• Key note lectures

    Drugs & Microbes

    Peter Pickkers

    immunoparalysis associated with sepsis

    About a decade ago it was thought that suppressing the initial inflammatory and cytokine response in sepsis could be beneficial. This has led to several clinical trials, which without exception were negative. Recently it has become clear that during sepsis patients also develop a form of immunoparalysis. In this phase patients are immunecompromised and patients may die because of secondary infections. Consequently , restoring the immune response might be a useful strategy in these patients. In Nijmegen translational research is performed on this subject. Professor Peter Pickkers is a pioneer on this area. He uses a model in which healthy volunteers are exposed to endotoxin during a short period of time. This model can be used to investigate mechanisms and possible future treatments for immunoparalysis associated with sepsis.

    Benjamin Marsland

    The importance of host-microbe interactions in respiratory diseases

    Pulmonary immune homeostasis is maintained by a network of tissue resident cells that continually monitor the external environment, and in health, instruct tolerance to innocuous inhaled particles while ensuring efficient and rapid immune responses can be mounted against invading pathogens. We recently found that in mouse models of allergic airway inflammation both changes in diet and the microbiota had profound effects upon immune homeostasis and inflammation. In particular, the following two concepts became evident. First, there are windows of development early in life that, if altered, can set the immune system on a trajectory towards allergy later in life; second, changes in the intestinal microbiota and consequently the systemic metabolome can influence the nature of immune responses in the lung. In this context, the current understanding of the impact of the microbiota in immune development and function, and in the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung will be discussed. It is proposed that host interactions with microbes are critical for establishing the immune landscape of the lungs, and represent targets for future therapeutics.

    Marc Bonten

    Importancy of good bugs - Microbes and the Immune System

    Ton Rijnders

    Success stories from the European Lead Factory

    The European Lead Factory (ELF) is a public–private partnership supported by the Innovative Medicines Initiative (IMI). In the past 5 years, it has provided researchers throughout Europe with a unique platform for translation of innovative biology and chemistry into high-quality starting points for drug discovery. It combines high-throughput screening (HTS) infrastructure and hit follow-up capabilities with an exceptional collection of small molecules to advance research projects from both private companies and publicly funded researchers. Established in 2013, its unique collaborative model has so far resulted in >6,000 hit compounds with a defined biological activity from over 100 successfully completed HTS and hit evaluation campaigns, >200,000 novel innovative screening compounds that complement the 327,000 compounds contributed by the big pharma, >30 protein–ligand structures, two patents and two start-up biotech’s. Intrinsic to its setup, ELF has and will enable breakthroughs in areas with unmet medical and societal needs such as Anti-Microbial Resistance, where no individual entity would be able to create a comparable impact in such a short time.

    The presentation will highlight some successful case studies from the target programme portfolio, including drug discovery programmes within the field of Anti-Microbial Resistance and an outlook towards the future of the European Lead Factory.

    Jan Kluytmans

    Control of antimicrobial resistance in healthcare and the environment

    Antimicrobial resistance is one of the main challenges facing our global human population today. Excessive use of antibiotics in healthcare as well as in livestock farming is associated with the mergence of drug-resistant microbes that are taking an increasing toll on human health. New antibiotics have not been developed since the 1980s and are not foreseen on short notice.

    The Netherlands is one of few countries that has been able to keep resistance rates low by a restrictive use of antibiotics in humans and pro-active infection control policy in healthcare facilities. After the turn of the century resistance emerged in livestock production and this was associated with increasing resistance in humans. The veterinarians and livestock producers have reacted by reducing the use of antibiotics dramatically (±70%). This and other strategies to prolong the effectiveness of antibiotics will be discussed.

    Ulrich Förstermann - Ariëns lecture

    Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis

    Expert in the regulation of vascular functions. He has contributed to the identification of eNOS and eNOS-controlled oxidative stress. He has 430 publications on his name and a H-factor of 84, including a PNAS article with> 870 citations, he also contributed> 60 publications with more than 100 citations and 50 book (chapters) From pharmacologists. In addition to leading scientist, he is an ambassador to pharmacology and has led the German Pharmacology Association for many years and has been president of the EPHAR (European Pharmacology Association).

