.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Thomas Euler
Centre for Integrative Neuroscience, University of Tübingen, Germany
What the mouse eye tells the mouse brain:
Recording the entire visual representation along the vertical pathway in the
retina
Right at the first synapse, the stream of incoming visual information is split into multiple parallel
channels. Complex circuits and, in particular, synaptic interactions in the retina’s two synaptic layers
tune these channels to distinct sets of visual features. Cracking the “retinal code”, that is understanding how the visual scenery is encoded by the outputs of the ~20 RGC types, is a major aim of
vision research. We study the signal at different processing stages of the retinal signal channels by
recording from the majority of cells in the vertical cone photoreceptor pathway. We use 2p imaging
in the mouse retina to measure Ca2+ activity evoked by a comprehensive set of stimuli, including
frequency/contrast modulated full-field and white noise stimuli. So far our database contains
recordings of ~100 BCs and >10,000 RGCs. We have implemented a probabilistic framework for
clustering RGCs into functional types based on their responses to different visual stimuli. Clustering is
refined and verified by employing anatomical/genetical reference data. For the cells in the ganglion
cell layer, ~25-29 functional clusters can be distinguished, some of which were already verified using
our single cell data. Our results suggest that this dataset allows us to study the computations performed along the retina’s vertical pathway and to obtain a complete sample of the information the
mouse eye sends to the mouse brain.
Born in Darmstadt, Germany, I studied biology at the University of Mainz
and did my diploma and PhD work (advisors: H. Wässle, C. Neumeyer) at
the Max-Planck Institute for Brain Research (Frankfurt/M.). After a postdoc
with R.H. Masland at the Mass. General Hospital/Harvard Medical School in
Boston, MA (USA), I came back to Germany to join the department of W.
Denk at the Max-Planck Institute for Medical Research (Heidelberg), where
I started applying optical methods (2p microscopy) for functional
recordings in the retina. In 2009, was appointed full professor at the CIN at
the University of Tübingen, where I continued working on different aspects
of signal processing in healthy and diseased mammalian retina.
Since my diploma thesis, I am fascinated by the intricacy of the retinal network – the first stage of
visual information processing in the brain. The retina does not only convert the incoming stream of
photons into electrical signals, but critically performs a detailed and highly specific analysis of the
observed scene. All visual information sent from the retina to the brain travels through the optic
nerve, the main bottleneck of the visual system – therefore prior to transmission to the brain,
important aspects of the visual scene (e.g. contrast, brightness, "colour", edges, motion and its
direction, edges and trajectories of potential objects, etc.) must be extracted and compressed. The
importance of retinal signal processing is highlighted by the fact that this important decision – what
is relevant and therefore kept, and what can be safely discarded – is made already in the retina. The
computational capabilities of its intricate but highly defined neuronal network rely on about 70 types
of neurons organized in a plethora of interconnected microcircuits. My group aims at unravelling
function and organization of retinal microcircuits towards a better understanding of the underlying
computational principles. Furthermore, we are interested in the mechanisms that implement retinal
microcircuits during development and how microcircuits change during retinal degeneration.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Hannah Monyer
Head of the Dept. Clinical Neurobiology, Medical Faculty of the University of Heidelberg &
German Cancer Research Center (DKFZ) Heidelberg, Germany
GABAergic neurones – their role for synchronous network activity
A major research focus in our lab is to study the contribution of GABAergic interneurones for
rhythmic synchronous activity. We investigate preferentially the hippocampus, and more recently
the medial entorhinal cortex, two brain structures that are crucially involved in spatial coding and
spatial memory. Genetic manipulations aimed at reducing the excitatory drive and hence the
recruitment of GABAergic interneurones or abolishing the electrical coupling between GABAergic
interneurones. Our studies highlight the functional role of local GABAergic interneurones for spatial
or temporal coding in the hippocampus. The genetic manipulations were always associated with
distinct spatial memory deficits. These results will be summarized and discussed in the context of
current models of memory formation and storage.
