Current research

A vast number of our genes has evolved to provide the immune system with appropriate arms to combat a large variety of pathogens. In the past decades, molecular characterization of pathways that regulate intercellular (membrane receptors, cytokines) and intracellular (apoptosis and signalling cascades, gene regulation) communication has contributed tremendously to progress in immunology. Importantly, this molecular knowledge has provided insight into the pathogenesis many immune mediated diseases diseases. More recently, translation of these new insights into immuno-intervention strategies have been made. This field of immunotherapy is highly successful and rapidly expanding.

The Department of Experimental Immunology has focus on molecular and cellular immunology. Within the department fundamental research is combined with translational and clinical research in the areas of transplantation immunology, rheumatology, hemato-oncology, pediatric immunology, allergy, pulmonary immunology, and viral immunology. In addition, we use findings from our various research programs to innovate our diagnostic tools.

Research areas

The various research areas that cooperate in an integrated fashion within the department are listed below. Click on the title for more information.


Our group at the Dept of Experimental Immunology has studied apoptosis regulation in normal and pathological immune cells since 2002. Since 2014, we are expanding our research lines to include wider fundamental and translational aspects in Immuno-Hematology. We study human and (genetically modified) murine tissues in two themes of research, centered around Chronic Lymphocytic Leukemia. Our projects are sponsored by NWO, DCF, the European Union, private funding agencies, the AMC foundation and we collaborate in sponsored research agreements with pharmaceutical companies.

In addition, three NWO Veni laureates started their projects in 2014, of which two have finished: Felix Wensveen studied selection of high affinity T and B cells, and Victor Peperzak investigated regulation of pro-survival Mcl-1 in malignant B cells, and has moved to the University of Utrecht end of 2015. Rianne van der Windt studies Immunometabolism (see dedicated sections below).

Theme 1. Hemato-oncological work on Chronic Lymphocytic Leukemia (CLL), in close collaboration with hematologist dr Arnon Kater. We study three interrelated areas:

a) CLL genetics and molecular diagnostics (PhDs Alexander Leeksma and Zhenghao Chen, technicians Ingrid Derks and Dieuwertje Luijks)

b) The leukemic microenvironment and novel drugs (Postdoc Erik Slinger, PhDs Fabio Brocco, Marco Haselager, Raquel Delgado, technican Hanneke ten Burg)

c) Interaction between the immune system and CLL (PhDs Iris de Weerdt, Tom Hofland, Anne Martens, technican Sanne Terpstra and MD Sanne Tonino)

Theme 2 Shaping the immune response. We study the adaptive immune response, in particular the function of B and T lymphocytes. The ultimate goal of this research is to apply the insight obtained in novel vaccination strategies and immunotherapies. We focus on two topics:

a) Clonal diversity and affinity (Veni laureate Felix Wensveen)

b) Cellular metabolism (PhD Armando van Bruggen, Veni laureate Rianne van der Windt and MD Arnon Kater)

Theme 1 Hemato-oncological work on CLL

a) CLL genetics and molecular diagnostics. Mutations or deletions of the tumor suppressor p53 or its upstream kinase ATM are prime determinants of poor prognosis in CLL. We have implemented an in-house RT-MLPA probe kit to detect functional defects in these pathways (1-3). These studies were performed in close collaboration with the European Research Initiative on CLL (ERIC). In addition, we are analysing the novel deleterious mutations that have been described in recent years in CLL in Notch, SF3B1 and MyD88 genes. We have reported our findings on the effects of SF3B1 mutation on the DNA damage response (4), and will continue this work by Alexander Leeksma. A novel project will investigate the effects of CLL cancer mutations on the metabolism of the leukemic cells (Zhenghao Chen).

b) The leukemic microenvironment and novel drugs. Most research on CLL is done on cells obtained from peripheral blood of patients. Yet, these cells do not represent the cycling CLL cells that reside in so-called proliferation centres in lymph nodes and bone marrow. There, they are protected from apoptosis and more resistant against cancer therapeutics. It is generally assumed that chemo-resistant clones from those sites cause the inevitable relapses that occur in this disease.

