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Hosting organisation:

Karolinska Institutet, Sweden

Coordinator:Qiang Pan Hammarström,
IRB Participants:

Davide Robbiani, Director

Luca Varani, Group Leader

Partners:

Karolinska Institutet, Sweden

JRC-Joint Research Centre-European Commission, Belgium

Technische Universität Braunzchweig, Germany

Fondazione IRCCS Policlinico San Matteo, Italy

Research area:

EU – Horizon 2020 – SC1-PHE-CORONAVIRUS-2020

Duration:01.04.2020 to 31.03.2022
Website:http://www.covidantibody.eu

ATAC aims at developing passive immunotherapy against COVID-19. Human antibodies will be obtained from blood of CoV-recovered donors from China and Italy with three independent approaches: polyclonal gamma-globulins, B cell monoclonals and phage libraries. Antibodies will be characterized by rapid experimental and computational work, optimized, produced and tested in consultation with EMA to ensure prompt embedding of regulatory aspects.

The partners have outstanding experience in all aspects of the project, collaborated previously and worked on antibody therapy for diseases including SARS and MERS-CoV. Reagents and experienced personnel are already available ensuring quick and efficient progress, with initial deliverables within 3 months.

Besides providing a lead human antibody candidate for therapy, ATAC will rapidly disseminate results to help respond to the current COVID-19 epidemic. Results of the 2 years project will also further our understanding of CoV neutralization, contributing to future vaccination and therapeutic strategies.

The team includes the Karolinska Institutet (SE, Pan-Hammarström and Hammarström, coordinators), the Institute for Research in Biomedicine (CH, Varani and Robbiani); the Joint Research Centre- European Commission (BE, Calzolai); Technische Universität Braunschweig (DE, Hust) and Policlinico San Matteo (IT, Baldanti). The partners’ outstanding expertise is attested by high impact publications on antibody treatment for emerging infectious diseases.

Hosting organisation:

Karolinska Institutet
Coordinator: Lars Klareskog
IRB Participants:

Federica Sallusto, Group Leader
Research area:

Innovative Medicine Initiative
Duration: 01.09.2017 to 31.08.2022

In line with IMI2 goals for improved therapies and precision medicine, the aim of this proposal is to prevent and treat RA or its progression by inhibiting maturation/expansion of pathogenic autoimmune responses through immune tolerising treatments of subjects not only in early stages of joint inflammation (undifferentiated arthritis and early RA) but also in even earlier defined stages i.e. before onset of joint inflammation, when patients have arthralgia and/or bone loss, or sub-clinical stages of joint inflammation.
Today, no drugs are approved for these early phases of RA development, where symptoms such as pain and fatigue cause major loss of life quality and where successful interference would prevent onset of disease. Thus, an important part of our work will be to achieve a better understanding of this as yet unexplored phase of disease. In the proposed project we will develop and validate new methods to identify individuals at high risk for RA, tools to monitor disease progress and expand and further develop cohorts suitable for these purposes.
Furthermore we will validate and standardise methods to monitor immune tolerance to be used in clinical trials for tolerising therapies for RA.
The aim is thus to interfere with the specific immune reactions that contribute to RA symptoms in such a way that a specific and long-lasting therapeutic effect (ultimately a cure) is accomplished for a major proportion of RA patients and prevention of diseases is accomplished in individuals at high risk for RA.
Investigator-initiated as well as company-sponsored clinical trials in well stratified patient groups will be performed in collaboration with SMEs and/or contributing pharma companies and their immune effects studied using the same panel of biomarkers allowing for standardisation across protocols. Our ambition is also to disseminate our experiences from RA to other rheumatic and other immune-mediated diseases.

Hosting organisation:

National Center of Competence in Research (NCCR) ‘RNA & Disease’

Coordinator:Prof. Oliver Mühlemann, University of Bern
IRB Participants:

Silvia Monticelli, Group Leader

Research area:

RNA and disease

Duration:01.09.2017 to 31.08.2020
Website:http://www.nccr-rna-and-disease.ch/tiki-index.php?page=AssociateOverview

The NCCR ‘RNA & Disease’ is a research instrument of the Swiss National Science Foundation, and is a coordinated, interdisciplinary research program aiming at identifying disease mechanisms resulting from aberrant RNA functions.

Silvia Monticelli will participate to this network with a project about the role of microRNAs (miRNAs) in the regulation of human T cell activation and functions in multiple sclerosis (MS). This project will be performed in collaboration with Prof. Jonathan Hall (ETH Zurich).

MS is a chronic neuroinflammatory disease initiated by autoreactive T lymphocytes; however, the frequency of circulating autoreactive lymphocytes is similar between people with MS and healthy individuals and, at least in animal models, it is also comparable to the frequency of T cells specific for foreign viruses, indicating that the mere presence of such autoreactive cells is not sufficient to explain their pathogenicity. Mechanisms likely to be crucial in MS include therefore all those processes that regulate the threshold, magnitude and quality of T lymphocyte responses. Among the factors that are gaining importance in the control of T cell responses in normal and diseased conditions are miRNAs, short noncoding RNA molecules that have become clear determinants of cellular fate and responses in a wide variety of different systems. MiRNAs are now considered increasingly important in autoimmunity, and similarly to infectious diseases, for which miRNAs are already in clinical trial, they could be potentially considered as a novel therapeutic strategy. However, due to the complex interactions usually existing between miRNAs and their targets, it is essential to first dissect the effects of a given miRNA network, which is exactly the scope of this project.

