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Warrenton 11 Saxton River 2 Boston 38 Athens/Vari N.Haven L 76 Tokyo N.Y. Chantilly S 55 Snowbird Rockville 40 Keystone Bethesda Rehovot Stanford Washington Z 24 San Diego Albuquerque
La Jolla Indian Wells Dallas Alabama 1 S 9 4 7 Austin Houston Z 22 13 J36 Annual Report 17 Z 20 S 51 L 6 9 Z 2006 23 1 Institute for Research in Biomedicine, Istituto di Ricerca in Biomedicina HCMC
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Rosenön, Stockholm Niagara Falls 6 8 4 M S Edimburgh S52 L 8 5 Z28 Z29 L 81 2 Foreword / Giorgio Noseda, President of the Foundation Council Table of Contents 4 Introduction / Professor Antonio Lanzavecchia, Director
6 Cultivating Discovery
29 8 Advancing Discovery 10 Teaching Discovery 31 6 L65 12 Focusing Discovery S 4 14 SHAPING PROTEINS / Protein Folding and Quality Control / Maurizio Molinari 37 35 J 39/40 16 SIGNAL TRANSDUCTION / Cell Migration Chemokine Receptors / Marcus Thelen 18 DEVELOPMENT / T Cell Development / Fabio Grassi L64 L 79 20 STEM CELLS / Haematopoiesis / Markus Manz J35 Z2 G 6 22 HIV-AIDS / Viral Replication, Pathogenesis and Immunity / Jeremy Luban 1 6 16 24 INFLAMMATION / Chemokine Activities / Mariagrazia Uguccioni 26 IMMUNITY / Cellular Immunology / Federica Sallusto 28 ANALYTIC VACCINOLOGY / Immune Regulation / Antonio Lanzavecchia Warrenton 11 32 Overview / Science at the Institute & Life in the Institute Saxton River 2 38 Athens/Vari 34 Multiplying Discovery Boston 36 • Education PhD Programme and PhD Students N.Haven L 76 Tokyo 39 • Lectures and seminars given by IRB Scientists in 2006 N.Y. 44 • Special PhD Lecture and Seminars Programme Chantilly S 55 Snowbird Rockville 40 46 Enabling Discovery 48 • The Institute Keystone Bethesda Rehovot 50 • Financial Data 2006 Stanford Z 24 Washington 52 Contributing Discovery 54 • Publications 2006 San Diego Albuquerque 56 Impressum La Jolla Indian Wells Dallas Alabama 1 S 9 4 7 Austin Houston Z 22 13 J36 17 Z 20 S 51 L 69 Z23 1
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Melbourne When we formed the Foundation for the Institute for Research in Biomedicine in 1997 our objective was to create the ideal conditions for the establishment of Professor a world-class research institute in Ticino. The overwhelming success of the IRB Giorgio Noseda, in its first six years attests to our having to accelerate this program. reached that ambitious goal. Scientific Since 2000 the institute has grown to President and academic productivity of the IRB 77 people; 8 group leaders, 21 research- of the Foundation are well documented in 159 publications ers, 33 students, 8 technicians and an and 17 PhD thesis granted to our stu- administrative staff of 7. This growth has Council dents. The growth of the annual budget put intense pressure on our lab space from 3.8 million Fr. in 2000 to more than and infrastructure. To ease this pressure, 11.3 million Fr. in 2006 is due to both in June of 2006 we expanded our facili- the trust demonstrated by our public ties through the transformation of a local and private sponsors as well as by the building into a state of the art laboratory increasing ability of our researchers to and animal facility. attract competitive grants. Joining the IRB as tenants in this new Preparing the ground for success is building will be Humabs, a young U.S. not the same as managing success based biotechnology company that has however. The year 2006 saw an impor- recently opened a swiss office in Ticino. tant strategic transition begin for the Humabs has licensed IRB technology, de- Foundation Council. No longer the “new veloped by Prof. Antonio Lanzavecchia, kid on the block”, the IRB now success- for the production of monoclonal anti- fully competes head to head with the bodies. The Foundation believes strongly leading research institutions worldwide. in the importance of academic and Remaining competitive at this level the industrial alliances to foster important Foundation and the Institute must offer and effective research programs without ideal conditions, which include solidity, compromising independence. predictability, management excellence, While the Foundation takes stock of as well as an increased involvement in the past six years we also look forward the academic landscape of Switzerland to with renewed enthusiasm to the chal- provide recognition of the excellence of lenges that lie ahead. We will transition our researchers. ourselves to be in the best position In 2006 we prepared our renewed possible to achieve our ambitions and requests to the Cantonal and Federal go- the ambitions of our scientists. vernments for increased future funding. We solidified our connections with Swiss Universities and in particular opened Giorgio Noseda, MD discussions with the Swiss polytechnic President Foundation Council institutes. In December of 2006 the IRB, together with the EPFL, the CHUV (University of Lausanne) and the Ludwig Institute for Cancer Research formed the Swiss Institute for Vaccine Research. These four institutes will pursue a coordi- nated program for research on vaccines. Funds provided by the Bill and Melinda Gates Foundation to individual research- ers will be matched by the Confederation
