Maarten Witte

About

Maarten Witte is group leader in the Department of Molecular Cell Biology & Immunology and part of the MS center Amsterdam. Throughout his career, he has been fascinated by the interplay between perhaps the two most complex systems in the human body, the immune and central nervous system (CNS), and how neuroinflammation contributes to neuronal damage in neurological diseases. Supported by grants from the US Department of Defense, Institute of Chemical Immunology (NWO) and an MS fellowship from the Dutch MS research foundation, his group aims to elucidate the immunological mechanisms that drive neurodegeneration in several neurological diseases, in particular multiple sclerosis (MS). To disentangle these neurodegenerative pathways, they study human post-mortem tissue and various in vitro and in vivo model systems using both state-of-the-art microscopy and single cell approaches. 

Research Line

Although the central nervous system has traditionally been defined as ‘immune-privileged’, research over the last decades has taught us that there is considerable interaction between the peripheral immune system and the brain in both health and disease. Similarly, we have come to appreciate that CNS-resident immune cells, particularly microglia, are not only involved in protecting the brain from pathogens and clearing debris, but play multiple critical roles in development, homeostasis and degeneration of the CNS. 

Inflammation-driven neurodegeneration in MS

Here, we aim to identify which infiltrated peripheral immune cell subsets drive neurodegeneration in progressive MS and to elucidate the mechanisms involved. We are particularly interested in the role of meningeal immune cells and how they might affect cortical microglia and neurons. Hopefully, this will allow us to identify novel therapeutic targets to stop neurodegeneration in progressive MS, which at present cannot be treated.

Neuron-microglia crosstalk in health and disease

Recent literature suggests that direct, physical interaction between microglia and neurons is essential in maintaining neuronal function during brain homeostasis, and can be both neuroprotective and neurodegenerative under neuroinflammatory & neurodegenerative conditions. We aim to study cause and consequence of this physical interaction in health and disease by using newly developed photoactivatable ligands. These photochemical tools allow us to control the activation of individual microglia in vitro and in vivo and to subsequently assess the interaction between microglia and neurons.

Key publications

  1. van Olst L, Rodriguez-Mogeda C, Picon C, Kiljan S, James RE, Kamermans A, van der Pol SMA, Knoop L, Michailidou I, Drost E, Franssen M, Schenk GJ, Geurts JJG, Amor S, Mazarakis ND, van Horssen J, de Vries HE, Reynolds R, Witte ME. Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration. Acta Neuropathologica 2021 Jun;141(6):881-899.

  2. Rodríguez-Lorenzo S, Konings J, Van der Pol S, Kamermans A, Amor S, Van Horssen J, Witte ME*, Kooij G*, De Vries HE*. Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells. Acta Neuropathologica Communications 2020 Feb 26;8(1):24. * authors contributed equally
  1. Witte ME, Schumacher AM, Mahler CF, Bewersdorf JP, Lehmitz J, Scheiter A, Sánchez P, Williams PR, Griesbeck O, Naumann R, Misgeld T, Kerschensteiner M. Calcium influx through plasma-membrane nanoruptures drives axon degeneration in a model of multiple sclerosis. Neuron 2019 Feb 20;101(4):615-624.
  1. Witte ME, Mahad D, Lassmann H, Van Horssen J. Mitochondrial dysfunction contributes to neurodegeneration in Multiple Sclerosis. Trends in Molecular Medicine 2014 20(3):179-87.
  1. Witte ME, Nijland P, Reijerkerk A, Drexhage JA, Gerritsen WH, Vent I, Van Het Hof B, De Vries HE, Van Der Valk P, Van Horssen J. Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathologica 2013 125(2):231-43.