Coordinator:Institut National de la Santé et de la Recherche Scientifique ((INSERM)
IRB Participants:

Antonio Lanzavecchia, Director

Partners:

39 partners

Research area:

H2020-PHC-2015-single stage-RTD

Duration:01.01.2016 to 31.12.2020

Despite enormous progress in the prevention and treatment of HIV/AIDS, the global response cannot keep pace: 35 million people are living with HIV worldwide with ca 6,000 new infections each day. Numerous HIV prevention strategies (such as PrEP and PEP), though proven successful, are difficult to sustain long-term. A vaccine still represents the most effective tool in the combat against HIV from a public health perspective. To date, many prophylactic and therapeutic vaccine concepts have been developed and several efficacy trials have been conducted but with limited success. There is an urgent need to develop better vaccines and tools predictive of immunogenicity and of correlates of protection at the early stage of vaccine development to mitigate the risks of failure.

EHVA APPROACH

To address these complex and challenging scientific issues, EHVA aims to develop a Multidisciplinary Vaccine Platform through a global and innovative alliance notably:

• Multidisciplinary expertise from vaccine discovery, to immune monitoring to clinical development

• State-of-the-art innovative technologies to profile immune responses and virus reservoir

• Access to large cohort studies bringing together top European clinical centres in the fields of  prophylactic and therapeutic vaccines

• Access to a panel of experimental HIV vaccines under clinical development as benchmark

• Liaison with African leading scientists/programs fostering future testing of EHVA vaccines in Sub-Saharan Africa

• Engagement of industrial expertise for downstream vaccine development

EHVA OBJECTIVES

EHVA plans to develop and implement:

• Discovery Platform with the goal of generating novel vaccine candidates inducing potent neutralizing and non-neutralizing antibody responses and Tcell responses

• Immune Profiling Platform with the goal of ranking novel and existing (benchmark) vaccine candidates on the basis of the immune profile

• Data Management/Integration/Down-Selection Platform, with the goal of  providing statistical tools for the analysis and interpretation of complex data and algorithms for the efficient selection of vaccines

• Clinical Trials Platform with the goal of accelerating the clinical development of novel vaccines and the early prediction of vaccine failure.

Hosting organisation:

Institut National de la Sante et de la Recherche Médicale, Paris, France

Coordinator:Prof. Xavier de Lamballerie
IRB Participants:

Federica Sallusto, Group Leader

Research area:

H2020-SC1-2016-2017 SC1-PM-22-2016

Duration:01.10.2016 to 30.09.2019
Website:http://www.zikalliance.eu

ZIKAlliance is a multidisciplinary project with a global “One Health” approach, built: on a multi-centric network of clinical cohorts in the Caribbean, Central & South America; research sites in countries where the virus has been or is currently circulating (Africa, Asia, Polynesia) or at risk for emergence (Reunion Island); a strong network of European and Brazilian clinical & basic research institutions; and multiple interfaces with other scientific and public health programmes. ZIKAlliance will address three key objectives relating to (i) impact of Zika virus (ZIKV) infection during pregnancy and short & medium term effects on newborns, (ii) associated natural history of ZIKV infection in humans and their environment in the context of other circulating arboviruses and (iii) building the overall capacity for preparedness research for future epidemic threats in Latin America & the Caribbean. The project will take advantage of large standardised clinical cohorts of pregnant women and febrile patients in regions of Latin America and the Caribbean were the virus is circulating, expanding a pre-existing network established by the IDAMS EU project. I will also benefit of a very strong expertise in basic and environmental sciences, with access to both field work and sophisticated technological infrastructures to characterise virus replication and physiopathology mechanisms. To meet its 3 key objectives, the scientific project has been organised in 9 work packages, with WP2/3 dedicated to clinical research (cohorts, clinical biology, epidemiology & modeling), WP3/4 to basic research (virology & antivirals, pathophysiology & animal models), WP5/6 to environmental research (animal reservoirs, vectors & vector control) , WP7/8 to social sciences & communication, and WP9 to management. The broad consortium set-up allow gathering the necessary expertise for an actual interdisciplinary approach, and operating in a range of countries with contrasting ZIKV epidemiological status.

Hosting organisation:

Institute for Research in Biomedicine

Coordinator:Marcus Thelen
IRB Participants:

Marcus Thelen, Group Leader

Partners:

Cornelia Halin, ETH Zürich, Institut für Pharmazeutische Wissenschaften (CH)

Daniel Legler, Universität Konstanz, Biotechnologie Institut Thurgau (CH)

Antal Rot, University of York (UK)

Research area:

SNSF – Sinergia

Duration:01.11.2015 to 31.10.2018
Website:http://www.ackr.usi.ch

Atypical chemokine receptors (ACKR), unlike the classic (typical) chemokine receptors, do not trigger cell migration. These receptors rather act as decoy, eliminating or trancytosing chemokines. Research from the recent years has shown that ACKRs play a key role in the regulation of the chemokine system. In this project, the similarities and discrepancies of the function of three atypical receptors (ACKR1, ACKR3 and ACKR4) will be assessed.

The group of atypical chemokine receptors (ACKR1-4) has recently been defined as receptors that are structurally related, although they do not follow the classical scheme of G-protein coupled receptors and do not interact with G-proteins. Nevertheless ACKRs can contribute through their capacity as effective eliminators of chemokines to form gradients. Francis Crick concluded already in the 70s that the persistence of spatial chemoattractant gradients requires the presence of corresponding sinks in juxtaposition to their sources. Such gradients of chemokines are essential for effective innate and adaptive immune responses.

The project aims to demonstrate that gradients of chemokines exist in lymphoid tissue and, with a special focus on the function of ACKR. The consortium expects that the results will bring new insights into the regulation of immune response, which can be important, both in the fight against pathogens and in autoimmunity.