Foreword 3 Manz and colleagues have shown that mice reconstituted with a human This report provides an overview of the hemato-lymphoid system can be suc- activity at the Institute for Research in cessfully infected with viruses that target The aim of the SVRI is to boost vaccine Biomedicine (IRB). human cells but normally do not infect research and development via creation In 2006 two research groups have animals. This work provides, for the first of common platforms and recruitment been recruited. Markus Manz, after time, a small animal model for long-last- of young talents. Effective collaborations completing ing HIV infection and is supported by the have been established with the Institute the qualification in hematology and on- Bill & Melinda Gates Foundation Grand of Oncology of Italian Swizerland (IOSI) cology at the University of Tubingen, has Challenges in Global Health program. in the field of transcriptional profiling Professor expanded his research program on stem The need to advance the study of the hu- and in the study of the effect of irra- cell biology, hematopoietic differentia- man immune system is illustrated by the diation on adoptive immunotherapy. Antonio Lanzavecchia, tion, and blood cell maligancies. Jeremy finding by Sallusto and colleagues that Markus Manz has taken clinical respon- Luban, on sabbatical from the Columbia the development of a particular type of sibilities at the IOSI, a move that is ex- Director of the University since 2005, has joined the in- inflammatory effector cells, called Th17, pected to facilitate translational research Institute for Research stitute as a group leader in August 2006. is differentially regulated in humans in the field of haemato-oncology. His research on the innate mechanisms as compared to mice. A very dynamic The urgent need to expand labora- in Biomedicine of resistance to HIV-1 will strengthen program stems from the development tory space, core facilities, and the animal the IRB program in this important field. of a proprietary method to clone human house has been partially met by the rapid In addition, his laboratory is undertak- memory B cells which has been licensed refurbishment of a new building called ing the challenging task of tracking viral to an american startup company, Hum- IRBis located a few hundred meters transport inside infected cells using a abs LLC, that is establishing its laborato- from the main site, and by establishing a novel microscopy approach. ries in Bellinzona. Using this proprietary cutting edge imaging facility, generously Scientists that have left the IRB in this method broadly neutralizing antibodies supported by private donations and the period have found positions in leading have been isolated against viruses such Confederation. We are grateful to the institutions in Switzerland, Germany, as SARS, Dengue, H5N1, Cytomegalo- City of Bellinzona for hosting us in these Italy, USA, Canada, UK, Japan and virus and HIV-1. These antibodies can two buildings and for sharing our vision Singapore. be used not only to confer immediate of the future. The IRB continues to play an impor- protection by passive administration to After six years of activity I am confi- tant role in education by training gradu- virus-exposed or infected individuals, but dent to say that the IRB has fulfilled the ate students through collaborations with also as tools to identify the antigens that initial expectations and has become an Swiss Universities, in particular Basel, elicit neutralizing antibodies, a proc- internationally visible centre for basic Bern, Fribourg, Lausanne and Zurich and ess that has been defined as “analytic and translational research. This fact is participates in an international PhD pro- vaccinology”. Another example of how witnessed by the success in obtaining gram with the Vita-Salute San Raffaele basic research can open new therapeutic grants not only from the Swiss National University in Milan, Italy. The students avenues comes from Molinari’s labora- Science Foundation and the European furthermore benefit from an intensive tory where they have shown in a model Union, but also from foreign agencies lecture series held by renowned scientist system that an antibody can inhibit the among which are the Bill & Melinda from all over the world, organized with formation of Alzheimer lesions in vivo. Gates Foundation, the Wellcome Trust, the generous support of the Gustav & The translational programs above and the US National Institute of Health. Ruth Jacob Foundation. In turn, the IRB stem directly from strong basic research, The Institute is especially fortunate greatly profits from the curiosity and am- which remains the mission of the IRB. in receiving core funding from its main bitious work of our young scientists. At The scientific impact of this research rests sponsors, the Helmut Horten Founda- present 30 graduate students are enrolled on the 159 IRB publications which deal tion, the Cantone Ticino and the Swiss at the IRB and since beginging in 2002, with molecular aspects of protein traf- Confederation. Our gratitude also goes 17 students have successfully completed ficking and quality control, cell signaling to the many individuals who support us their training. migration and differentiation, and with through donations and fellowships. We Research at the IRB has increasingly fo- immune effector mechanisms in normal believe that the progress and achieve- cused on the study of host defense mecha- and pathological conditions. ments of the Institute will reward their nisms in the human system. IRB research- IRB scientists have established an ef- dedication to the advancement of sci- ers have developed coherent programs fective network of collaborations with ence. that have the potential to be translated leading institutions in Europe, America into novel therapies. and Asia. The IRB is a Founding member of the Antonio Lanzavecchia, MD Swiss Vaccine Research Institute (SVRI) Director together with the CHUV, the EPFL and the Ludwig Institute in Lausanne.
4 Introduction Cultivating Discovery
The IRB seeks to provide the ideal conditions for the creation of new knowledge.
Palazzo Fabrizia was built in 1965 by architects Luigi Snozzi and Livio Vacchini. In 2000 the building was converted from office space to laboratories 6 Cultivating for the IRB. IRB scientists participate in the virtuous cycle of discovery by asking important questions, learning what is known, building new knowledge and sharing their discoveries.
Advancing Discovery
8 Advancing Teaching Discovery
The cowbell is rung to call students to a seminar
The IRB is a dynamic teaching institute with 30 full time graduate students from Swiss and international universities.
10 Teaching Focusing Discovery
IRB research programs explore how the human body defends itself.
The cafeteria is in the heart of the building, an open space where students and scientists gather and exchange ideas.
