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Microfluidics-based analysis of human T cell migration on a single cell level

Applicant Mehling Matthias
Number 154733
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Immunology and Immunopathology
Start/End 01.07.2015 - 30.06.2018
Approved amount 618'171.00
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All Disciplines (2)

Discipline
Clinical Immunology and Immunopathology
Immunology, Immunopathology

Keywords (6)

T cells; single cell; multiple sclerosis; migration; microfluidics; heterogeneity

Lay Summary (German)

Lead
Charakterisierung des Migrationsverhaltens von T-Lymphozyten auf Einzelzellebene
Lay summary

Inhalt und Ziel des Forschungsprojekts

Die Migration von Lymphozyten spielt beim Aufbau von Immunreaktionen eine zentrale Rolle. Ihr liegt ein komplexes und exakt reguliertes Zusammenspiel von Chemokinen genannten Botenstoffen und ihren entsprechenden Rezeptoren auf der Zelloberfläche von Immunzellen zugrunde. Neben dem Aufbau von schützenden Immunreaktionen ist die Migration von Immunzellen aber auch bei der Entstehung von Autoimmunerkrankungen wie der Multiplen Sklerose von grundlegender Bedeutung.

Übergeordnetes Ziel unseres Forschungsprojekts ist es, das Migrationsverhalten von humanen T-Zellen gesunder Probanden und von Patienten mit Multipler Sklerose auf Einzelzellebene mit Hilfe einer von uns entwickelten Microfluidics-Technik zu charakterisieren. Mit Hilfe dieser Technik werden wir zunächst das spontane Migrationsverhalten von aus dem Blut isolierten naiven und Gedächtnis-T-Zellen auf Einzelzellebene zu quantifizieren. In einem nächsten Schritt planen wir die Charakterisierung des Migrationsverhalten von aus dem Nervenwasser isolierten T-Zellen, die zum Grossteil aus dem bei der Multiplen Sklerose entzündeten zentralen Nervensystem stammen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unser Projekt wird zum Verständnis des Migrationsverhaltens von T-Zellen auf Einzelzellebene und somit zum Verständnis adaptiver zellulärer Immunantworten beitragen. Die Untersuchung des Migrationsverhaltens von aus dem Nervenwasser isolierten T-Zellen wird zu einem verbesserte Verständnis der Multiplen Sklerose zugrundeliegenden Mechanismen führen und kann als Basis für neue Therapieansätze dienen.

