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Group van Wijk

Research interests

Chronic inflammatory disorders such as Inflammatory Bowel Disease (IBD) and Juvenile Idiopathic Arthritis (JIA) represent a major health burden affecting over 10 million people in Europe alone. Current treatments suppress but do not cure disease, and there is still a fundamental gap in our understanding of how inflammation persists. My group focuses on T cell development, regulation and plasticity in health and chronic inflammation and addresses conceptual and mechanistic immunological questions with a strong link to the clinic. We are especially interested in what happens locally, in the (inflamed) tissues. We combine front-running profiling techniques such as (single-cell) RNA-sequencing, epigenetics, TCR sequencing, and CyTOF with (customized) functional assays. The ultimate goal is to break the self-sustaining loop of chronic inflammation.

 

Projects:

 

T cell regulation in chronic inflammation

Juvenile idiopathic arthritis (JIA) is one of the most common childhood chronic inflammatory diseases with serious disability and loss of quality of life. During local treatment, synovial fluid (SF) containing high numbers of immune cells is aspirated, providing a unique model to compare blood T cells with cells from the local inflammatory environment. Under healthy conditions regulatory T cells (Treg), control and down-regulate immune responses to prevent excessive tissue damage. There is still a fundamental gap however in our understanding of immune regulation and development in (autoimmune) inflammatory settings. One of our key findings has been that not intrinsic Treg defects, but instead, T effector cells that become resistant to suppression by Treg are the main reason for impaired T cell regulation at the site of inflammation and we are currently investigating the mechanisms of resistance induction. In addition we are investigating clonal expansion and “hyper-specialization” of Treg under inflammatory conditions (collaboration Dr. B. Vastert, Dr. J. van Loosdregt).

 

Tissue T cells

Inflammation itself is mostly evident in specific target tissues such as the intestine in IBD. In recent years, the novel concept of tissue resident T cells that have undergone specific tissue-instructed differentiation has emerged. Because of their long-term persistence in tissue they are likely culprits for relapses of tissue inflammation. Additionally, derailment of local regulatory processes, involving (unique) tissue resident Treg, may also foster disease. We are only beginning to understand human tissue T cell functional specialization, and my lab has optimized T cell tissue/tissue exudate isolation techniques that allow access to these satellite control rooms of persistent inflammation and relapse. To define common pathways of differentiation and possible derailment we are currently comparing T cells from different tissues (amongst others gut, skin, muscle, uterus, joint) and from multiple inflammatory diseases (collaborations Dr. B Oldenburg, Dr. B van Rijn, Dr. A. van Royen, Dr. D. Hijnen)

 

Naïve T cells

Naïve CD4 T cells represent the foundation of the total differentiated CD4 T cell pool and live up to 20 times longer than effector/memory T cells. They have long been regarded as relatively quiescent cells, but this has recently been challenged by the identification of IL-8 production as a signatory effector function of human naïve T cells. By investigating the naïve T cell department in thymectomized children (collaboration with Dr. N. Jansen) my lab has now demonstrated that naïve CD4 T cells can functionally differentiate without becoming classical effector CD4 T cells. Therefore, chronic inflammation may have profound effects on the naïve CD4 T cell compartment and thereby contribute to disturbed CD4 T cell homeostasis. We are currently investigating the differentiation of human naïve T cells in healthy, inflammatory and lymphopenic settings.

 

Ctrl-alt-delete: autologous hematopoietic stem cell transplantation for autoimmune disease.

The only therapy so far that can induce a long-term drug-free remission in refractory IBD but also in other chronic inflammatory diseases such as JIA is autologous HSCT. Although the underlying mechanisms are incompletely understood, extensive immune ablation followed by autologous stem cell infusion seems to be able to rewire a faulty immune system. My group has shown in an animal model for syngeneic SCT in autoimmune disease, that renewal of both CD4 Teff and Treg compartments are crucial for the restoration of the immune balance. Furthermore, we have recently demonstrated that also in patients, HSCT induces functional renewal of the circulating Treg compartment. Together with the Gastroenterology department (Dr. B. Oldenburg) we are currently collecting  patient material (blood and tissue biopsies) from a clinical study on HSCT for refractory Crohn’s patients to get insights on the effect of HSCT on both circulating T(reg) and tissue resident T(reg) cells, and relate this to clinical outcome.

Keypublications

  1. van den Broek T, Delemarre E, Janssen W, Nievelstein R , Broen J, Tesselaar K, Borghans J, Nieuwenhuis E , Prakken B , Mokry M , Jansen N, van Wijk F. Neonatal Thymectomy reveals Differentiation and Plasticity within Human Naïve T-cells. J Clin Invest, 2016 Mar 1;126(3):1126-36Schadenberg AWL, van den Broek T, Siemelink MA, Algra SO, de Jong PR, Jansen NJG, Prakken BJ, van Wijk F. Differential homeostatic dynamics of human Treg cell subsets following neonatal thymectomy J Allergy Clin Immunol. 2014 Jan;133(1):277-280. > View publication
  2. Delemarre E*, van den Broek* T, Mijnheer G, Prakken B, Spierings E, van Wijk F. Autologous SCT benefits autoimmune patients through Treg functional renewal and TCR diversificationBlood 2016 Jan 7;127(1):91-101  * equally contributed > View publication
  3. Petrelli A, Wehrens E, Scholman R, Prakken B, Vastert S, van Wijk F. CD8 T cell resistance to suppression at the site of autoimmune inflammation is self-sustained and can be reversed by TNF-a and IFN-g blockade. Arthritis and Rheumatol2016 Jan;68(1):229-36. doi: 10.1002/art.39418. > View publication
  4. Delemarre E, Roord S, van den Broek T, Zonneveld-Huijssoon E, de Jager W, Rozemuller H, Martens A, Broere F, Wulffraat N, Glant T, Prakken B, van Wijk F. Autologous stem cell tranplantation restores immune tolerance in experimental arthritis by renwal and modulation of the Teffector compartment. Arthritis Rheumatol2014 Feb;66(2):350-6. > View publication
  5. Wehrens EJ, Mijnheer G, Duurland CL, Klein M, Meerding J, van Loosdregt J, de Jager W, Sawitzki B, Coffer PJ, Vastert B, Prakken B, van Wijk F. Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood 2011 Sep 29;118(13):3538-48. > View publication

Members Group van Wijk

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Phd students

Students

Collaboration with clinical principle investigators