12 Focusing SHAPING PROTEINS
Protein Folding and Quality Cystic fibrosis, Alzheimer’s disease, Parkinson’s disease, Hungtington disease, Creutzfeld-Jakob’s disease, diabetes mellitus. This is a very short selection of Control the several hundreds of *human diseases* with profoundly different traits but common aethiology1: *protein misfolding*. Several of these diseases are he- 1 Aethiology: reditary and most of them are rare, affecting less than 1 in 2000 individuals. The cause or origin of a disease or disorder as For some of them, as an example for all neurodegenerative syndromes affect- determined by medical ing old people, a sharp increase in frequency is expected in the next decades diagnosis. due to extension of the human life span. Proteins2 are fundamental components of all living cells and include many 2 Proteins: substances, such as enzymes, hormones, and antibodies, that are necessary The smallest structural unit of an organism that is for the proper functioning of an organism. They are fabricated in a specialized capable of independent organelle present in all our cells and named the endoplasmic reticulum. functioning, consisting of one or more nuclei, To be functional, proteins must acquire a specific structure in the endo- cytoplasm, and various plasmic reticulum in a series of tightly regulated processes defined as *protein organelles. folding*. Failure to do so, will result in the destruction of the defective protein and in the loss of its activity. The cell and the organism will eventually suffer as a consequence of the absence of this specific protein’s function and this elicits a disease state. The aim of our work is to understand how our cells fabricate the proteins. How correct protein folding is ensured, what happens if protein folding is not possible, how misfolded proteins are destroyed. We are convinced that a de- tailed knowledge of the processes that regulate protein production in our cells will allow intervention to alleviate symptoms, to delay disease onset and even to arrest and revert disease progression for all human pathologies caused by defects in acquisition of the functional protein shape. Maurizio Molinari The studies performed in reducing the in vivo earned his PhD in by Molinari’s group production of amyloid Laboratory Biochemistry at the at the IRB have -Beta (Aβ), a toxic Maurizio Molinari, PhD, 2000. ETH-Zurich in 1995. made a significant peptide that deposits Group Leader: From 1996-1997 he contribution to the in the human brain was a post-doc in the knowledge of the and elicits neurodege- Members: Verena Calanca, Technician, 2000 • Carmela Galli-Molinari, Resear- laboratory of Cesare mechanisms devised nerative processes cher, 2000 • Tatiana Soldà, Technician, 2004 • Omar Vanoni, PhD student, 2004 • Montecucco at the by cells for the pro- associated with Alzhe- Dept. of Biomedicine, duction of functional imer’s disease. Tito Calì, PhD student, 2006 • Silvia Olivari, PhD student, 2006. University of Padua, polypeptides and for Dr. Molinari has Italy and subsequently efficient disposal of received the Science in the laboratory of folding-defective Award 2002 from the Ari Helenius at the proteins. Foundation for study ETH-Zurich (1998- The knowledge ac- of neurodegenerative 2000). Since October quired on the mecha- diseases, the Kiwanis 2000 he is group nisms of protein pro- Club Award 2002 for leader at the IRB in duction and transport Medical Science, the Bellinzona. along the secretory Friedrich-Miescher line of mammalian Award 2006 and the cells allowed the group Research Award Aetas to set up a novel 2007. approach based on intracellular expres- sion of specific single chain antibodies, that proved very efficient 14 Focusing Focusing 15 CELL MIGRATION
Signal Transduction Cell migration1 is essential for development and survival of multicellular or- 1 Cell migration: ganisms. Generally, single cells move along cues to reach their destination. Cell migration is essential in development and immunity. The process requires polarization, i.e. the formation of a morphological distinct Cell migration occurs also front and a rear end, of the cell along the axis of attraction. The intracellular under pathological conditions. Cell migration is regulated pathways which sense the attracting signal and transduce it into remodeling by multiple pathways. of the actin cytoskeleton and the sequential activation of adhesion molecules Can we specifically interfere is a central focus of our research. with good and bad? Leukocyte trafficking is largely regulated by chemokines and their respective receptor. Migration of cells expressing subsets of receptors is further controlled by spatially restricted secretion of chemokines. The mechanism is important for immune homeostasis, but is also essential for acute and chronic immune responses such as inflammation. In addition, some cancer cells appear to use the chemokine systems for metastasis.
Laboratory Group Leader: Prof. Dr. Marcus Thelen, PhD, 2000.
Members: Sylvia Thelen, PhD, 2000 • Tiziana Apuzzo, PhD student, 2006 • Ulrike Naumann, PhD student, 2006 • Silvia Volpe, PhD student, 2006 • Simona Infantino, PhD student, 2003 • Elena Palmesino, PhD student, 2002.
Marcus Thelen Since 2000 he is a obtained his PhD group leader at the in 1985 from the Uni- IRB. In 1994 he obtai- versity of Bern study- ned the Venia Docendi ing the bioenergetics and later in 2001 was of mitochondria. awarded an Honorary He was a PostDoc Professor title from at the Theodor-Kocher the University of Institute in Bern from Bern where he still is 1985 to 1989, later member of the Medi- from 1989 to 1991 cal Faculty. at the Rockefeller Prof. Thelen has University in New published more than York. In 1992 he was 60 papers. His resear- awarded a START ch covers several fellowship from the aspects of biochem- Swiss National Sci- istry, cell biology and ence Foundation and human immunoogy. headed a laboratory His focus is on signal at the Theodor-Kocher transduction in Institute, University chemokine receptor of Bern. mediated cell activati- on and migration.