Hosting organisation:

GlaxoSmithKline
Coordinator: Daniel Sikkema, GlaxoSmithKline
IRB Participants:

Antonio Lanzavecchia, Director
Research area:

Innovative Medicines Initiative
Duration: 01.03.2012 to 28.02.2018
Website: http://www.abirisk.eu

Biopharmaceuticals are drugs that are biological in origin (i.e. are made of proteins or DNA for example) and are manufactured using biotechnology. A number of biopharmaceuticals are already in use and have dramatically improved quality of life for patients with serious, hard to treat conditions such as multiple sclerosis, Crohn’s disease, diabetes, rheumatoid arthritis, haemophilia A and some cancers. However, in some patients, biopharmaceuticals can trigger an immune reaction, a phenomenon known as immunogenicity. When this happens, the immune system produces antibodies (ADAs) that neutralise the drug, which can reduce the effectiveness of the biopharmaceutical. In some patients, the immune response causes side effects such as a rash, chest pains, or a fall in blood pressure. In the most severe cases, it can trigger anaphylactic shock and even prove fatal.

Immunogenicity – the known unknowns

Diverse factors appear to be involved in immunogenicity. On the drug side, both the compound and the route and duration of administration seem to play a role, while on the patient side, the type of disease, age, genetic background and interactions with other medicines may be risk factors.

Therefore it is extremely hard to predict which biopharmaceuticals will have immunogenicity problems; although many tests exist, these are not always accurate. Furthermore, knowing which patients are at greatest risk of mounting an immune response to a given biopharmaceutical is extremely difficult.

Reducing the risks

Yet even though immunogenicity continues to pose a problem in the development of new drugs, until now there has been no major effort to solve the problem.

Enter the ABIRISK project, which aims to give biopharmaceuticals a much-needed boost and represents the first concerted effort to tackle the immunogenicity problem by bringing together leading experts from hospitals, academia, industry, and small companies.

The kick-off meeting for the ABIRISK project took place in Paris on March 1st-2nd, 2012. The ABIRISK project consortium is presently made up of thirty-five partners, twenty-four of which are academic institutions, nine are EFPIA member companies and two are small and medium enterprises (SMEs). Thirteen countries are represented: The United Kingdom, France, Italy, Germany, Switzerland, Denmark, Belgium, the Netherlands, Spain, Sweden, Austria, Israel and Czech Republic.

The project will set up laboratory tests to probe the immunogenicity of several biopharmaceuticals that are already used on patients. The scientists will then match their test findings with the effect the drug actually has on patients. This will help the team to develop tools that are better at predicting immunogenicity during drug development.

Many pharmaceutical companies, academic institutions and patient registries have large amounts of data on biopharmaceuticals and patients’ responses to them. In ABIRISK, these diverse databases will be assembled into a single immunogenicity databank that will help researchers pinpoint the factors that influence a drug’s immunogenicity and patients’ risk of it. This will allow the researchers to generate tools that will accurately predict whether a patient will mount an immune response to a biopharmaceutical and how that immune response will affect the efficacy and safety of the drug.

Safer, more effective drugs for patients

Immunogenicity means many patients today are denied the life-changing benefits of biopharmaceuticals. ABIRISK will ultimately result in a new generation of biopharmaceuticals with lower immunogenicity that can be safely and effectively used by more patients. In addition, the project will allow clinicians to determine which patients will respond best to which biopharmaceutical, thereby preventing patients from suffering the side effects of a drug that does not suit them.

For Europe’s pharmaceutical industry, better tests will help companies identify the safest, most effective biopharmaceuticals and weed out those that pose a high immunogenicity risk earlier in the drug development process. This will save companies both time and money. Finally, by adding to our knowledge of the mechanisms behind immunogenicity, the project will help to improve regulatory guidelines for the approval of biopharmaceuticals.

Hosting organisation:

Institute for Research in Biomedicine
Coordinator: Maurizio Molinari
IRB Participants:

Maurizio Molinari, Group Leader
Partners:

Matthias Peter, Department of Biology, Institute of Biochemistry, ETH Zürich (CH)

Fulvio Reggiori, Department of Cell Biology, University of Groningen, Groningen (NL)
Research area:

SNSF – sinergia
Duration: 01.10.2014 to 30.09.2017
Website: http://p3.snf.ch/project-154421

The endoplasmic reticulum (ER) is the site of folding and assembly for about a third of the eukaryote proteome. This membrane-bound organelle contains high concentrations of molecular chaperones and enzymes that 1) prevent aggregation of non-native newly synthesized polypeptides, 2) catalyze rate-limiting reactions of the protein folding process, and 3) insure that only native and fully-assembled proteins can leave the compartment to be transported to their intra- or extracellular functional site. The ER also contains molecular chaperones and enzymes that recognize terminally misfolded polypeptides and orphan subunits of oligomeric complexes, extract them from the folding environment and regulate their transport across the ER membrane for delivery into the cytosol where they are degraded by proteasomes. This process is known as ER-associated degradation (ERAD). Balanced activity of the ER folding and ERAD machineries is instrumental to maintain cellular homeostasis. A substantial increase in the ER cargo load, accumulation of misfolded polypeptides and environmental changes elicit an adaptation program known as the unfolded protein response (UPR). The UPR is triggered by ER stress sensors embedded in the ER membrane, and involves the activation of transcriptional/translational programs resulting in expansion of the ER volume, attenuated synthesis of ER cargo proteins and increased production of ER-resident chaperones and enzymes. Emerging evidence shows that the specific engulfment of part of the ER into autophagosomes through a selective type of autophagy, which has been named ER-phagy or reticulophagy, plays a key role in the maintenance of ER homeostasis in two important aspects of the cell response to ER stress. First, ER-phagy teams up with the ERAD machinery to clear accumulated protein aggregates from the ER. Second, it counteracts the uncontrolled expansion of the ER that occurs during ER stress. If UPR activation does not alleviate the ER stress or does not allow adaptation to it, cell death programs are activated. In contrast, if the cellular response relieves the stress condition, a recovery phase starts whereby the volume of the ER and the content of ER-resident proteins return to pre-stress levels. Our preliminary data lead us to propose a third role for ER-phagy in reducing the ER size and content during the recovery phase initiated upon termination of ER stress.