  • We study peripheral blood CLL cells in co-culture systems that mimick the chemoresistant and/or proliferative situation in lymph nodes using CD40 and cytokines which represent T cell signals (5).
  • A recently finished project has studied other components of the microenvironment, such as the effects of monocytic cells on CLL cells (6, 7).
  • Two novel projects will address important signaling pathways (BCR, CD40, TLR9) from the cell surface to NF-kB and CLL survival (Marco Haselager, Raquel Delgado)
  • The best studied model for CLL is the TCL-1 transgenic mouse. The BH3-only protein Noxa is overexpressed in CLL (7), and its expression is lower in lymph node than in peripheral blood (8), which suggests that is linked with survival and/or drug sensitivity. We found decreased lifespan of Tcl-1/NoxaKO mice (see figure 1), confirming a role for Noxa in CLL pathobiology (8). In addition, together with various pharmaceutical companies, we have started to investigate combined Ibrutinib and Venetoclax treatment in the TCL1 model.
  • Novel treatments. Pre-clinical studies to assess the efficacy of novel drugs and drug combinations that might circumvent chemoresistance. Compounds we are currently studying various BH3 mimetics (see figure 2), kinase inhibitors, novel CD20 and CD40 antibodies (9-11).
  • Side studies of Clinical trials– to be updated soon!

Figure 1:

Crossing NoxaKO mice with CLL-prone Tcl-1 transgenic mice shows accelerated mortality in Noxa/KO/Tcl-1 mice. (Erik Slinger unpublished)
Crossing NoxaKO mice with CLL-prone Tcl-1 transgenic mice shows accelerated mortality in Noxa/KO/Tcl-1 mice. (Erik Slinger unpublished)

Figure 2:

CLL cells cultured under conditions intended to mimic the lymph node environment become insensitive for ABT-737, a so-called BH3 mimetic drug that targets Bcl-2 and Bcl-XL. (Rachel Thijssen unpublished)
CLL cells cultured under conditions intended to mimic the lymph node environment become insensitive for ABT-737, a so-called BH3 mimetic drug that targets Bcl-2 and Bcl-XL. (Rachel Thijssen unpublished)

c) Interaction between the immune system and CLL. CLL is characterized by an immune dysfunction, which is presumed to result from aberrant functioning of both T cells as well as (leukemic) B cells. These conclusions are based on non-specific activation experiments of lymphocytes in vitro. In contrast, we recently demonstrated that the function of virus-specific T cells was still intact in CLL samples (see figure 3) (12). This demonstrates that the changes in T cell characteristics in CLL are more heterogeneous than presently assumed.

Several new immunotherapeutic strategies for CLL (e.g. immune checkpoint blockade and adoptive transfer of chimeric antigen receptor (CAR) T-cells) rely on T-cell mediated cell death. Although immune checkpoint blockade and CAR T-cell therapy have shown promising results in Non-Hodgkin lymphoma’s, first trials in CLL have shown only moderate responses thus far. The acquired T-cell dysfunction is generally considered to be responsible for the hampered effectivity of T-cell therapies in CLL. Therefore, understanding the biology of this acquired immune dysfunction in CLL, finding means to restore T-cell function, and identifying populations with retained functionality may provide solutions to improve the efficacy of these novel therapies in CLL patients. We have several ongoing projects on this theme:

  • We aim to thoroughly analyze the bidirectional interactions between CLL and T cells in the context of chronic viral infections, by studying how CLL affects the composition and function of (virus-specific) T cells and why various virus-specific T cells may be differentially affected by CLL.
  • We study subsets of cytotoxic immune cells (including gd T cells and NK cells) with specific characteristics which may make them excellent mediators in immune therapy.
  • In collaboration with the VUmc we explore novel forms of antibodies (nanobodies) for use in immunetherapy for CLL

Figure 3:

Interferon-γ production by CMV-specific T cells from healthy controls (HC) or CLL patients is comparable. CLL B cells are poor antigen presenters. (From te Raa et al Blood 2013)
Interferon-γ production by CMV-specific T cells from healthy controls (HC) or CLL patients is comparable. CLL B cells are poor antigen presenters. (From te Raa et al Blood 2013)

