ESR 1: Initiate a pilot prevention trial in individuals at high risk for developing rheumatoid arthritis

PhD research

Host:

Dr Ronald van Vollenhoven

PI | Professor and Chair | MD PhD

Amsterdam Rheumatology and immunology Center (ARC)

Rheumatology & Clinical Immunology

Location AMC | D3-220 | Meibergdreef 9 1105 AZ Amsterdam

T: +31205668998  |  E: This email address is being protected from spambots. You need JavaScript enabled to view it.

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

Duration: 48 months

Background

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease of unknown etiology. In the majority of affected individuals the disease is chronic with a life-long need for treatment. Individuals at high risk (>80%) of developing RA in the following 2 years can now be identified using a combination of clinical and laboratory-based variables. Therefore, it is of great interest to determine if an immunomodulatory treatment can prevent the disease. To demonstrate this, a randomized clinical trial is needed.

Approach 

High-risk individuals are encountered in rheumatology practice and may also be actively recruited through existing patients (family history being a risk factor). The ESR will work on the design of a clinical trial for such individuals, including developing the structure of the trial, seeking input from all stakeholders (such as at-risk individuals and patients), formatting according to standard protocols, obtaining the necessary approvals, and developing a recruitment plan. The ESR will actively recruit participants to the trial, obtain informed consent, and liaise with the clinical team to ensure that the study procedures are followed. Participants will also be asked to consent to collecting biomaterials, including synovial and lymph node tissues when applicable.  

Our research team

Working together within the Amsterdam Rheumatology and immunology Center (ARC) and being embedded in the Amsterdam Infection & Immunity Institute (AI&II) gives us excellent opportunities to work closely together with both rheumatologists as well as immunologists on clinical and translational research projects. Collaboration with the large group of rheumatologists within the ARC as well as with the funding and patient advocacy organization ReumaNederland provides access to at-risk individuals. 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. 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. 

Your profile

We are looking for a highly motivated and enthusiastic researcher with:

  • - A master degree in Biomedical Sciences or similar
  • - Demonstrated interest in or affinity for autoimmune diseases research
  • - You have a flexible, pro-active team spirit but you can also work independently
  • - You like to show initiative and you have talent for focus and organization
  • - You have excellent communications skills in English, both written and verbal.

Our offer

All ARCAID ESRs receive a full employment contract for 4 years, according to the Collective Employment Agreement (CAO) of the Dutch University Medical Centres. The monthly salary based on a 36-hour work starts from €2.422,- with yearly increments to a maximum of € 3.103,-. This 4-year PhD position is funded by the  Marie Skłodowska-Curie actions of the European Union's Horizon 2020 COFUND program under grant agreement No 847551. There is no separate budget available for mobility as it is already included in the ESR salary. ESRs may attend external courses, conferences or workshops. If applicable or required, additional expenses for training and conference participation and the travel to a Partner Organisation will be covered by the project. The ESR salary meets the requirements of the Dutch Immigration Department to allow family members to move to the Netherlands. It is at the convenience of the ESR to decide on this family movement since the Amsterdam UMC will not cover additional expenses regarding mobility of spouse nor for the required accompanying residence permits. In addition to their individual scientific projects, all fellows will have the opportunity to attend international progress meetings, scientific conferences and summer schools. Additionally, they benefit from further continuing education, which includes internships and secondments, a variety of training modules as well as transferable skills courses. See recruitment procedure.

Your application

See recruitment procedure. You can apply using the online application form. For more information about the project you can contact Dr. Ronald van Vollenhoven.

ESR 2: Clinical studies of treating-to-target in patients with systemic lupus erythematosus

PhD research

Host:

Dr Ronald van Vollenhoven

PI | Professor and Chair | MD PhD

Amsterdam Rheumatology and immunology Center (ARC)

Rheumatology & Clinical Immunology

Location AMC | D3-220 | Meibergdreef 9 1105 AZ Amsterdam

T: +31205668998  |  E: This email address is being protected from spambots. You need JavaScript enabled to view it.

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

Duration: 48 months

Background

Systemic lupus erythematosus (SLE) is an uncommon chronic autoimmune disease of unknown etiology. In the majority of affected individuals the disease is chronic with a life-long need for treatment, and despite treatment outcomes have been disappointing. An expert panel has recommended that treatment should be based on the T2T principle in order to obtain better outcomes, but to demonstrate this formally, a randomized clinical trial is needed. 