To establish a causal relationship between neuronal activity and behaviour, it will be required to
manipulate activity of selective neurones “online”. To this end we use optogenetics combined with in
vivo recordings in freely moving mice. Our first study involves on line identification and manipulation
of a specific class of interneurones, namely parvalbumin-positive cells in the medial entorhinal
cortex. The study gave insight into neuronal connectivity and the contribution of identified neurones
in the medial entorhinal cortexfor spatial coding.
In addition I will present data demonstrating the presence of long-range GABAergic cells that connect
the hippocampus and entorhinal cortex bidirectionally. Also these data will be discussed in a larger
context, since there is good reason to believe that long-range GABAergic neurones are more
abundant in the forebrain as previously thought. By virtue of their connectivity – the target cells are
most often local interneurones - this class of cells is ideally suited to synchronize brain regions over
long distance. Similarly to local GABAergic interneurones, long-range GABA cells do not constitute a
homogenous cell population. Based on the expression of neurochemical markers, we were able to
identify several subtypes. Thus, the hippocampus harbors parvalbumin- and somatostatin-positive
long-range GABA cells that project to extrahippocampal regions. In addition, within one class further
specification may reflect the differential targeting. For instance, based on retrograde labeling studies
we postulate that hippocampal long-range somatostatin-positive cells targeting the septum and
entorhinal cortex constitute discrete neuronal subpopulations.
Hannah Monyer graduated in 1982 from Medical School at the
University of Heidelberg in Germany. From 1984 to 1986 she was a
resident in the Department of Neurology at the University of Lübeck.
Then she went to the USA for a postdoc to the Stanford University
Medical Center. In 1989, she came back to Heidelberg to the Center for
Molecular Biology where she became professor in 1994. Since 1999, she
is Head of the Department of Clinical Neurobiology, and she has a joint
professorship at the Medical Faculty of Heidelberg and the DKFZ
(German Cancer Research Center). Her scientific fields of interest are
synaptic plasticity, postnatal neurogenesis, and cellular and network
mechanisms underlying learning and memory.
Hannah Monyer received several prizes and grants, among them the „Prix Franco-Allemand
Gay-Lussac Humboldt” (2005) and the ERC Advanced Grant „GABAcellsAndMemory” (2009).
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
E.R.(Ron) de Kloet
Leiden Academic Center for Drug Research, Leiden University Medical Center, The Netherlands
Stress in the Brain: from adaptation to disease
‘Stress is the spice of life’ said Hans Selye, who coined the word ‘Stress’ in 1936 and referred to stress
as an essential condition for health, but also noted that stress can enhance vulnerability to disease,
particularly if the reactions to stress spin out of control. In control of stress reactions particular genes
are important that mediate the action of stress hormones, and on which also stressful (early) life
experiences leave an epigenetic mark. In my lecture, I will examine therefore ‘Stress in the Brain’
through the action of the stress hormone cortisol released by the adrenals. Cortisol readily enters the
brain and promotes emotion and motivation by activation of specific amygdala-cortical pathways.
Cortisol also controls the hippocampus, a seahorse-like brain structure where emotions are burned
into memory and where the birth of new nerve cells is regulated, even at old age. I will discuss the
action of cortisol as a double edged sword: cortisol facilitates coping and behavioural adaptation, but
if coping fails the very same hormone promotes the onset and course of stress-related mental
disorders. This research provides leads towards medicines that can promote a mechanism of
plasticity and resilience still present in the diseased brain, which seems a promising strategy to
maintain mental health.
Born in Maarssen, I studied Chemistry and got my PhD in the
Neurosciences (promotor prof. dr. David de Wied) at the University of
Utrecht, while employed with the pharmaceutical company Organon.
After a post-doc period of 2 years at the Rockefeller University in New
York City, I worked until 1990 in the Rudolf Magnus Institute in
Utrecht as a basic neurobiologist on the action of neuropeptides in the
regulation of memory processes. From October 1, 1990 I was
appointed full professor in Medical Pharmacology at Leiden University
& Leiden University Medical Center. In 2004 followed my appointment
as Academy professor of the Royal Netherlands Academy of Arts and
Sciences until 2014, which allowed me to continue working while
becoming emeritus in 2009.