Group members

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Carla Rodriguez-Mogeda, MSc

PhD student
My research focuses on understanding meningeal inflammation in progressive multiple sclerosis. I am specifically interested in the role of B cells, in how they get to the meninges and how they might interact, directly or indirectly, with other immune cells such as microglia. To do this, I use different single-cell techniques for proteomics and transcriptomics, and confocal and multispectral microscopy. - Your photo (if you

Other PI's

Alsya Affandi: NWO Veni award for nanovaccine and dendritic cells research

Alsya Affandi receives the prestigious Veni grant of 280,000 euros from The Dutch Research Council NWO, for his research in developing nanovaccines for treatment of cancer and autoimmunity.

Our immune system is key for protection against pathogens and malignant cells. Impairment of the immune system can lead to failure to clear viral or bacterial infection, or to prevent tumor development. On the other hand, uncontrolled immune responses can also lead to the development of chronic autoimmune diseases. Dendritic cells (DCs) are the master regulators of immune system with tremendous immunotherapy potential, however current DC-based therapies are still lacking effectiveness in treating these diseases.

To overcome this challenge, Alsya Affandi’s research proposal “Nanotrivax: three-component nanobody-vaccines targeting human dendritic cells for immunotherapy” aims to use nanobodies to deliver vaccine components specifically towards DCs. 

The NWO talent programme awards the Veni funding to highly promising young scientists who have recently obtained their PhDs that will enable them to develop their own ideas in the period of three years. From the ENW and ZonMW domains, 89 researchers have been awarded these grants, in which Alsya Affandi is among the four laureates from Amsterdam UMC.

 

 

Febe van Maldegem

About

Febe van Maldegem is group leader in the Department of Molecular Cell Biology & Immunology. Her work focusses on the complex role of the tumour microenvironment in non-small cell lung cancer (NSCLC), crucial for mediating anti-tumour immunity, but more frequently imposing resistance to therapy. Key to her work is the use of highly multiplex technologies, such as Imaging Mass Cytometry with which the tumour microenvironment can be studied in great detail, revealing the activation states as well as the spatial context of the many cells within the tissue. Febe van Maldegem’s research program, supported by award of the Amsterdam UMC fellowship, aims to improve therapeutic options for patients with non-small cell lung cancer by rationalising the design of combination, mindful of the important role for the tumour microenvironment in determining success.

Research Lines

The NSCLC TME as biomarker and therapeutic target

In order to understand how we can manipulate the TME to benefit therapeutic strategies, we will first need to better understand the dynamics within this complex system. This research line asks the basic questions: How does the TME evolve over time during tumour development, and what are the selective forces that drive this evolution? In several in vivo models for non-small cell lung cancer we study the changes in TME composition, at early time points from tumour onset into advanced tumour stages and under different experimental conditions. Imaging Mass Cytometry will provide detailed phenotypic and spatial characterisation of the cellular relationships in the tissue. The resulting spatial TME profiles will be used to generate biomarkers for response to therapy and to design novel therapeutic targets aimed at disrupting or enhancing cellular interactions. 

Video, sequentially highlighting 15 out of the 27 markers this small lung tumour was stained for using Imaging Mass Cytometry (CX3CR1, PECAM, aSMA, EPCAM, B220, CD103, LY6G, CD8, CD4, CD11c, CD68, F480, CD45, CD44, MHC-II)

Rationally combining chemoradiotherapy with immune checkpoint inhibitors (ICI)

Neoadjuvant (chemo)radiotherapy (CRT) is the current  standard of care for low grade NSCLC, but the field is moving towards combinations with ICI. Chemotherapy and radiotherapy can benefit immune responses by inducing immunogenic cell death, but can also be toxic to the immune cells. We will assess the impact of this treatment combination by analysing patient samples from current clinical trials, comparing different combinations of these therapies in pre- and post-treatment biopsies. In vitro and pre-clinical studies will be used to optimise the treatment dosing and scheduling, to provide a rational basis for design of the next generation of clinical trials.  

