ESR 6:Mesenchymal stromal cells as key orchestrators in RA. - POSITION FILLED

PhD research

Host:

Dr Lisa van Baarsen

PI | Associate Professor | PhD

Amsterdam Rheumatology and immunology Center (ARC)

Rheumatology & Clinical Immunology

Experimental Immunology

Location AMC | K0-105 | Meibergdreef 9 1105 AZ Amsterdam

T: +31205668043  |  E: This email address is being protected from spambots. You need JavaScript enabled to view it.

http://ams-rc.com/medewerkers/baarsen/

Duration: 48 months

Background

Mesenchymal stromal cells (MSC) not only provide structure to tissues but control immune cell activation in an organ-specific manner. The regulatory and cell intrinsic networks controlling this organ-dependent MSC function are unclear. These organ-specific MSC capacities may be exploited for therapeutic purposes for example in rheumatoid arthritis (RA). Synovial tissue MSC of RA patients are characterized by their proinflammatory proliferative phenotype and epigenetic modifications, while bone marrow MSC of RA patients display a reduced capacity to support haematopoiesis. However, the exact mechanism of these organ-specific MSC defects is not clear and it is unknown whether this MSC defect is induced by inflammation, or should be considered as a primary event occurring in a pre-clinical stage.

We propose that MSC in lymphoid organs and synovial tissue are defective before onset of RA and a key driver in the development of RA. Because of their crucial function in regulating immune responses, we postulate that such malfunctioning MSC create a tissue-specific microenvironment in which immune cells are not properly controlled leading to the development of RA. To study this we have access to a unique cohort of prospectively followed RA-autoantibody positive individuals at risk of developing RA from who synovial, lymph node and bone marrow samples are collected. Preliminary data obtained in our research group by studying synovial and lymph node biopsies of these RA-risk individuals suggest stromal cell activation before onset of disease, supporting our hypothesis.

Approach 

Key objectives are: 1. Phenotyping and comparing tissue-specific MSC during health and disease, starting from a discovery-based genomics approach; 2. Investigating whether tissue-specific MSC-mediated effects on immune cell activation are altered before onset of RA, by performing co-culture experiments of MSC with immune cells; 3. MSC modulation as a tool to normalize altered immune responses observed in RA(risk).

Our research team

It is our ambition to unravel the molecular and biological processes leading to systemic autoimmune diseases by studying unique human lymphoid and synovial tissue biopsies obtained during the pre-clinical and earliest phases of rheumatoid arthritis. These studies will lay the foundation for the development of novel therapies to prevent and treat this chronic disabling immune-mediated autoimmune disease.

Working within the recently established Amsterdam Rheumatology and immunology Center (ARC) and being embedded within the Amsterdam Infection & Immunity Institute (AI&II) gives us the excellent opportunity to work closely together with both rheumatologists as well as immunologists on translational research projects. Collaboration with several rheumatologists within the ARC enables the use of unique biomaterials from patients with different stages and types of autoimmune diseases. For our research program lymph node biopsy procedures are performed in close collaboration with the department of Radiology, while synovial tissue biopsies are routinely collected within our department. Bone marrow biopsy procedure will be performed in collaboration with haematologist Dr. Hazeberg of the Department of Haematology. We have a close collaboration with Prof.dr. Mebius (VUMC) who has a strong track record in lymph node immunobiology using sophisticated in vivo lymph node transplantation models. We are involved in several national and international research projects, allowing excellent possibilities for collaborations with other research groups in academia as well as industry. 

This multidisciplinary research environment empowers state-of-the-art immunological studies during various stages of autoimmunity as well as the translation of our findings into novel therapeutic approaches. The vanBaarsen group currently consists of 5 PhD students (2 at VUMC), 1 postdoc (at VUMC) and 2 research technicians. This project will be performed in close collaboration with ARCAID PI’s Prof.dr. Antoine van Kampen and Prof. dr. Reina Mebius.