I am fascinated by ‘Adaptation to Stress’; how stress hormones act in the brain, how they drive
emotions affecting cognition and how resilience to stress can help to promote recovery in the
diseased brain. My research covers experiments from gene to behaviour, and as a basic scientist my
ambition is to translate knowledge to the clinic and to create value for commercialization. I
discovered how stress hormones possibly can precipitate mental disorders and affect
neurodegenerative processes, and how this mechanism can be used to develop a new class of
medicines. With an oeuvre of more than 500 scientific articles and awarded with international
recognition I became august 25, 2010 “Knight of the Order of the Dutch Lion”.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Alan Sher
National Institute of Allergy and Infectious Diseases (NIAID), USA
Self-regulation of CD4+ T cell effector function in the immune response to
Toxoplasma gondii
An excellent example of host-protective negative regulation of CD4 T cell function occurs during the
Th1 response to Toxoplasma gondii, an intracellular protozoan parasite. This IL-12-driven response
results in production of high levels of IFNat efficiently control parasite replication in
both hematopoetic and non-hematopoetic cells. Nevertheless, the exuberant cytokine production
occurring in T. gondii infection can also be host detrimental, an outcome first documented in acutely
infected IL-10-/- mice that, while successfully controlling parasite growth, succumb to cytokine-storm
mediated immunopathology. Subsequent studies have revealed similar pathological sequelae in T.
gondii-infected IL-27R-/- animals and in chronically infected mice deficient in 5-lipoxygenase .The
common feature of these three genetic deficiencies is that each results in the over-expression of IL12 by APC, which in turn leads to uncontrolled Th1-type responses. Recently, we have defined an
additional non-redundant pathway by which CD4+T cells self-regulate their Th1 function during
T.gondii infection through the induction of glucocorticoids (GC) . When infected with toxoplasma,
mice that selectively lack GC receptor expression in T cells (GRlck-Cre) undergo acute mortality despite
displaying parasite burdens indistinguishable from control animals and unaltered levels of the innate
cytokines IL-12 and IL-27. Similarly, no major differences in peripheral T cell levels were observed
despite diminished thymic atrophy in the infected GRlck-Cre mice. Mechanistically, the excessive
immunopathology of infected GRlck-Cre animals was associated with hyperactive Th1 cell function in
vivo, but not in vitro. Importantly, CD4 T cell depletion in either wild-type or GRlck-Cre mice led to
ablation of the GC response after infection. Moreover, adoptive transfer of CD4+ T cells in
toxoplasma-infected RAG-/- animals was required for GC induction. These findings establish a novel
IL-10-independent immunomodulatory circuit in which Th1 cells trigger a GC response that in turn
dampens their own effector function. In the case of T. gondii infection, this self-regulatory pathway is
critical for preventing collateral tissue damage.
This work was supported by the intramural research programs of the NIAID and NCI, NIH
Alan Sher received his Ph.D. from the University of California, San
Diego, and did his postdoctoral training in the Division of Parasitology
at the National Institute for Medical Research in Mill Hill, London. In
1980, after several years as a research associate and then assistant
professor in the department of pathology at Harvard Medical School,
he joined the National Institute of Allergy and Infectious Diseases
(NIAID) as a section chief in the Laboratory of Parasitic Diseases (LPD).
Alan Sher became chief of the Laboratory of Parasitic Diseases in
2003 and was promoted to NIH Distinguished Investigator in 2011.
Alan Sher received several awards, among those the U.S. PHS
Superior Service Award and the NIH Director’s Mentoring Award. He
is member of the American Academy of Microbiology, the American
Association for the Advancement of Science and the Brazilian
Academy of Sciences. Alan Sher is editor of several journals, among those The Journal of
Experimental Medicine and Nature Reviews in Immunology.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Matteo Iannacone
San Raffaele Scientific Institute, Milan, Italy
Determinants of intrahepatic effector CD8+ T cell trafficking and antigen
recognition
Effector CD8 T cells play a critical role in viral clearance and liver disease during HBV infection, but
the mechanisms by which these cells home to the liver and recognize viral antigens are not
completely understood. Through the use of intravital imaging and mouse models of HBV
pathogenesis, we show here that >95% of intrahepatic effector CD8 T cells arrest occurs within liver
sinusoids independently of selectins, integrins, chemokines, vascular adhesion protein (VAP)-1,
endothelial activation and MHC/TCR interaction but it critically requires platelets and CD44hyaluronic acid interaction.