16 Focusing Focusing 17
DEVELOPMENT
T Cell Development The experiments performed in the lab are principally focused on the charac- terization of signal transduction pathways at different developmental stages of the murine T cell1. A first aim is to define signaling microdomains, which 1T cell: are involved in transducing the signal by the pre-T cell receptor (pre-TCR) T cell or T lymphocyte, a white blood cell, which He has been a Special and promote T cell as well as thymus development. A second aim pursued plays a central role in Fellow of the in the lab is to characterize signaling pathways controlled by Ca2+2 during cell-mediated immunity. The abbreviation “T” stands Leukemia & Lympho- immunopathological T cell responses leading to inflammation and tissue de- ma Society at Harvard for thymus since it is the Medical School in struction. Another topic studied by our group is the impact of T cell activation principal organ for T cell Boston. He is Associate during an inflammatory response on hematopoiesis and bone homeostasis. development. A polymorphic receptor on the cell surface, Professor of Biology the T cell receptor (TCR), at the University of confers specificity for distinct Milan. targets to every T cell. In September 2002, Laboratory he joined the IRB Group Leader: Fabio Grassi, MD, PhD, 2002. 2 Ca2+: Fabio Grassi earned as head of the T Cell Calcium ions. his degree in Medicine Development lab. Members: Anna Casati, PhD student, 2005 • Denise Ferrera, PhD student, 2003 at the University of His research is Pavia and a PhD. in focused on molecular • Ursula Schenk, PhD, 2005 • Micol Ferro, Undergraduate student, 2005. Microbiology at the as well as cell biology University of Milan. of T cell differentia- He worked at the Uni- tion in the thymus, versity of Umeä in signal transduction of Sweden, the Institut the T cell in secondary Pasteur and Hopital lymphoid organs and Necker in Paris, the in T cell mediated San Raffaele Scientific inflammatory condi- Institute in Milan. tions.
18 Focusing Focusing 19 STEM CELLS
Hematopoiesis Throughout life, a small fraction of hematopoietic stem cells (HSCs)1 self- 1 Hematopoietic Stem renew in the bone marrow and generate all cells of the hemato-lymphoid Cells (HSCs): system, a system with very high cellular turn-over. Because of its ready acces- Small population of cells in adult bone marrow that for sibility, hematopoiesis is currently one of the best studied mammal adult stem the life of an individuum are cell differentiation systems, and is likely paradigmatic for other physiologic capable to both self-renew (maintain themself) and give (e.g. liver, skin, central nervous system) and pathologic (tumors, leukemia) rise to all hemato-lymphoid stem cell regenerated compartments. Beyond its model character for basic re- system cells as erythrocytes, search, hematopoietic stem cell transplantation (formerly bone marrow trans- platelets, and all white blood cells (immune system cells). plantation) is so far the only successfully working clinical stem cell therapy, mostly applied for the treatment of malignant hematologic disease or im- munodeficiencies. Also, hematopoietic stem cells currently provide the major gateway for clinical gene therapy. The hierarchically structured, unidirectional differentiation process from HSCs to terminally differentiated cells involves progressive loss of self-re- newal ability, proliferation capacity, and lineage differentiation potentials. In my laboratory, we are studying regulation of physiologic and pathologic he- mato-lymphopoieis in steady-state, and inflammatory conditions, as well as in neoplasia in both mice and men. Our hypothesis is that HSC maintenance, subsequent commitment and ex- pansion to different cellular lineages is largely controlled externally, depend- ing on varying demand. To evaluate this, we characterize and isolate human and murine hematopoietic stem- and progenitor cells as well as bone marrow stroma cell components (mesenchymal stroma cells, MSCs), study and sub- sequently modify their transcriptional profile, and test their responsiveness to physiologic stimuli and to pharmacologic compounds in both in vitro and in Markus G. Manz From 2004 to 2006 a knowledge that vivo assays. received his degree in he finished his hema- eventually will be val- In depth understanding of physiologic maintenance and differentiation Medicine 1995 from togy/oncology training uable for the develop- the Eberhard-Karls- at the University of ment of new strategies pathways from HSCs to mature cells of the hematopoietic system will eventu- University in Tue- Tuebingen, while to interfere with this ally provide new insights and improved therapeutic methods to treat hemat- bingen, Germany. maintaining the IRB process, e.g in states of opoietic and immune system diseases. Between 1995 and lab as an Associate infection, immunodefi- 1999, he trained in Group Leader. ciency, autoimmunity, internal medicine at Since September hemato-lymphoid the Tuebingen Medical 2006 he is group cancers, or in solid or- Laboratory School, from 1999 to leader at the IRB and gan and hematopoietic Group Leader: Markus G. Manz, MD, 2002. 2001 he worked as associated hematolo- cell transplantation. a postdoctoral fellow gist at the Oncology In 2004 he received in the laboratory of Institute of Southern the prestigious Artur- Members: Patrick Ziegler, PhD, 2006 • Michael A. Schmid, PhD student, 2006 Irving Weissman at Switzerland (IOSI), Pappenheim Award • Steffen Boettcher, MD student, 2006 • Aya Onai, PhD, 2004-2006 • Nobuyuki Stanford, USA, and Bellinzona. of the German Society Onai, PhD, 2004-2006 • Roxane Tussiwand, PhD student, 2003-2006. in 2002 he became Markus Manz sci- of Hematology and group leader at IRB. entific interest focuses Oncology. on hematopoiesis and immune system development. His research is driven by the urge to understand basic mechanisms of immune system maintenance and regeneration in steady- 20 Focusing Focusing 21 state and disease, HIV-AIDS