Approach 

Patients with SLE will be recruited through our outpatient clinics and through referrals. The ESR will work on the design of the clinical trial, including developing the structure of the trial, seeking input from all stakeholders (including patients), formatting according to standard protocols, obtaining the necessary approvals, and developing a recruitment plan. The ESR will actively recruit participants to the trial, obtain informed consent, and liaise with the clinical team to ensure that the study procedures are followed. Participants will also be asked to consent to collecting biomaterials, including synovial and lymph node tissues when applicable.

Our research team

Working together within the Amsterdam Rheumatology and immunology Center (ARC) and being embedded in the Amsterdam Infection & Immunity Institute (AI&II) gives us excellent opportunities to work closely together with both rheumatologists as well as immunologists on clinical and translational research projects. Collaboration with the large group of rheumatologists within the ARC as well as with the funding and patient advocacy organization ReumaNederland provides access to sufficient numbers of patients. 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. 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.

Your profile

We are looking for a highly motivated and enthusiastic researcher with:

  • - A master degree in Biomedical Sciences or similar
  • - Demonstrated interest in or affinity for autoimmune diseases research
  • - You have a flexible, pro-active team spirit but you can also work independently
  • - You like to show initiative and you have talent for focus and organization
  • - You have excellent communications skills in English, both written and verbal.

Our offer

All ARCAID ESRs receive a full employment contract for 4 years, according to the Collective Employment Agreement (CAO) of the Dutch University Medical Centres. The monthly salary based on a 36-hour work starts from €2.422,- with yearly increments to a maximum of € 3.103,-. This 4-year PhD position is funded by the  Marie Skłodowska-Curie actions of the European Union's Horizon 2020 COFUND program under grant agreement No 847551. There is no separate budget available for mobility as it is already included in the ESR salary. ESRs may attend external courses, conferences or workshops. If applicable or required, additional expenses for training and conference participation and the travel to a Partner Organisation will be covered by the project. The ESR salary meets the requirements of the Dutch Immigration Department to allow family members to move to the Netherlands. It is at the convenience of the ESR to decide on this family movement since the Amsterdam UMC will not cover additional expenses regarding mobility of spouse nor for the required accompanying residence permits. In addition to their individual scientific projects, all fellows will have the opportunity to attend international progress meetings, scientific conferences and summer schools. Additionally, they benefit from further continuing education, which includes internships and secondments, a variety of training modules as well as transferable skills courses. See recruitment procedure.

Your application

See recruitment procedure. You can apply using the online application form. For more information about the project you can contact Dr. Ronald van Vollenhoven.

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.

 

ESR 5: Study the molecular and cellular features of human lymph node T cells during the earliest phases of systemic autoimmunity - 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

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease with an unknown etiolology. To ultimately cure or prevent this destructive disease it is essential to understand the earliest changes in the immune system. It is now well established that autoantibodies can be present years before the onset of RA. This indicates that changes in the immune system precede the development of RA and detection of these autoantibodies allows us to identify individuals who are at risk of developing RA. Moreover, we can use these individuals characterized by having systemic autoimmunity but no arthritis, as a model to study the earliest phases of autoimmune disease. In general, immune responses are initiated in lymphoid organs where naïve T cells are activated after antigen recognition presented by antigen presenting cells. Upon activation and influenced by cellular interactions and the cytokine milieu, activated T cells will differentiate towards an inflammatory or regulatory phenotype to ensure an adequate immune response. Since the maintenance of peripheral tolerance to self-antigens and the initiation of adaptive immune responses occur in peripheral lymphoid organs, we set-up a research line focused on studying lymph node (LN) biopsies obtained during the preclinical and earliest phases of RA. T cell responses have been well-studied in peripheral blood and synovial tissues of RA patients. However, not much is known about their initial activation, phenotype and function in LNs during the preclinical and earliest phases of RA and other autoimmune diseases. Recently, we discovered that the frequency and functional capacity of different T cell subsets in both peripheral blood and LN tissue are affected already during the RA-risk phase. A striking discovery in RA-risk and RA patients was the reduced cytokine production in LN T cells (but not blood T cells) upon in vitro stimulation (Ramwadhdoebe et al 2016).