    Martine Smit

    Viral hijacking of receptor proteins​

    Pathogenic herpesviruses hijack and alter cellular signaling after viral infection through expression of viral G protein-coupled receptors (GPCRs). These viral GPCRs show highest homology to chemokine receptors, which are known to involved in the immune system but are also involved in the development of cancer. We have shown that several viral GPCRs, including the CMV-encoded chemokine receptors, signal in a constitutive manner, rewire proliferative and inflammatory signaling pathways and reprogram energy metabolism. Interestingly, expression of these receptors has been detected in tumor samples of glioblastoma patients and its expression induced tumor formation in orthotopic xenograft model systems.

    Altogether, by modulating inflammatory and proliferative signaling pathways, viral GPCRs may effectively rewire cellular signaling networks and contribute to tumour progression. Insight into these mechanisms is crucial for the treatment of virus-associated pathologies.

    Christian Ottman

    Peptides modulating protein interactions

    Protein-protein interactions (PPIs) are mediated very often between a well-folded, globular protein interacting with a peptide motif from its partner protein. This makes synthetic peptides derived from recognition motifs involved in PPIs excellent first generation PPI inhibitors. The class of 14-3-3 adapter proteins are a good example for being involved in the aformentioned PPIs, binding for example to peptide recognition motifs of Tau (Alzheimer's Disease), LRRK2 (Parkinson's Disease), C-Raf (Cancer), CFTR (Cystic fibrosis), and ExoS (Infection). We show, how structural knowledge of these interfaces can be used for the design of potent peptidic PPI modulators.

    Simon Rozendaal

    Medicines as a motor of progress

    Since 1800 progress in the world has been staggering. People are wealthier, hunger has diminished, air and water-pollution are almost gone and life expectancy has doubled. Many factors have contributed tot his unchallenged leap forward, one of them being medicines and vaccines. Simon Rozendaal tries to analyse what that contribution is. Rozendaal is a chemist by education, has been science writer for over 40 years (Elsevier and NRC Handelsblad), has published many articles on medicines and the pharmaceutical industry and has written two optimistic books on progress in the world.

    Albert Heck - Galien lecture

    The Dark Side of the Proteasome, and its impact on Cancer Immunotherapy

    In the cells of our body the proteasome generates from self- and foreign proteins the epitopes that are presented by human leukocyte antigen (HLA) class I molecules at the outer surface. When these peptides are foreign/pathogenic or tumour-associated neo-antigens they can recruit specific cytotoxic T cells eliciting an immune response, ultimately destroying the infected/cancer cells. Mass spectrometry based immunopeptidomics represents presently the method of choice to survey the on the cell surface presented HLA-ligandome, in a quest to detect antigens of pathogenic or tumour origin.

    So far, these peptide antigens were thought to correspond to linear sequences directly originating from the cellular proteins targeted to the proteasome for destruction. However, besides cutting proteins into pieces the proteasome can also cut and paste, termed proteasomal splicing, which potentially generates novel epitopes not representing the original protein/gene. We recently observed that proteasome-generated spliced peptides can account for one-third of the entire HLA class I immunopeptidome. These peptides could only be identified by using a novel mass spectrometry based peptide sequencing technique developed by us and by using a supercomputer facility used to search the big data.

    The widespread appearance and abundance of proteasome-catalysed peptide splicing events has implications for immune-biology and autoimmunity theories and may provide a previously untapped source of epitopes for use in vaccines and cancer immunotherapy.

    TBA - IMI (Innovative Medicines Initiative)

    DRIVE-AB (Driving reinvestment in research and development and responsible antibiotic use)

    DRIVE-AB is tasked with defining responsible use of antibiotics, identifying the antibiotic-related public health priorities, calculating the societal value of having new antibiotics available for these priorities, developing and costing new economic models to promote the desired antibiotic innovation, and sustainable use of the resulting, novel antibiotics. The purpose of the project is to transform the way policymakers stimulate antibiotic innovation and to ensure that these new antibiotics are used sustainably and available equitably

     

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