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BRIDGING THE GAP 2014

Joint Symposium CCHD-IAI

We thank the following sponsors for their generous support:

CELL COMMUNICATION

IN HEALTH AND DISEASE





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



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)



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)



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-to-

date 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



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

Session III Chair: Monika Bradl

16:00-17:00 Don Mahad Mitochondria and progressive MS




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

Session VI Chair: Barbara Bohle

17:00-18:00 Alan Sher Self-regulation of CD4+ T cell effector function in the immune response to Toxoplasma gondii




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 Margottin-Goguet

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



ABSTRACTS



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.



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.



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.



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.

http://en.wikipedia.org/wiki/Symbiotic



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.



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.



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.



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 under-standing 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 per-formed 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.



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).



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”.



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 IFN- at 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 IL-12 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.



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 CD44-hyaluronic 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 diapedesis-independent 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.



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.



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”.



SPECIAL THANKS TO

Wolfgang Schütz Stefan Böhm Sylvia Pagler Maria Sibilia Rainer Zenz THE SPEAKERS

Grant McFadden Don Mahad Hannah Monyer Annette Oxenius Paul Kubes Ron de Kloet Joel Weinstock Mihaela Skobe Alan Sher

Federica Sallusto Thomas Euler Matteo Iannacone Florence Margottin-Goguet Stefan Rose-John

THE CHAIRS

Giulio Superti-Furga Monika Bradl Thomas Klausberger Mathias Müller Brigitte Hantusch Michael Freissmuth

Maria Sibilia Irene Lang Barbara Bohle Robert Eferl Stefan Böhm Sylvia Knapp

Veronika Sexl THE SPONSORS

THP Medical Products Becton Dickinson Austria Biozym New England Biolab Szabo-Skandic Lactan GmbH&CoKG

VWR StarLab Biovendor Janssen-Cilag

CCHD Meduni Wien FWF CeMM IAI

The title image was kindly provided by Markus Müllner and Berend Snijder, CeMM: "MCF10A cells treated with a selection of kinase inhibitors"







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