Approach 

We hypothesize that already before the development of autoimmune disease, as a result of loss of tolerance and prolonged antigen exposure, T cells become dysfunctional resulting in an exhaustive phenotype. Longitudinal analyses of RA-risk individuals will determine whether skewed T cell differentiation towards a proinflammatory and/or exhausted phenotype with sustained capacity of delivering B-cell help is associated with changes in autoantibody profile, inflammation and/or disease progression. Using state-of-the-art technologies including flow/mass cytometry, single-cell RNA sequencing and cellular metabolism, the PhD student will determine the frequency, phenotype and function of inflammatory, regulatory and exhausted/senescent T cells in LN biopsies obtained from healthy individuals, RA-risk individuals and RA patients. In addition, the PhD student will delineate the mechanism of the reduced cytokine production observed in LN T cells of RA-risk individuals and RA patients and investigate whether this defect can be restored.  

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 Prof.dr. Niek de Vries.

 

ESR 7: The B cell lineage in ANCA-associated vasculitis: functional characterisation and identification of novel targets

PhD research

Host:

Dr. S.W. Tas

Internist-Rheumatologist

Department of Rheumatology & Clinical Immunology

Laboratory for Experimental Immunology

Amsterdam UMC, location AMC

Meibergdreef 9

Duration: 48 months

Background

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe systemic autoimmune disease affecting small-sized blood vessels. B lineage cells play a crucial role in AAV, as activated ANCA-producing B lineage cells are present in inflammatory lesions. Moreover, serum BAFF levels and activated peripheral blood (PB) B cells are higher in patients with active disease compared to patients in remission and healthy donors (HD), and there is a clear correlation between serum BAFF levels and ANCA titers. Both newly generated proliferating, short-lived plasmablasts or plasma cells (PCs) in the blood or lymph node (LN)/spleen and long-lived memory PCs residing in survival niches in the bone marrow (BM) or inflamed tissues can secrete autoantibodies. However, detailed studies on B lineage cells in LN and BM compartments are hitherto largely lacking in AAV.

The important role of B lineage cells in AAV is further substantiated by clinical trials with the B cell-depleting monoclonal antibody rituximab (anti-CD20) demonstrating efficacy both in the induction and maintenance of remission in AAV patients. Nevertheless, rituximab targets not only pathogenic B cells and short-lived plasmablasts/PCs, but also regulatory B cells. Furthermore autoreactive long-lived PCs in the BM that have an important role in chronicity of disease by persistent autoantibody production are not depleted, suggesting B-cell-independent long-term survival of some PCs. With the exception of the proteasome inhibitor bortezomib, current immunosuppressive treatments do not deplete long-lived PCs.

Several signal transduction pathways such as Bruton's tyrosine kinase (BTK), Syk, JAK/STAT, MAPK, PI3K, and nuclear factor (NF)-κB have been described to play an important role in B cell responses. The NF-κB family of transcription factors has a key role in the regulation of immune responses and dysregulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases. NF-κB signalling can be activated via two activation pathways. The canonical pathway is dependent on inhibitor of κB (IκB) kinase (IKK)β and controls NF‐κB activation in response to pro‐inflammatory stimuli, such as cytokines and Toll-like receptor ligands, but also in response to BCR or TCR activation. The noncanonical NF‐κB pathway, which is regulated by NF-κB-inducing kinase (NIK), can be activated by members of the TNF-R superfamily such as CD40, TACI, BCMA and BAFF-R, and is crucial in shaping adaptive immune responses. Proliferation, survival and maturation of B cells is largely noncanonical NF-κB signalling dependent. Importantly, transcription factors of the noncanonical pathway are required for germinal center (GC) B-cell development, and analysis of human tonsillar tissue revealed that PCs and their precursors in the GC expressed increased noncanonical NF-κB activity. Furthermore, PCs depend on the TNF-R superfamily ligands BAFF and a proliferation-inducing ligand (APRIL; binds to TACI) for survival and antibody production.

Our unpublished studies demonstrate that novel small molecule NF-κB inhibitors significantly reduced T cell-dependent and -independent B proliferation in PBMC cultures, whereas T cell proliferation was largely unaffected. Furthermore, this also resulted in reduced CD27highCD38high plasmablast differentiation. However, we will also identify other signalling pathways that are important in B cell responses and generate novel small molecule inhibitors.

Aim: to identify and target signalling pathways in B lineage cells that promote proliferation, differentiation into (long-lived) PCs and/or maintenance of these cells in lymph node or bone marrow niches, and autoantibody production thereby contributing to disease activity in AAV.