Viral Replication, Pathogenesis Study of retroviruses has led to major advances in fundamental biology, most notably the discovery of oncogenes and the modification of the central Jeremy Luban earned and Immunity dogma1. In this spirit, we investigate mechanisms of HIV-1 replication and 1 The Central Dogma of an M.D. at the College of Physicians and pathogenesis with the goal of advancing understanding of the basic workings Molecular Biology: Surgeons, Columbia a framework for understanding of the cell. Through the development of genetic and biochemical screens2 we University in New that genetic information is York, in 1987. He attempt to identify cellular factors of importance to HIV-1 and, more gener- directional, generally going from ally, to cell physiology. In effect, we exploit HIV-1, using the virus to elucidate DNA to RNA to protein. Study underwent clinical he served as director of retroviruses demonstrated training in Internal of the Columbia- mechanisms of cell cycle progression and cytokinesis, signal transduction and that genetic information can also Medicine and Sub- Rockefeller Center for cytokine expression, protein folding and degradation, as well as pathogen move in the “reverse” direction specialty fellowship AIDS Research. recognition and antigen presentation. Our research is basic in nature but by from RNA to DNA. training in Infec- His laboratory tious Diseases, as focuses on host factors shedding light on mechanisms of HIV-1 replication and immune system eva- 2 Screens: well as postdoctoral that regulate HIV-1 sion we hope to contribute to the development of drugs and vaccines that procedures for identifying individual genes, gene pro- training in Biochem- replication and confer target this virus. ducts, or chemicals that istry in the laboratory innate immunity to modify, or are responsible of Stephen Goff. this deadly virus. for, a phenotype of biological He became a Pro- Among the HIV-1 interest. fessor at Columbia regulatory factors Laboratory University with dual discovered by his lab Group Leader: Jeremy Luban, MD, 2006. appointments in the are the human Department of proteins cyclophilin Medicine (1993) and A and TRIM5. Members: Caterina Strambio de Castillia, PhD, 2005 • Martha Neagu, MD, the Department of Dr. Luban became PhD student, 2005 • Thomas Pertel, PhD student, 2005 • Christina Helbig, PhD Microbiology (1995). a group leader at the student, 2006 • Nadia Rahm, 2006. In addition to teaching IRB and relinguished medical students, his position at physicians, and PhD Columbia University graduate students in 2007.
22 Focusing Focusing 23
INFLAMMATION
Chemokines: Tissue
Expression, Our research interest remains focused on Chemokine activities in physiology and pathology, with emphasis on mechanisms governing fine tuning modu- Function and lation of their expression and activity. The breakdown in the control of leu- She is Assistant Pro- fessor of Immunology Activity kocyte mobilization contributes to the pathogenesis of chronic inflammation at the School of Rheu- as well as tumour development. Chemokines, are produced constitutively or matology, University Modulation upon specific induction in virtually all tissues of the human body (Figure 1). of Bologna, since 2000. We have recently shown (Paoletti et al., Blood 2005; Sebastiani et al., EJI 2005) Dr. Uguccioni’s research has covered that non-ligand chemokines can enhance the activity of CCL19 and CCL21 aspects of human on CCR7, and of CCL22 on CCR4, respectively. Western blot and binding haematology and im- experiments have shown the formation of heteromeric complexes suggest- Mariagrazia munology: chemokine ing these complexes as the cause of the observed synergism. Interestingly, Uguccioni received a activities, leukocyte degree in Medicine activation and traffic, the available structure and structure-function data, albeit scarce to date, col- from the University of natural chemokine lectively implicate residues in the first β‑strand as mediators of heteromeric Bologna (Italy) where antagonists, and association and synergism(Sebastiani et al., EJI 2005). It is thus tempting to she specialized in chemokine expression Haematology in 1994. in human pathology. speculate that heteromeric chemokine complexes may mimic those homo- From 1993 to 2000 Recently, her group meric dimers that form via association of their β‑sheets, featuring an interface she was a member of is focusing on chemo- composed of the first β‑strands. However, the molecular reasons as to why a the Theodor Kocher kine activities in heteromeric complex should be more active than a homomeric one remain, Institute, University human pathology of Bern (Switzerland), and has identified at present, completely obscure, and the analysis of this phenomenon is part and since 2000 she is a novel regulatory of our ongoing research. Surface representations with electrostatic potentials Head of the Chem- mechanism of of chemokines show similarities among selective agonists and known natural okine Expression and leukocyte trafficking antagonists, thus indicating this analysis as an additional instrument for dis- Function Laboratory induced by synergy- at the IRB. inducing chemokines. closing the potential of different chemokines as natural antagonist or synergy inducing molecules. We have hypnotized that the synergism induced by heteromeric chem- okine interactions may be a widespread phenomenon, positively regulating diverse chemokine activities such as chemotaxis, cellular adherence, receptor internalization, and protein kinase phosphorylation. Therefore, we are con- ducting additional in vitro studies to dissect in detail the mechanisms govern- ing these activities.
Laboratory Group Leader: Mariagrazia Uguccioni, MD, 2000.
Members: Maria Gabriela Danelon, Technician, 2001 • Katrin Kuscher, PhD student, 2004 • Tamara Visekruna, PhD, 2005 • Daniel Venetz, MD, PhD student, 2006 • Denise Bottinelli, undergraduate student, 2006.