The major goal of this collaborative project is to identify the components and regulatory mechanisms underlying ER-phagy during cell recovery from ER stresses, which, to our knowledge, has remained totally unexplored until now. We will closely collaborate among 3 leading research groups, two in Switzerland and one in the Netherlands, to exploit our complementary experimental expertise and model systems (budding yeast and mammalian cells). Identified factors and principles will also be tested in the context of the two documented types of ER-phagy, i.e. clearance of ER aggregates and buffering ER expansion, to also shed light onto these poorly characterized processes and to determine whether ER-phagy operates through similar mechanisms under different stimulus conditions. Our studies will reveal important aspects of the coordinated cross talk between ER quality control, ER stress, ERAD and ER-phagy, which is crucial to maintain cell and organism homeostasis. The importance of these studies is highlighted by the growing interest and clinical use of proteostasis-modifying substances and autophagy modulators to contrast the onset and progression of several diseases caused by protein misfolding that leads to the accumulation of toxic aggregates.

Hosting organisation:

Institute for Research in Biomedicine
Coordinator: Antonio Lanzavecchia
IRB Participants:

Antonio Lanzavecchia, Director
Partners:

Thierry Calandra, Infectious Disease Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne (CH)

Annette Oxenius, Institute for Microbiology, ETH Zürich, Zürich (CH)

Giuseppe Pantaleo, Division of Immunology and Allergology, Centre Hospitalier Universitaire Vaudois, Lausanne (CH)
Research area:

SNSF – Sinergia
Duration: 01.08.2013 to 31.07.2016
Website: http://p3.snf.ch/project-147662

The immune response relies on the coordinated action of different cells of the immune system, which are constantly confronted with commensal microorganisms (microbiome) and with persistent viral infections (virome). In contrast to the microbiome, which has been shown to modulate the immune response, the virome received much less attention. This project therefore aims at assessing how the virome impacts the composition, properties and function of immune cells, in both humans and animal models.

In this project, we aim to understand to what extent chronic viral infections impact on the response to vaccines, on the susceptibility to infection, on the predisposition to autoimmunity and on the acceleration of immunological ageing. Three research and clinical centers located in Bellinzona, Lausanne, and Zurich will cooperate to reach this ambitious goal. They will take advantage of complementary expertise and resources to study well defined cohorts of patients with chronic viral infections using state-of-the-art analytical technologies such as multiparameter and mass-tag barcoding flow cytometry, single cell gene expression profiling, high throughput cellular screening methods and with next generation repertoire sequencing. Studies in mouse models of chronic infection will complement and synergize with the human studies. By combining the data obtained in the three centers this Sinergia project will give rise to the most comprehensive view of the impact of chronic viral infections on the homeostasis and the functionality of the immune system.

Hosting organisation:

Sclavo Vaccines Association (SVA)
Piazza La Lizza, Siena, Italy

Coordinator:Rino Rappuoli
IRB Participants:

Antonio Lanzavecchia, Director

Federica Sallusto, Group Leader

Mariagrazia Uguccioni, Group Leader, Vice Director

Research area:

HEALTH.2011.1.4-4 High impact initiative for better immunisation

Duration:01.10.2011 to 30.09.2016
Website:http://www.aditecproject.eu
http://www.aditecproject.eu/fileadmin/user_upload/Documenten/News/Publication_Im…

Vaccines so far have been developed mostly by following an empiric approach. To prevent and possibly cure unresolved and emerging infectious diseases we need to fully exploit the potential of the human immune system. Progress in science and technology makes it possible to achieve what was previously deemed impossible. The scope of this project is to produce knowledge necessary to develop novel and powerful immunization technologies for the next generation of human vaccines. This goal requires a multidisciplinary approach in which diverse but complementary scientific disciplines and technologies converge. Therefore some of the most competitive European research groups from public institutions and biotechs have agreed to join forces in ADITEC, together with top US groups on systems biology and adjuvants to support this enterprise.

A systems biology approach will be used to study licensed and experimental vaccines in patient characterization studies and in clinical trials, to investigate the effect of adjuvants, vectors, formulations, delivery devices, routes of immunization, homologous and heterologous primeboost schedules, as well as the impact of host factors such as age, gender, genetics and pathologies. Animal models will be used to complement human studies, and to select novel immunization technologies to be advanced to the clinic.

To address these issues in a coordinated manner, ADITEC is organised on a matrix structure in which research themes and experimental approaches feed into each other. Training curricula will be created to impact on the formation of the next generation of EU researchers in the field. ADITEC scientists and institutions are part of the Sclavo Vaccines Association (SVA), which is dedicated to vaccines and vaccine research. SVA, acting as the coordinating institution, guarantees the long-term commitment and sustainability of this initiative, beyond the duration of ADITEC itself.

Hosting organisation:

Universitätsklinikum Heidelberg
im Neuenheimer Feld 672, Heidelberg, Germany

Coordinator:Thomas Jaenisch
IRB Participants:

Federica Sallusto, Group Leader

Research area:

HEALTH.2011.2.3.3-2 Comprehensive control of Dengue fever under changing climatic conditions

Duration:01.09.2011 to 31.08.2016
Website:http://www.idams.eu/

The overall concept of this research project is to assemble a consortium of international experts working together to develop new and innovative tools to be applied to the control of dengue in a global context. The core of the application focuses on parallel strategies aimed at:

  • improving diagnosis and clinical management of dengue through two linked work packages designed a) to identify readily available clinical and laboratory parameters and/or viral and immunological markers, that differentiate between dengue and other common febrile illness within 3 days of fever onset, and b) to identify any of the available markers that are predictive of the likelihood of evolving to a more severe disease course
  • assessing the risk of dengue spread though linked work packages focused on a) mapping and modelling techniques to define the current extent of dengue disease globally and to evaluate possible scenarios of spread or risk to previously uninfected regions in the future, and b) developing effective and affordable early warning and outbreak response systems.