After their initial arrest, effector CD8 T cells exhibit an intrasinusoidal crawling behavior that is
inhibited by antigen recognition. CD8 T cells recognize hepatocellular antigens in a diapedesisindependent manner by extending protrusion through sinusoidal fenestrae and this process is
required to allow T cell extravasation.
These findings reveal the dynamic behavior of effector CD8 T cells within the liver and extend our
understanding of the role these cells play in the pathogenesis of hepatotropic viral infections.
Matteo Iannacone is MD with a PhD in molecular Medicine and a
specialization in Internal medicine from the University Vita-Salute
San Raffaele in Milan. From 2002 to 2010 he worked as a post
doctoral fellow first at “The Scripps Research Institute”, La Jolla (CA),
then at the Harvard Medical School, Boston, M. In 2010 he won the
prestigious Armenise-Harvard Career Development Award and in
2011 an ERC Starting Grant and he recently came back to Milan and
started his own laboratory (http://www.iannaconelab.com/) at the
Division of Immunology of the San Raffaele Scientific Institute, with
a focus on Experimental Imaging techniques.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Florence Margottin-Goguet
Cochin Institute, INSERM, Paris, France
How the SAMHD1 restriction factor counteracts HIV in non-dividing cells
To establish infections in vivo, HIV retroviruses have to face powerful cellular defenses including both
intrinsic and innate immunity. In a simplistic view, intrinsic immunity refers to the existence of
restriction factors that inhibit the virus as soon as it has entered into the host cell, while innate
immunity refers to the establishment of an antiviral state mediated by the production of IFN-α.
SAMHD1 is the last discovered restriction factor against HIV. It is a dGTP-dependent deoxynucleoside
triphosphates (dNTP) hydrolase. We have shown that its mechanism of action relies on its ability to
inhibit the reverse transcription step by reducing the pool of dNTP in myeloid cells. In contrast,
SAMHD1 does not restrict the virus in cycling cells where dNTP levels are abundant, reaching
maximal concentrations in S phase. Therefore, nucleotide depletion appears as a powerful
mechanism of defense in quiescent cells that do not replicate their nuclear DNA. More recently, the
study of SAMHD1-mediated restriction led us to ask whether, on the one hand, SAMHD1 contributes
to the early antiviral effect of IFN-α and whether, on the other hand, SAMHD1 controls the
proliferation status of the host cell.
Florence Margottin-Goguet (or Florence Margottin) graduated in
1993 with a doctorate in Cellular and Molecular Biology from the
University Pierre and Marie Curie in Paris, where she found how
gene transcription occurs through a common mechanism for all
genes. Starting from 1993, she got interested in infectious
diseases, first malaria at the Pasteur Institute of French Guyana,
second AIDS at the Cochin Institute in Paris under the supervision
of R. Benarous. During this postdoctoral period, she described the
first example of "ubiquitin ligase hijacking" in the HIV field.