Approach 

  1. To functionally characterise signalling pathways in B lineage cells from AAV patients in different compartments of the immune system
  1. To investigate the immunological and downstream molecular effects of targeting these signalling pathways in AAV B lineage cells
  1. To study the effects of targeting the identified signalling pathways in an animal model of AAV

All required expertise is present in our department. State-of-the art assays to investigate B cell function are up and running. Moreover, we have access to CyTOF PhosphoFlow and have access to novel highly selective small molecule inhibitors of various signalling pathways. ChIP- and RNA-sequencing are also regularly performed in our department. For the in vivo part of this proposal we collaborate with Prof. Pusey (Imperial College, London, UK) to study the potential of targeting signalling pathways in B cells in an animal model of AAV.

Expected results

The proposed research will provide valuable information on the role of signalling pathways in B cells and identify novel genes in B cells regulated by these pathways using RNA- and ChIP-sequencing. In addition, these studies will reveal immunological and molecular differences between HD and AAV patients. A better understanding of the importance of various signalling pathways in B lineage cells may open up new strategies for therapeutic intervention in AAV and possibly also other autoimmune diseases characterised by autoantibody production like primary Sjögren’s Syndrome, SLE and RA. This is particularly important in systemic autoimmune diseases as good therapies for these patients are currently often lacking and consequently there is a high unmet need.

Our research team

The Amsterdam Rheumatology & immunology Center, AMC/University of Amsterdam (Head: Prof.R.F. van Vollenhoven) is recognized as a NFU Center of Expertise for vasculitis and has extensive experience with fundamental and translational immunological research. The proposed project will be supervised by Dr. S.W. Tas, an expert in signal transduction and immunology. He received a NWO Veni grant in 2008, followed by a ZonMw Clinical Fellowship in 2011. These grants enabled him to develop a novel research line “The role of signalling pathways in chronic inflammation” and to build an (independent) research group. Besides working as a rheumatologist, he heads the AMC bioplatform and currently supervises 6 PhD-students, a postdoc and a technician. Dr. Tas is also member of the steering group of the ARCH vasculitis consortium that aims to improve care for patients with vasculitis. Dr. J.P. van Hamburg is a senior-postdoc in the group of Dr. Tas who obtained expertise on immunology, including the analysis of T-B-cell interaction, and molecular biology at the Erasmus MC (Rotterdam) and the University of California (San Diego, USA). The current project will be done in close collaboration with the group of Prof. C.D. Pusey (Imperial College School of Medicine, London, UK) who has extensive experience in a versatile animal model of ANCA-associated vasculitis. The proposed research will be performed primarily in the Laboratory for Experimental Immunology of the AMC (Head: Prof. T. Geijtenbeek).

Your profile

  • Candidates should have
  • - a Master’s degree in biomedical sciences, medical or molecular biology, or medicine
  • - The candidate needs to demonstrate advanced skills in laboratory methods, ideally evidenced by experience with cell culture, molecular assays, flow cytometry, and/or RNA sequencing
  • - Excellent higher education track record and strong scientific curiosity.
  • - Fluent spoken and written English skills
  • - Good social skills

In addition, the following experience would be helpful, but not essential:

  • - Certification and experience of working with animals
  • - Experience with health services research methods

We seek a highly motivated scientist who enjoys an interdisciplinary environment and an interdisciplinary project, able to work independently but also as part of a team.

Our offer

All ARCAID ESRs receive a full employment contract for 4 years, according to the Collective Employment Agreement (CAO) of the Dutch University Medical Centres. The monthly salary based on a 36-hour work starts from €2.422,- with yearly increments to a maximum of € 3.103,-. This 4-year PhD position is funded by the  Marie Skłodowska-Curie actions of the European Union's Horizon 2020 COFUND program under grant agreement No 847551. There is no separate budget available for mobility as it is already included in the ESR salary. ESRs may attend external courses, conferences or workshops. If applicable or required, additional expenses for training and conference participation and the travel to a Partner Organisation will be covered by the project. The ESR salary meets the requirements of the Dutch Immigration Department to allow family members to move to the Netherlands. It is at the convenience of the ESR to decide on this family movement since the Amsterdam UMC will not cover additional expenses regarding mobility of spouse nor for the required accompanying residence permits. In addition to their individual scientific projects, all fellows will have the opportunity to attend international progress meetings, scientific conferences and summer schools. Additionally, they benefit from further continuing education, which includes internships and secondments, a variety of training modules as well as transferable skills courses. See recruitment procedure.

Your application

See recruitment procedure. You can apply using the online application form. For more information about the project you can contact Dr Sander Tas.