These four work packages are supported by a fifth work package dedicated to networking and translational activities to ensure that outputs from the various research activities are used to maximal advantage.

Coordinator:Carole Bourquin
IRB Participants:

Federica Sallusto, Group Leader

Mariagrazia Uguccioni, Group Leader, Vice Director

Research area:

Swiss National Science Foundation – Doctoral Programmes (ProDoc)

Duration:01.10.2012 to 30.09.2015
Website:http://p3.snf.ch/project-141773

Cell migration is fundamental to immunosurveillance and inflammation but also to tumor invasion and metastatic dissemination. Chemokines and their receptors play a central role in positioning immune and tumor cells with spatiotemporal precision. In the multi-step extravasation of circulating cells, chemokines trigger their arrest to the vascular endothelium, then make them move across the vascular wall and along surface-bound chemokine gradients to their destination. In the immune system, this is relevant to homeostatic recirculation of lymphocytes through lymphatic tissues as well as to recruitment of leukocytes to tissues during acute or chronic inflammation. In cancer, in addition to migration, chemokines also promote tumor cell proliferation and survival, and contribute to the formation of metastatic niches. Thus expression of chemokine receptors on circulating immune or tumor cells is critical to coordinate complex tissue responses. In addition to chemokines a number of factors (e.g. HGF or Ang2) have been recognized to exert chemotactic activity. In this ProDoc Research Module (RM) three PhD students will work on complementary and interlaced projects dedicated to address the roles of chemotactic factors and their cognate receptors in myeloid, lymphoid and tumor cell migration. The knowledge obtained will be integrated into our current understanding of the cellular and molecular basis of pathophysiological events such as acute and chronic inflammation, tumor progression and metastasis. Results generated by this research module have the potential to guide the development of novel therapeutic strategies. The present RM will be integrated as RM3 in a highly synergistic manner (as outlined in the cartoon below) in the existing ProDoc CellMigration, which currently consists of a Training Module (TM), and two research modules, RM1 and RM2. Associating RM1 with RM3, ProDoc Student 13 will investigate the role of CCR2, CX3CR1, Tie2 and their respective ligands in the migration of myeloid subsets into the brain during immunosurveillance and neuroinflammatory disorders such as multiple sclerosis. To this purpose this student will use novel mouse models and mesoscopic and live cell imaging tools and human samples. Research of ProDoc Student 14 will define how synergies between soluble mediators enhance T cell recruitment into tumors, with relevance to natural anti-tumor immune responses and cancer immunotherapy protocols. Work by this student with have natural interactions with RM1 and RM2. Finally, ProDoc Student 15 will study the modulation of chemokine activity in spontaneous and therapy-induced breast cancer metastasis by exploiting recent results and tumor models obtained in the partner laboratories. Research topics addressed within RM3 will be highly related and complementary to experiments proposed in RM1 and RM2 of the running ProDoc CellMigration Program. Embedding three additional PhD students to work in collaborative projects focusing on the role of soluble mediators involved in immune and tumor cell migration will exploit to the fullest the potential for collaborative efforts within the ProDoc consortium. This program provides the framework for an internationally visible training program for highly qualified PhD students in the field of cell migration, excellence of which cannot be achieved at this level in the individual laboratories alone.

Hosting organisation:

Fondazione Humanitas per la Ricerca
Via Manzoni 56, Rozzano, Italy
Coordinator: Alberto Mantovani
IRB Participants:

Mariagrazia Uguccioni, Group Leader, Vice Director
Research area:

HEALTH.2011.1.4-5 New therapeutic approaches in chronic inflammatory and autoimmune diseases
Duration: 01.01.2012 to 31.12.2015
Website: http://www.eumbrella.org
http://ec.europa.eu/programmes/horizon2020/en/news/inflammation-needs-closure

Resolution of inflammation is a key determinant of pathology, and an active process which involves diverse pathways and molecules. The general objective of the TIMER Consortium is to identify and validate new molecules involved in the resolution of inflammation as a basis for the development of innovative therapeutic strategies in chronic inflammatory and autoimmune diseases. The project will involve discovery of new natural or synthetic pro-resolving molecules for plant and animals and investigation on endogenous inflammation pro-resolving mechanisms identified by various partners of the Consortium, including atypical chemokine receptors, decoy receptors, and microRNA. Tapping resources of natural compounds will be a major thrust.

Efforts will be mainly focused on the regulation by pro-resolving agents on two molecular systems of key relevance in inflammation: the chemokine system, which regulates recruitment, permanence and egress of leukocyte in tissues; and the TLR/IL-1R system, which is central for the activation of infiltrating leukocytes., To this purpose, the project will capitalize on, and bring added value to a strong tradition of the Consortium in the fields of: leukocyte recruitment and activation; negative regulators of inflammation; industrial-academic collaboration; identification and characterization of innovative inhibitors of natural origin; European-Brazilian collaboration.