24 Focusing Focusing 25 IMMUNITY
Cellular Immunology Specific immune responses require the timely interaction of various cell types within specific microenvironments. In the primary response the rare antigen specific naive T cells need to maximize the possibility of encounter with an- tigen. They do so by continuously recirculating through secondary lymphoid organs where they are stimulated by antigen-presenting mature dendritic cells (DCs). Soluble antigens can reach the lymph node directly but in most cases they are carried by migrating DCs that capture antigen in peripheral tissues and subsequently move through the lymphatics to the draining lymph node. One goal of our laboratory is to understand how the number, localization and activation state of DCs in lymph node impact on T cell priming and im- mune responses. A second goal of our research is to dissect the signals by which DCs de- termine differentiation of proliferating T cells towards the Th1, Th2 or Th17 lineage and how migratory capacity and effector function are coordinately regulated in differentiating T cells. Based on their migratory capacity and ef- fector function we have originally characterized two subsets of memory T
cells: central memory T cells (TCM) express homing receptors for lymph nodes and have no or low level effector function. In contrast effector memory T cells
(TEM) lack lymph node receptors and have immediate effector function. We are investigating the molecular basis underlying the functional proper-
ties and the differentiation potential of TCM and TEM, their heterogeneity and the signals required for their generation and maintenance. We are also inter- ested to define the composition of memory subsets in different pathological and physiological conditions to gain insights into the role these subsets play in the immune responses. Federica Sallusto contributions are the received her degree development of in Biology at the a method to culture Laboratory University of Rome human dendritic cells, Group Leader: Federica Sallusto, PhD. La Sapienza. Between the discovery that Th1, 1989 and 1996 she Th2 and Th17 cells worked at the Depart- express distinct sets of Members: Alfonso Martin-Fontecha, PhD, 2000 • Annalisa Macagno, PhD, ment of Immunology, chemokine receptors 2002 • Miroslav Hons, PhD student, 2004 • Eva V. Acosta-Rodriguez, PhD, 2005 of the Italian National and the definition of • Martina Beltramello, PhD, 2005 • Rebekka A. Geiger, PhD student, 2005 • Institute of Health central and effector Dirk Boumjohann, PhD student, 2006 • Thomas Duhen, PhD, 2006 • Andrea first as a postdoctoral memory T cell subsets. fellow and then as a She published more Reboldi, PhD student, 2006. research scientist. than 80 papers and She worked at the was the recepient of Basel Institute for Im- the Pharmacia Allergy munology as a visiting Research Foundation scientist from 1993 to Award in 1999. 1994 an as a member Since 2000 Fede- from 1996 to 2000. rica Sallusto is the Her research is Head of the Cellular focused on dendritic Immunology Labora- cell biology, T cell acti- tory at the IRB. vation, differentiation and T cell traffic. Among her original
26 Focusing Focusing 27 ANALYTIC VACCINOLOGY
Immune Regulation The research of our group remains focused on three main themes. First, we study the impact of innate immunity on the adaptive immune response with special emphasis on the activation of dendritic cell and the regulation of po- larizing cytokines such as IL-12, IL-23, IL-1 and IL-6. Second, we continue to test in different experimental systems the role of the cumulative strength of stimulation (SoS) on the generation of effector and memory T cells. Cur- rent results from our as well as other groups support our initial proposition that SoS is the critical factor in determining the extent of CD4 and CD8 T cell differentiation. We are particularly interested to understand the mecha- nisms that control the generation of T and B memory cells and the dynamics of memory cells in the central and effector compartment. A third new avenue of research which is progressively expanding is prompted by two methods that have been originally developed in our laboratory that allow an accurate analysis of memory B cell frequencies and the efficient retrieval of human monoclonal antibodies from cells obtained from immune donors. We feel that our research has the potential to impact in the field of vac- cination at least in three areas: i) development of novel adjuvants capable of driving strong and selected immune responses; ii) identification of in vitro correlates of the immune status to evaluate vaccine efficacy and iii) adoptive immunotherapies with antigen-specific T cells or human monoclonal anti- bodies retrieved from the memory repertoire.
Laboratory Group Leader: Antonio Lanzavecchia, MD, 2000.
Antonio Lanzavecchia Cloëtta prize in 1999, Members: Afonso Almeida, PhD, 2005 • Nadia Bernasconi, PhD, 2000 • Dav- earned a degree in Dr. Lanzavecchia has ide Corti, PhD student. 2004 • Giulia Di Lullo, PhD, 2005 • Jens Geginat, PhD, Medicine at the Uni- published more than versity of Pavia where 200 papers. 2000-2006 • Isabella Giacchetto-Sasselli, Technician, 2000 • Greta Guarda, he specialized in Pae- His research has PhD student, 2004 • Laura Lozza, PhD student, 2005-2006 • Giorgio Napolitani, diatrics and in Infec- covered several aspects PhD, 2002 • Debora Pinna, PhD student, 2005 • Laura Rivino, PhD student, tious Diseases. of human immunol- 2003-2006 • Claudia Ruprecht, PhD student, 2002-2006 • Chiara Silacci, Tech- From 1983 to 1999 ogy: antigen process- he was a member of ing and presentation, nician, 2005 • Janine Stubbs, PhD, 2006 • Stefan Wirths, MD, 2002-2006 • Erica the Basel Institute dendritic cell biology, Dunder, PhD student, 2006. for Immunology and lymphocyte activation since 1999 he is the and traffic, T and B founding director of cell memory. the IRB in Bellinzona. Recently he devel- He has been Professor oped a method for of Immunology at the the efficient isolation University of Genoa of human monoclonal and at the University antibodies from me- of Siena. mory B cells, which Awarded the EMBO has been successfully medal in 1988 and the applied to infectious diseases such as SARSCoV, H5N1, HCMV, Dengue, Malaria and HIV-1.
28 Focusing Focusing 29 Participating in Individual donors infrastructure, and If you or your foun- Tom Brooks, Director Discovery and foundations parti- special instruments dation would like to of Communications cipate in the success of that enable new areas participate in the futu- and Development, the IRB by sponsoring of discovery. re development of the [email protected] student fellowships, IRB please contact: + 41 91 820 0327
OCTOBER • Daniel Venetz receives a Prestigious Cloëtta Foundation Fellowship.