Additionally, she cloned the beta-TrCP gene and identified the first
cellular substrates of this enzyme. In 2000, she moved to the
laboratory of Peter Jackson in Stanford University, where she
identified beta-TrCP as the ubiquitin ligase responsible for the
degradation of the mitotic inhibitor Emi1. Back in France in 2003,
she established her own group at Cochin Institute in Paris focusing
on host-pathogen interactions, especially viral auxiliary proteins. In 2007, her group was the first to
show that HIV-1 Vpr hijacks the Cul4A ubiquitin ligase via DCAF1 to trigger G2 arrest. Later on in
2012, her group identified the mechanism of action of the SAMHD1 restriction factor in myeloid cells
within an international collaboration network. Florence Margotttin-Goguet is a member of the
scientific committee of the french association Sidaction.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
Stefan Rose-John
Christian-Albrechts University, Kiel, Germany
The Biology of Interleukin-6 and Novel Strategies of Blockade
Cytokine receptors exist in membrane bound and soluble form. The IL-6/soluble IL-6R complex
stimulates target cells not stimulated by IL-6 alone, since they do not express the membrane bound
IL-6R. We have named this process 'trans-signaling'. The soluble IL-6R is generated via ectodomain
shedding by the membrane bound metalloprotease ADAM17. Soluble gp130 is the natural inhibitor
of IL-6/soluble IL-6R complex responses. Recombinant dimerized soluble gp130 protein (sgp130Fc) is
a molecular tool to discriminate between gp130 responses via membrane bound and soluble IL-6R
responses. We used neutralizing monoclonal antibodies for global blockade of IL-6 signaling and the
sgp130Fc protein for selective blockade of IL-6 trans-signaling in several animal models of human
autoimmune and infectious diseases. Inhibition of IL-6 trans-signaling was beneficial in a sepsis
model. Defense against bacterial infections rely on the membrane bound IL-6R. The extent of
inflammation is controlled by the release of the soluble IL-6R, which is mediated by the protease
ADAM17. Using the sgp130Fc protein or sgp130Fc transgenic mice we demonstrate in animal models
of inflammatory bowel disease, peritonitis, rheumatoid arthritis, atherosclerosis pancreatitis, colon
cancer, ovarian cancer and pancreatic cancer, that IL-6 trans-signaling via the soluble IL-6R is the
crucial step in the development and the progression of the disease. Therefore, sgp130Fc is a novel
therapeutic agent for the treatment of chronic inflammatory diseases and cancer and since June
2013 it undergoes phase I clinical trials as an anti-inflammatory drug.
Stefan Rose-John graduated in 1982 with a doctorate in Biochemistry
from the University of Heidelberg, Germany. From 1983 to 1984, he
was Research Associate at the Michigan State University and received
a stipend by the Max-Kade-Foundation and the German Science
Council. Starting from 1985, he was junior group leader at the
Department of Biochemistry in the German Cancer Research Center
in Heidelberg. In 1988, he became Assistant Professor at the
Department of Biochemistry at the Rheinisch-Westfaelische
Technische Hochschule Aachen, Germany. In 1994, he became
Associate Professor for Pathophysiology at the University of Mainz
Medical School, Germany. Starting from 2000, his current position is
Full Professor of Biochemistry and Head of Department of
Biochemistry at the University of Kiel, Germany. Stefan Rose-John is
member of the Society for Biochemistry and of the Society for
Immunology, Germany. Furthermore, he is co-owner and member of the executive board of the
Biotechnology Company “Conaris Research Institute”.
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
SPECIAL THANKS TO
Wolfgang Schütz
Stefan Böhm
Maria Sibilia
Sylvia Pagler
Rainer Zenz
THE SPEAKERS
Grant McFadden
Annette Oxenius
Joel Weinstock
Federica Sallusto
Florence Margottin-Goguet
Don Mahad
Paul Kubes
Mihaela Skobe
Thomas Euler
Stefan Rose-John
Hannah Monyer
Ron de Kloet
Alan Sher
Matteo Iannacone
THE CHAIRS
Giulio Superti-Furga
Mathias Müller
Maria Sibilia
Robert Eferl
Veronika Sexl
Monika Bradl
Brigitte Hantusch
Irene Lang
Stefan Böhm
Thomas Klausberger
Michael Freissmuth
Barbara Bohle
Sylvia Knapp
THE SPONSORS
THP Medical Products
New England Biolab
VWR
CCHD
Becton Dickinson Austria
Szabo-Skandic
StarLab
Janssen-Cilag
Meduni Wien
FWF
Biozym
Lactan GmbH&CoKG
Biovendor
CeMM
IAI
The title image was kindly provided by Markus Müllner and Berend Snijder, CeMM:
"MCF10A cells treated with a selection of kinase inhibitors"
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI
BRIDGING THE GAP 2014
Joint Symposium CCHD-IAI