Direct link to Lay Summary Last update: 03.07.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Growth differentiation factor 15 is increased in stable MS
Amstad Andrea, Coray Mali, Frick Corina, Barro Christian, Oechtering Johanna, Amann Michael, Wischhusen Jörg, Kappos Ludwig, Naegelin Yvonne, Kuhle Jens, Mehling Matthias (2020), Growth differentiation factor 15 is increased in stable MS, in Neurology - Neuroimmunology Neuroinflammation, 7(2), e675-e675.
Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis
Naegelin Y., Rasenack M., Andelova M., Von Felten S., Fischer-Barnicol B., Amann M., Mehling M., Kappos L., Sprenger T., Derfuss T. (2018), Shortening the washout to 4 weeks when switching from natalizumab to fingolimod and risk of disease reactivation in multiple sclerosis, in Multiple Sclerosis and Related Disorders, 25, 14-20.
Nano-scale microfluidics to study 3D chemotaxis at the single cell level
Frick Corina, Dettinger Philip, Renkawitz Jörg, Jauch Annaïse, Berger Christoph T., Recher Mike, Schroeder Timm, Mehling Matthias (2018), Nano-scale microfluidics to study 3D chemotaxis at the single cell level, in PLOS ONE, 13(6), e0198330-e0198330.
Varicella Zoster Virus-Specific T Cell Responses in Untreated Giant Cell Arteritis: Comment on the Article by England et al
Bigler Marc B., Hirsiger Julia R., Recher Mike, Mehling Matthias, Daikeler Thomas, Berger Christoph T. (2018), Varicella Zoster Virus-Specific T Cell Responses in Untreated Giant Cell Arteritis: Comment on the Article by England et al, in Arthritis & Rheumatology, 70(2), 318-320.
Locally Triggered Release of the Chemokine CCL21 Promotes Dendritic Cell Transmigration across Lymphatic Endothelia
Vaahtomeri Kari, Vaahtomeri Kari, Brown Markus, Hauschild Robert, De Vries Ingrid, Leithner Alexander Franz, Mehling Matthias, Kaufmann Walter Anton, Sixt Michael (2017), Locally Triggered Release of the Chemokine CCL21 Promotes Dendritic Cell Transmigration across Lymphatic Endothelia, in Cell Reports, 19(5), 902-909.
A microfluidic device for measuring cell migration towards substrate-bound and soluble chemokine gradients
Schwarz Jan, Bierbaum Veronika, Merrin Jack, Frank Tino, Hauschild Robert, Bollenbach Tobias, Bollenbach Tobias, Tay Savaş, Tay Savaş, Sixt Michael, Mehling Matthias, Mehling Matthias (2016), A microfluidic device for measuring cell migration towards substrate-bound and soluble chemokine gradients, in Scientific Reports, 6, 36440.
The Immune-Metabolic Basis of Effector Memory CD41 T Cell Function under Hypoxic Conditions
Sarah Dimeloe, Matthias Mehling, Corina Frick, Jordan Loeliger, Glenn R. Bantug, Ursula Sauder, Marco Fischer, Réka Belle, Leyla Develioglu, Savas Tay, Anja Langenkamp, Christoph Hess (2016), The Immune-Metabolic Basis of Effector Memory CD41 T Cell Function under Hypoxic Conditions, in The Journal of Immunology, 2016(196), 106-114.

Collaboration

Group / person Country
Types of collaboration
Department of Neurology, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Microfluidics Group, Department of Biosystems Sciences and Engineering, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
25th Cytomeet, Berne Talk given at a conference Migration of dendritic cells in micro&luidic substrate-bound and soluble chemokine gradients 26.01.2016 Bern, Switzerland Mehling Matthias;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Multiple Sklerose: Aus der Forschung für die Praxis German-speaking Switzerland 2019
Talks/events/exhibitions Tag der Biomedizin German-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
179662 Microfluidics based analysis of immune cell navigation modes and migration in non-linear chemokine gradients 01.07.2018 Ambizione

Abstract

To mount a protective immune response, a highly orchestrated positioning of lymphocytes is essential. This intricate process is enabled by a complex and precisely regulated interplay of chemokines/chemokine receptors and adhesion molecules, directing migration of T cells to and within non-lymphoid and secondary lymphoid tissues. Conversely, migration of autoreactive lymphocytes is fundamental to the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Most of our insight into T cell migration is based on the monitoring of bulk cell populations in animal models. For human T cells, a relatively limited set of migration-characteristics have been recapitulated in vitro, again mostly by using bulk cell populations. While important understanding of mechanisms underlying T cell migration derives from these studies, potential heterogeneity of migration between individual cells is not interrogated using this approach. Also, clinical samples containing only small numbers of T cells are not amenable for analysis using classical in vitro migration assays. Specifically, understanding the migration characteristics of CSF-derived T cells in MS patients -the closest routinely accessible approximation to pathogenic cells in this disease- would be of particular interest.In recent years, introduction of microfabrication technologies resulted in the generation of so-called microfluidic devices, which allow monitoring of cells on a single-cell level with high spatio-temporal resolution. Together with the microfluidics group at ETH Zurich, we have developed a microfluidic device specifically designed to studying the migration characteristics of primary human T cells. This device allows the highly precise build-up of chemokine gradients. Characterizing migration properties of individual human CD4+ memory T cells (CD4 TM) ex vivo, we have already established the proof of concept that this technique can overcome previous limitations of standard migration assays.The General Aim of this proposal is to explore the migration characteristics of primary human T cells from blood and/or cerebrospinal fluid from patients with MS and controls on a single cell level. Linking this information with clinical information carries the potential to establish a functional immune profile comprising data on T cell parameters with an established role in disease pathogenesis.
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