Science at • The first annual meeting of the the Institute European project INNOCHEM is held NOVEMBER in Bellinzona. Maria- • Christina Helbig grazia Uguccioni receives a Boehringer JULY scientific coordinator Fellowship. DECEMBER • Student Exchange of the project plays • The IRB becomes a JUNE between the lab of SEPTEMBER host to more than • Federica Sallusto Founding Member of APRIL • H5N1 (BIRD FLU) Maurizio Molinari • Jeremy Luban 100 guests from and Marcus Thelen the Swiss Institute for • International Day of research by Antonio and the University of officially joins the around the world. recieve Fellowships Vaccine Research to- Immunology, initiated Lanzavecchia is fast- Kyoto. IRB as a Group Lea- from the Integramm gether with the EPFL, MARCH by European Federa- tracked for support by der and receives • The model developed program of the E.U. the CHUV, and the • Claudia Ruprecht tion of Immunological MAY the Wellcome Trust. • The Bill and Melin- his first SNF Grant. by Markus G. Manz Ludwig Institute. of the lab of Antonio Societies (EFIS). • Simona Infantino da Gates Foundation AUGUST is validated by an • Laura Rivino Lanzavecchia, defends of the lab of Marcus • Elena Palmesino funds two projects, • Janine Stubbs joins • Markus Manz re- important study with of the lab of Antonio • Silvia Monticelli FEBRUARY her thesis “On the • Roxanne Tussiwand Thelen, defends her of Marcus Thelen’s lab, PTVDC and VDAC to the IRB as a Post Doc joins IRB as full-term University at Zurich. Lanzavecchia, defends joins the IRB as a JANUARY • Maurizio Molinari role of regulatory T of the lab of Markus thesis “RDC1, and defends her PhD the- advance the search for in the Lab or Antonio group leader. her PhD thesis “Dis- junior Group Leader. • DEC-VAC Begins receives the Friedrich cells and microbial Manz, defends her orphan receptor with sis “CXR4 associated an HIV vaccine. Lanzavecchia. • Nobuyuki Onai secting the human A 5 year EU funded Miescher Award 2006 products in the control PhD thesis at the similarities to Chemo- proteins and their role Participating in two • Patrik Ziegeler joins from Manz Lab CD4+ T cell memory • The European Union project to develop HIV for outstanding achie- of T and V cell immu- Università Vita e kine receptors” in cell specific receptor studies from IRB • Dirk Baumjohann the IRB as Post Doc becomes assistant pool”, at the Univer- issue the first Calls vaccines based on vements in the field of ne responses”, at the Salute San Raffaele, at the University of function”, at the Lanzavecchia and receives Prestigious in the Lab of Markus Professor at Aktia sity of Fribourg, in the F.P.7 program dendritic cells. Biochemistry. University of Basel. Milano. Bern. University of Bern. Sallusto. Boehringer Fellowship. Manz. University, Japan. Switzerland. for research.
JANUARY FEBRUARY MARCH APRIL MAY JUNE JULY AUGUST SEPTEMBER OCTOBER NOVEMBER DECEMBER • Seminars: • Official visit from • Seminars: • Visits to the IRB: • The Ticino Delegati- • HRH Princess Chu- • Work begins on • The Swiss Science • United Kingdom • A delegation of • The second Musica • The Consiglio di > Hazel Pinheiro, the Swiss Center for > Giancarlo Pruneri, UBS Bellinzona on to Federal Govern- labhorn of Thailand the transformation and Technology Office Embassy represen- Cuban scientists visits e Molecole features the Stato of Ticino appro- Ambion Europe Ltd. Scientific Calculation European Institute Ticino Association of ment visit the IRB visits the IRB. of a local building inspect the IRB and tatives visit the IRB the IRB. music of Stockhausen. ves funding for resear- > Yair Reisner, Weiz- (CSCS). of Oncology, Milan, Natural Scientists, as part of a survey into a stateof-the- prepare a positive as part of an effort to Sponsored by B.S.I. ch for 2007-2012. mann Institute of Italy. and Lions. of Research in Ticino. • The first Musica e art research facility evaluation. increase swiss-UK col- • Seminars : Science, Rehovot, • Seminars: > Daniela Capello, Molecole evening Jazz and P3 laboratory. laboration in science. > Anna Mondino, • Alessandro Ciocca • High school students Israel. > Luca Scorrano, A. Avogadro Uni. of • Meeting with Ticino • The Horten Founda- features with the • Official visit of the Vita-Salute San is elected to the from Locarno complete > Ingmar AFM Venetian Institute of Eastern Piedmont, Middle School Science tion holds their annual Carlo Uboldi Trio. • The Swiss National Swiss Federal Resear- • Joerg Staheli takes Raffaele University, Consiglio di Fon- their optional biology Heijnen, Kantons- Molecular Medicine, Novara, Italy. teachers. meeting at the IRB. Sponsored by UBS Fund agrees to support ch Station. over as Director of the Italy. dazione of the IRB. course with a project spital Aarau, Aarau, Padua, Italy. > David A. Thorley- Bellinzona. the purchase of a cal- Biopolo Ticino and > Ian Colditz, CISRO at the IRB. Switzerland. > Bettina Borisch, Lawson, Tufts Univer- • The annual IRB • Seminars: cium imaging system • Seminars: hosts ELISSI meeting. Livestock Industries, • Seminars: CMU, Geneva, Swit- sity School of Medici- student Retreat is held > Stephanie Brooking, • IRB News released proposed by Fabio > Martin Lohse, Uni- Armidale, Australia. > Bernard Malissen, • Middle School Stu- zerland. ne, Boston, USA. at the convent in Ambion Europe Ltd. in new monthly Grassi. versity of Würzburg, • The council of the > Anna Villa, CNR- Centre d’Immunolo- dents visit the IRB > Dennis R. Burton, > Fiona