Key publications

Mugarza E, van Maldegem F, Boumelha J, Moore C, Rana S, Sopena ML, East P, Ambler R, Anastasiou P, Clavijo PR, Valand K, Cole M, Molina-Arcas M, Downward J. Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers. Preprint in bioRxiv, October 19, 2021.  doi: 10.1101/2021.10.18.464819, Submitted for publication.

 

Van Maldegem F, Valand K, Cole M, Patel H, Angelova M, Rana S, Colliver E, Enfield K, Bah N, Tsang VSK, Mugarza E, Moore C, Hobson P, Levi D, Molina-Arcas M, Swanton C, Downward J. Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry. Nature Communications. 2021 Oct 8;12. doi: 10.1038/s41467-021-26214-x

 

van Maldegem F, Downward J. Mutant KRAS at the Heart of Tumor Immune Evasion. Immunity. 2020 Jan 14;52(1):14-16. doi: 10.1016/j.immuni.2019.12.013

 

Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, Herbert E, Horswell S, Li LS, Janes MR, Hancock DC, Downward J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999

 

van Maldegem F, Maslen S, Johnson CM, Chandra A, Ganesh K, Skehel M, Rada C. CTNNBL1 facilitates the association of CWC15 with CDC5L and is required to maintain the abundance of the Prp19 spliceosomal complex. Nucleic Acids Res. 2015 Aug 18;43(14):7058-69. doi: 10.1093/nar/gkv643

 

Group members

Other PI's

Gijs Kooij: Pro-resolving lipid mediator Lipoxin A4 reduces neuro-inflammation in MS models

A research group of the multiple sclerosis (MS) Center Amsterdam, led by assistant professor Gijs Kooij, studied the clinical potential of pro-resolving lipid mediator Lipoxin A4 in MS and model systems. They discovered that this lipid mediator not only ameliorated neuro-inflammation, but also that it dampened pro-inflammatory T cell responses in MS patient-derived cells. These results are now published in Cell Reports.

NWO Subsidy for innovative research into mini-brains

 Elly Hol of UMC Utrecht Brain Center and Elga de Vries of Amsterdam UMC receive 1.3 million euro subsidy from NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) for their innovative research into mini-brains!

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The development of drugs for brain diseases is difficult for several reasons. Unfortunately, the blood-brain barrier, which is there to prevent all kinds of undesirable substances from entering the brain, also causes important medicines to be stopped. In addition, animal models with which research is carried out mimic but limit the disease in patients.
 
The research by Elly Hol and Elga de Vries, called CONNECT, aims to develop a human cell model that is closer to the patient than current cell and animal models. They do this by using the latest technology from human stem cells to develop blood-brain barrier cells and link them to mini-brains.

More about the granting of a total of 5 million euros for research into human measurement models on the 
NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) website : https://lnkd.in/d-5A8gC

Sanne Verberk – publication in Frontiers in Immunology on the role of macrophage ACLY in regulating inflammatory responses and disease outcomes

Our second paper on ATP citrate lyase (Acly) is published in Frontiers in Immunology!

In our previous paper we showed beneficial effects of targeting macrophage-specific Acly in the context of atherosclerosis. Here, we showed that despite a marked regulation of inflammatory responses in vitro, macrophage Acly deficiency does not translate into huge alterations in other acute and chronic inflammatory disorders in vivo.

Lynn van Olst – Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Multiple sclerosis (MS) is the most common chronic neurodegenerative and neuroinflammatory disease in young adults and despite availability of many disease-modifying therapies most patients will eventually develop secondary progressive MS. Here, we uncovered two distinct MS-specific phenotypes of brain resident immune cells, microglia, that are driven by local meningeal inflammation and differentially associate with neuronal damage. Results suggest that these phenotypes may occur sequentially during chronic meningeal inflammation and that microglia lose their protective properties over time, leading to neuronal loss. Hence, timely targeting of the processes contributing to microglial activation in the progressive MS cortex provides an interesting therapeutic strategy to combat progressive MS.