Coordinator:Curzio Rüegg
IRB Participants:

Federica Sallusto, Group Leader

Research area:

Swiss National Science Foundation – Doctoral Programmes (ProDoc)

Duration:01.01.2012 to 31.12.2014
Website:http://p3.snf.ch/project-137079

Malignant cell transformation is the result of the accumulation of multiple genetic and epigenetic cell-autonomous events leading to uncontrolled cell proliferation and survival. Transformed cells, however, require support from the surrounding normal tissue (i.e. the tumor microenvironment) in order to progress to life-threatening invasive and metastatic cancers. Compared to normal quiescent tissue, the tumor microenvironment is characterized by profound changes in cellular composition, such as the appearance of cancer-associated fibroblasts, angiogenic blood and lymphatic endothelial cells, and the accumulation of many immune, inflammatory and bone marrow-derived cells (BMDC). Collectively these cells cooperate to promote tumor growth, invasion and metastatic spreading. Cell migration is key to many events of cancer progression: tumor cells acquire migratory and invasive capacities during transformation, migration is necessary for metastatic spreading, angiogenic endothelial cells migrate toward the growing tumors, and immune, inflammatory and BMD-cells migrate to primary tumors and metastatic sites. In this ProDoc research module we will address complementary topics of cancer research involving cell migration. With ProDoc Student 3 we will investigate mechanisms of breast cancer metastasis to the brain. We have recently established a model of spontaneous breast cancer metastasis to the brain in immunocompetent mice and identified clinically relevant genes that are functionally involved in this process. We will use this model to investigate how brain metastatic cells migrate across the blood-brain barrier, how the brain parenchyma modulates their invasive capacities once they have passed the blood-brain barrier, and whether BMDC contribute to breast cancer cell entry into the brain. A main focus of this module concerns the role of immune, inflammatory and BMDC in tumor progression. With ProDoc Student 4 we will study the role of TLR9-mediated activation of myeloid-derived suppressor cells (MDSC) on their ability to migrate into tumors. By analogy with dendritic cells, we are proposing that activation-induced maturation of MDSC may lead to changes in their homing and recirculation properties within the tumor-bearing host. A reduced recruitment of MDSC to the tumor microenvironment and draining lymph nodes is expected to impact on the anti-tumor immune response. This thesis will also investigate whether immune activation of MDSC might impinge on tumor metastasis. ProDoc Student 5 will investigate the role of endothelial Angiopoietin-2 (Ang-2) on the recruitment of BMDC into primary tumors and premetastatic niches. This project is based on the use of a transgenic mouse model for endothelial cell-specific Tetracycline-regulatable expression of human Ang-2 that we have recently established and characterized. In particular, we will characterize the effect of continuous and moderate increase of Ang-2 expression in endothelial cells on tumor vessel morphology and function, on the recruitment of BMDC and Tie-2 expressing monocytes (TEM) to primary and metastatic sites and on their contribution to tumor angiogenesis and metastasis. ProDoc Student 13 will investigate the role of endothelial cell-derived factors in promoting migration and invasion of adjacent tumor cells. We have previously observed that endothelial cell activation induces tumor cell motility, and by genome wide screenings we have identified candidate molecules promoting tumor cell migration. Here we will characterize the effect of some of these factors and their receptors. With ProDoc Student 14 we will use an orthotopic model for pancreas cancer to study the effect of innate immune activation on the migration of tumor-specific effector CD8 T cells to tumors and to identify strategies to enhance their recruitment in order to improve the efficacy of immunotherapy. Taken together, in this ProDoc module we will address important aspects of tumor cell, BMDC, immune, and inflammatory cell migration in cancer progression through five coordinated and integrated projects. Interactions across all partner laboratories are essential for each of these projects and are naturally based on the specific backgrounds and expertises of the collaborating groups. Interactions include the shared use of unique experimental models, the investigation of similar or related phenomena in different models and the integration of results across projects to generate novel hypotheses. Considering the important biomedical and clinical relevance of the projects pursued in this module, we will attempt, whenever possible, to rapidly validate experimental results with observations on human material.

Hosting organisation: Institute for Research in Biomedicine (IRB), Bellinzona
Coordinator: Fabio Grassi
IRB Participants: Fabio Grassi, Group Leader
Research area: ERA.Net RUS – Pilot Joint Call for S&T projects
Duration: 01.09.2012 to 31.08.2014

T lymphocytes control the immune response toward pathogens or self tissues by promoting or inhibiting inflammatory destruction, respectively. A defective control of immune response to self tissues results in autoimmune diseases. Adenosine triphosphate (ATP) constitutes the source of chemical energy for the majority of cellular functions. However, ATP is also released in the extracellular space as a soluble signaling molecule, which activates purinergic receptors and stimulates the pro-inflammatory function of T lymphocytes.

Upon de novo synthesis ATP binds magnesium ions thus reducing intracellular magnesium content. The reduction in free magnesium results in opening of a channel for magnesium influx called TRPM7, which further promotes lymphocytes activation. This project is aimed at studying the so far unexplored relationship between ATP synthesis, magnesium, purinergic signaling and TRPM7 activity in shaping T cell function.

Understanding the molecular mechanisms that govern T cell responsiveness will improve our knowledge of the pathogenesis of autoimmune diseases.

This study will be performed in collaboration with Susanna Zierler from the Ludwig-Maximilians-University, Walther-Straub-Institute for Pharmacology und Toxicology, Munich, Germany and with Yuri Negulyaev from the Russian Academy of Science Institute of Cytology, St. Petersburg, Russia.

Hosting organisation:

CSEM Centre Suisse d’Electronique et de Microtechnique SA – R&D
Rue Jaquet-Droz 2002, Neuchatel, Switzerland

Coordinator:Stéphane Follonier
IRB Participants:

Luca Varani, Group Leader

Research area:

KBBE.2010.3.2-04 Innovative aquatic biosensors

Duration:01.01.2011 to 31.12.2014
Website:http://www.fp7-radar.eu

RADAR is a 7-member consortium that aims to develop a robust, sensitive, and versatile label-free, biosensor platform for spot measurements and on-line monitoring of toxins and pollutants in food production processes and in the aquatic environment.
Specificity towards chemical pollutants and toxins is achieved by using recombinant receptors (namely the estrogen receptor and the aryl hydrocarbon receptor) whose amino acid sequences have been rationally designed based on genomic and functional information from aquatic organisms.
Sensitivity of the biosensor is increased by the unique combination of isotachophoretic pre-concentration step, and surface nanostructuring & chemical modification.
The integration of the label-free detection sensors with an on-line automated sample handling and a wireless communication system will yield a best-in-class biosensor platform for robust, specific and sensitive detection of EDCs and PAHs in difficult operating conditions.
To validate the RADAR biosensor the consortium will test the biosensors in fresh and marine water, in fish farms, and in food products such as fish, fruit juices, and milk. Through their contacts in these industries, the partners will evaluate the performance of the biosensors in such environments, analyzing a representative number of samples and reporting on the stability, ruggedness and accuracy of the sensors used under laboratory and real test conditions.
This project is expected to have a high economic impact, since our cost-effective sensor could find a worldwide distribution in most food production and water testing lines as supported by Agilent Technologies Inc.