Powrie, Uni- Bigorio. > Gisou van der Goot, format available in Germany. Polytechnic istitutes ITB, Segrate, Italy. gie Inserm- CNRS, for a lecture on immu- The Scripps Research versity of Oxford, UK. University of Geneva, english, german and • Seminars: > Amanda Proudfoot, visit the IRB. > Tim Sparwasser, Te- Marseille, France. nology. Institute, La Jolla, CA, • Seminars: Switzerland. italian. > Onur Boyman, Serono International chnische Universität > Anjana Rao, The USA. > Eric Prossnitz, Uni- > Kanta Subbarao, University Hospital of SA, Geneva, Switzer- • Visit of the Consiglio München, Germany. CBR Institute for • Seminars: > Alexandra Trkola, versity of New Mexico, National Institutes of • Seminars: Lausanne, Switzerland. land. di Stato of Canton Biomedical Research, > Ira Mellman, Yale University Hospital Albuquerque, Mexico. Health, USA. > Signe Hässler, > Thomas Duhen, > Douglas Richman, Ticino. Boston, USA. University School Life in Zurich, Switzerland. > Marisa Jaconi, Gene- > Peter Friedl, Uni- Uppsala University INSERM, Lyon, France. University of Califor- > Paul O’Shea Uni- of Medicine, New > Andrea Zisch, va, University, Swit- versity of Wurzburg, Hospital, Sweden. nia San Diego, USA. • Seminar Claudia versity of Nottingham, Haven, USA. the Institute University Hospital zerland. Germany. > Ralf Ignatius, Lengerke, Children’s UK. > Rolf Zinkernagel, Zurich, Switzerland. > Cameron Simmons, > Carmen Birchmeier, University of Berlin, Hospital, Boston, USA > Luca Varani, Stan- University Hospital Hospital for Tropical May-Delbrueck-Cen- Germany. ford University School Zürich, Zürich. Diseases, HCMC, trum für Molekulare of Medicine, Stanford, > Nicole Suciu Foca, Vietnam. Medizin, Berlin, USA. Columbia University, Germany. New York, USA.
32 Overview 2006 Overview 2006 33 Multiplying Discovery
Students trained at the IRB continue their scientific careers in institutes and universities around the world.
34 Multiplying Elena Palmesino Simona Infantino Laura Rivino Roxane Tussiwand Education. PhD Programme “CXCR4 associated proteins “RDC1, an orphan receptor “Dissecting the human CD4+ “Flt3 in dentritic cell develop- development of EAE in a mouse model and PhD students and their role in cell specific with similarities to chemokine T cell memory pool.” ment.” system. Collectivly, these findings might receptor function”. receptors”. Laura Rivino, David Jarrossay, Federica Sal- Roxanne Tussiwand and Markus Manz. lead to new pharmacological strategies Elena Palmesino and Marcus Thelen. Simona Infantino and Marcus Thelen. lusto, Antonio Lanzavecchia & Jens Geginat. In vivo steady-state type I natural in prevention and treatment of autoim- Understanding chemokine receptor- The orphan receptor RDC1 may func- Two types of regulatory T cells have IFN-producing and dendritic cell (DC) mune diseases and complications of The IRB provides high level sci- mediated signaling in different cellular tion as a chemokine receptor. We have been described: “natural” CD25+Foxp3+ development is largely dependent on organ or blood cell transplantation. entific education for graduate environments is the main focus of the characterized its expression pattern in Tregs and adaptive IL-10-secreting “Tr1” Flt3 signaling. Natural IFN-producing International PhD Program in Basic and students. The PhD programme, project. Ample evidence from our labora- leukocytes, in particular on B cells. So cells with unknown phenotype. Induc- and DC progenitors and their respective Applied Immunology; Università Vita e in collaboration with Swiss and tory and by others indicate that coupling far, we have tested most of the known tion and maintenance of CCR6 on TCR- downstream cell populations express the Salute San Raffaele, Milano of a given G‑protein coupled receptor to human chemokines as potential ligands, activated human T cells required TGF-b flt3 receptor, and Flt3 ligand (Flt3L)_/_ foreign universities, includes ex- downstream signaling cascades must be but could not identify a specific agonist. and absence of polarising cytokines. In mice have reduced while Flt3L-injected PhD Granted by Università Vita e Salute perimental work carried out at regulated in close proximity to the recep- Receptor internalization on primary human blood CCR6 was expressed on mice develop markedly increased num- San Raffaele, Milano. IRB under the direct supervi- tor and may vary between cell types. As a and transfected cells was measured as myeloid DC, on most natural Tregs and bers of both cell types. We could show Tutor: Professor Ruggero Pardi sion of a group leader as well as model we investigate the signaling prop- agonist induced response. Recent results on a fraction of antigen-experienced that SU11657, a small multitargeted seminars, lessons, and an annual erties of the chemokine receptor CXCR4 obtained in collaboration with our CD4+CD25-Foxp3- T cells. CD25-CCR6+ receptor tyrosine kinase inhibitor with PhD student retreat. Starting which regulates trafficking of leukocytes partners in Paris suggest that CXCL12 T cells possessed high IL-2 and IL-10 Flt3 affinity, suppressedin vitro natural and tissue cells and is involved in tumor binds RDC1 and induces its internaliza- producing capacities, but produced IL-10 IFN-producing and DC development in from 2004 the Institute organ- metastasis. The receptor also mediates tion in T cells. However, results form our only following weak TCR stimulation. Flt3L-supplemented mouse whole bone izes an International PhD lecture ce