Hosting organisation:

Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland

Federal University of Rio de Janeiro, Brazil

Coordinator:Luca Varani / Ana Paula Canedo Valente
IRB Participants:

Luca Varani, Group Leader

Research area:

Brazilian Swiss Joint Research Program (BSJRP)

Duration:01.01.2012 to 31.12.2013

The complementary expertise of the participants will be applied to Dengue virus, a neglected disease causing 500,000 hospitalizations and 20,000 deaths per year. The aim is to compare the binding of antibodies that recognizes  the surface protein of the four Dengue serotypes, searching for correlations between immunological, structural, dynamics and binding properties, to further the understanding of antibody/antigen interaction as well as a basis for drug design and improved vaccine strategies.

Hosting organisation:

Stichting Tuberculosis Vaccine Initiative
Edelhertweg Lelystad, Netherlands

Coordinator:Jelle Thole
IRB Participants:

Federica Sallusto, Group Leader

Research area:

HEALTH-2009-2.3.2-2 Identification and pre-clinical testing of new vaccine candidates for tuberculosis)

Duration:01.01.2010 to 31.12.2013
Website:http://www.tbvi.eu

With 14.4 million prevalent cases and 1.7 million deaths tuberculosis (TB) remains one of the most serious infectious diseases to date. An estimated 2 billion people are believed to be infected with Mycobacterium tuberculosis and at risk of developing disease. Multi- and extensively drug resistant strains are increasingly appearing in many parts of the world, including Europe. While with current control measures the Millennium Development Goals (MDGs) set for 2015 may be achieved, reaching these would still leave a million people per year dying from TB.
Much more effective measures, particularly more effective vaccines will be essential to reach the target of eliminating TB in 2050. Two successive FP5 and FP6 funded projects, Tuberculosis (TB) Vaccine Cluster (2000-2003) and TBVAC (2004-2008), have in the recent decade made significant contributions to the global TB vaccine pipeline, with four vaccines (out of nine globally) being advanced to clinical stages. Both projects strongly contributed to the strengthening and integration of expertise and led to a European focus of excellence that is unique in the area of TB vaccine development.
In order to sustain and accelerate the TB vaccine developments and unique integrated excellence of TBVAC, a specific legal entity was created named TuBerculosis Vaccine Initiative (TBVI). The NEWTBVAC proposal is the FP7 successor of TBVAC, and will be coordinated by TBVI.
The proposal has the following objectives:

  1. To sustain and innovate the current European pipeline with new vaccine discoveries and advance promising candidates to clinical stages;
  2. To design new, second generation vaccines based new prime-boost strategies and/or new (combinations of) promising subunit vaccines, that will impact on reduction of disease in exposed individuals;
  3. To sustain and innovative discovery, evaluation and testing of new biomarkers, that will be critically important for future monitoring of clinical trials.
    Hosting organisation:

    Integrated Systems Laboratory, EPFL, Lausanne, Switzerland

    Coordinator:De Micheli Giovanni
    IRB Participants:

    Fabio Grassi, Group Leader

    Research area:

    nano-tera.ch

    Duration:01.03.2010 to 28.02.2013
    Website:http://www.nano-tera.ch/projects/402.php#

    Personalized therapies require accurate and frequent monitoring of the metabolic response of living tissues to treatments. On-line monitoring of patients with specific physiological conditions (e.g., heart, cardiovascular, cancer diseases) is a key factor to provide better, more rationale, effective and ultimately low-cost health care. This is also required in professionals and recreational sportsmen training, as well as in elderly or disabled citizen care.

    Metabolism monitoring is a complex, slow and expensive process, mainly because of the unavailability of accurate, fast and affordable sensing devices that can detect and quantify multiple active compounds in parallel and several times a day. Indeed, systems available on the market use wearable devices (accelerometers, heartbeat monitoring system, etc) but do not measure metabolites. The only available real-time, implantable/ wearable systems for metabolic control are limited to glucose monitoring and used by diabetic patients. However, many different molecules present crucial relevance in human metabolism. They are monitored daily in general hospital practice by automatic blood sampling, but the analysis involves using off-line, large and expensive laboratory equipments.  This project seeks to develop research in the field of integrated smart biosensors for online metabolism analysis that significantly improves the quality and reliability of human measurements, while at the same time reducing analysis time and cost. The new system will investigate many different metabolic compounds of interest in cardiovascular diseases as well as inflammatory diseases and personalized nutrition, such as lactate, cholesterol, ATP, and others.

    To pursue this aim, an innovative technology will be developed by integrating software/hardware/ RF/micro/nano/bio systems in three devices: a fully implantable sensors array for data acquisition, a wearable station for remote powering and signal processing and a remote station for data collection and storage. Apart from multi-panel sensors capable of sensing several metabolites in parallel and in real-time, the expected major breakthroughs include new software algorithms for decoupling different contributions from different metabolites on the same sensor spot as well as a new CMOS design for the fully-implanted, complex and low consumption electronics for sensing and remote powering.

    Hosting organisation:

    Integrated Systems Laboratory, EPFL, Lausanne, Switzerland
    Coordinator: Sandro Carrara
    IRB Participants:

    Fabio Grassi, Group Leader
    Research area:

    SNSF – sinergia
    Duration: 01.01.2010 to 30.06.2013
    Website: http://p3.snf.ch/project-127547

    A fully mature biochip system capable of continuous monitoring drugs and biomarkers in blood, or in sub-cutaneous districts would constitute a major breakthrough in molecular medicine for personalizing therapy of complex diseases. To this end the following project aims will be pursued: (i) development of innovative sensors towards array drugs detection, including nanotechnology to improve sensor’s sensitivity and system level integration to improve sensor’s specificity, (ii) implementation of micro-electronic technology to decrease chip size for implantation in experimental animals (mice) as well as for convenient chip remote powering and data transmission, (iii) testing on an experimental model for a specific medical situation in which drugs toxicity and development of new therapies would benefit from the chip application, (iv) investigation of biochemical enzymes-substrates pharmacokinetics to identify the best P450 isoforms over more than 3.000 possible to be integrated onto the biochip to assure the detection of those exogenous and endogenous compounds which are relevant for the considered medical application. The project requires a strong convergence between micro-nano-bio-medical technologies. To address at best all these multidisciplinary demands, the project partnership includes experts on: (i) nano-sensing with special focus on P450 biosensors (S.Carrara/EPFL – Engineering), (ii) chip fabrication with focus on implantable systems (Dehollain’s /EPFL- Engineering), (iii) pathophysiology of T-cells for therapy of autoimmune diseases (Grassi’s group/IRB- biomedical), (iv) Pharmakokinetics and drugs side effects (von Mandach’s goup/Univ. Hospital of Zurich – biomedical) The motivation for this project stems from pharmacological treatments with high risk side effects, e.g. toxicity of commonly used drugs, where direct monitoring of the patient’s drug metabolism could dramatically influence pharmacological choices since high variability on a patient-by-patient basis characterizes metabolic pathways , as demonstrated in the literature by the case of nortriptyline. The social relevance of the project is on a better and more reliable diagnostics implantable system to be used also for personalized therapy and for new research in molecular medicine. The Economical Relevance of the project is in the pharmaceutical market. Our fully-electronics implantable biochip will provide a unique tool for industrial advancement in the field of drugs discovery and personalized therapy in Switzerland.

    Hosting organisation:

    Nederlands Vaccin Instituut-NVI
    Antonie van Leeuwenhoeklaan 9-11, PO Box 457, Netherlands

    Coordinator:Ernst Soethout
    IRB Participants:

    Antonio Lanzavecchia, Director

    Research area:

    HEALTH-2007-2.3.3-2 Identifying immunological mechanisms of protection for influenza vaccines

    Duration:01.04.2008 to 31.03.2012
    Website:http://www.imecs-flu.eu

    IMECS is a proposal of the FLUSECURE network aimed at combating the threat of new and re-emerging forms of highly pathogenic influenza in its first stages of a disease by identifying mechanisms of protection that are essential for a solid immune response to avian influenza. IMECS is uniquely featured by correlating research in humans directly to protection from influenza. The IMECS initiative was introduced since the recent H5N1 avian influenza vaccine trials results have shown limited success in inducing a protective immune response as compared to the standard human influenza vaccines.
    This despite large investments and multiple vaccine formulations tested. These results make clear that the mechanisms of immunity for avian influenza are inherently different from those for human/seasonal influenza. The IMECS initiative aims to elucidate these mechanisms and aims to provide essential knowledge for development of breakthrough pandemic vaccines as a result. The initiative thereto boosts the development of AI-correlates of protection for the clinical screening of vaccine candidates in healthy adults and in different target groups, the origin of subclinical AI infection in humans, as well as a research programme for the screening of vaccine candidates in vitro.

    Hosting organisation:

    Humanitas Mirasole, Milan, Italy

    Coordinator:Alberto Mantovani
    IRB Participants:

    Mariagrazia Uguccioni, Group Leader, Vice Director

    Research area:

    FP6- Integrated Project: LSH-2004-1.2.4-2

    Duration:01.11.2005 to 31.10.2010
    Website:http://www.innochem.org

    The general objective of INNOCHEM is to develop innovative chemokine-based therapeutic strategies for autoimmunity and chronic inflammation. The project is based on the scientific excellence of the participants, which have made major recognized contributions to the field since the very beginning of chemokine discovery, and on the construction of shared technological platforms.

    This includes: 

    i) proteomics and 

    ii) transcriptional profiling for the outline of the “chemokinome” in pathophysiological conditions and identification of new antagonists; 

    iii) molecular modelling of agonist/antagonist receptor or agonist/inhibitor interaction, for pharmacology and drug design; 

    iv) gene modified mice for target validation in autoimmune disorders. Genetic, structural, biological, and immunopathological studies will provide a framework for the development of innovative chemokine-based therapeutic strategies. The therapeutic approaches to be investigated are innovative and not limited to conventional antagonists. These will include decoy receptors, agonist binders, and non-competitive allosteric inhibitors.

    INNOCHEM: targeting chemokine/receptor interactions

    INNOCHEM: targeting chemokine/receptor interactions

    In addition to academic groups, therapy-oriented research includes 3 biotech SMEs, 1 medium and 2 big Pharma companies. The companies involved develop complementary non-overlapping approaches to target the chemokine system with recombinant and low molecular weight molecules. INNOCHEM is expected to conduct a “proof of principle” clinical study in volunteers in the first 18 months. The ambition of this project is to re-establish European leadership in basic and applied chemokine research by integrating academic and industrial cutting edge groups to develop innovative therapeutic strategies against autoimmunity and chronic inflammatory disorders.

    Institute for Research in Biomedicine

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