Theme 2 Shaping the immune response – ongoing work

a) Clonal diversity and affinity – Felix Wensveen. A key feature of the adaptive immune system is that it consists of millions of clones, each unique in its ability to bind antigen through its dedicated receptor. This system ensures an ability to recognize many different molecular structures of pathogens. However, its biological implication is that any given antigen activates many different clones which differ in their specificity and efficiency towards the invading pathogen. Systems must therefore be in place to select cells based on their antigen-affinity, in order to prevent wasting resources on cells of suboptimal efficiency. In B cells, we investigated how antigen-affinity selects for high-affinity clones in the first days after B cell activation. We found that B cell receptor affinity correlates with induction of the receptor for BAFF, an important cytokine that promotes B cell survival. BAFF stabilizes the pro-survival protein Mcl-1 through the PI3K signalling pathway. High-affinity B cells are therefore positively selected due to an increased ability to sustain Mcl-1 levels in response to BAFF. For memory T cells, increased diversity may in fact be beneficial in a recall response. T cells with sub-optimal specificity for the original infectious agent have an enhanced probability of recognizing re-infecting pathogens that have acquired mutations in their immune-dominant epitopes. Indeed, the memory cell pool is much more clonally diverse than the effector pool directed towards a given antigen. We investigated how this diversity is established and what control its boundaries. We find that low-affinity memory precursors proliferate less, but express higher levels of the transcription factor Eomes than cells of high affinity. In CD8 T cells, Eomes directly regulates the pro-survival protein Bcl-2, thus providing them with a survival advantage. This ensures that, despite their lower proliferation rate, low-affinity cells make a significant contribution to the memory cell pool.

b) Cellular metabolism. Recent studies have revealed the importance of metabolic processes for immune cell function (13, 14). In the tumor microenvironment tumor and T cells can interact, and may compete for nutrients, which can restrain T cell function. We perform several parallel studies:

  • We study how components of the tumor microenvironment impact CLL cell metabolism, and will use this knowledge for the rational design of novel therapies.
  • Since T cell function is impaired in CLL, we aim to elucidate alterations in T cell metabolism in CLL and determine their impact on T cell function. Initial findings show that CD8 T cells from CLL patients use more mitochondrial metabolism (oxidative phosphorylation) compared to T cells from age-matched healthy donors (see figure 4). In response to T cell receptor stimulation, CLL T cells show impaired switching to glycolysis. We currently further address how these metabolic changes develop, and how we can reverse those to improve T cell therapies.
  • We have previously established the importance of mitochondrial biogenesis and fatty acid oxidation during memory T cell formation. We currently aim to determine and target the underlying mechanisms regulating these processes in T cells in order to identify pathways for immune-therapeutics.

Figure 4:

Increased oxygen consumption rates in CD8 T cells derived from a CLL patient compared to T cells from  an age-matched healthy donor (van Bruggen unpublished)
Increased oxygen consumption rates in CD8 T cells derived from a CLL patient compared to T cells from an age-matched healthy donor (van Bruggen unpublished)

Group members


Prof. dr. Eric Eldering PhD

Prof. dr. Arnon P.Kater MD PhD

Dr. Sanne Tonino MD PhD


Dr Erik Slinger
Dr Felix Wensveen (Veni laureate– finished February 2017, transferred to Croatia)
Dr Rianne van der Windt (Veni laureate, expected finish end 2017)

PhD Students

Martijn H.A. van Attekum - obtained PhD in January 2017

Rachel Thijssen MSc – obtained PhD in November 2016

Iris de Weerdt

Tom Hofland

Alexander Leeksma

Armando van Bruggen

Fabio Brocco

Raquel Delgado

Anne Martens

Marco Haselager

Zhenghao Chen


Ing. Ingrid A.M. Derks

Sanne Terpstra

Hanneke ter Burg MSc

Dieuwertje M.P. Luijks


1. E E, C.A. S, H.L. A, A G, I.A. D, A.F. dV, McElgunn CJ, and J.P. S. Expression profiling via novel multiplex assay allows rapid assessment of gene regulation in defined signaling pathways. Nucleic Acid Research. 2003;31(23):e153.
2. Te Raa GD, Malcikova J, Mraz M, Trbusek M, Le Garff-Tavernier M, Merle-Beral H, Greil R, Merkel O, Pospisilova S, Lin K, et al. Assessment of TP53 functionality in chronic lymphocytic leukaemia by different assays; an ERIC-wide approach. Br J Haematol. 2014;167(4):565-9.
3. Te Raa GD, Malcikova J, Pospisilova S, Trbusek M, Mraz M, Garff-Tavernier ML, Merle-Beral H, Lin K, Pettitt AR, Merkel O, et al. Overview of available p53 function tests in relation to TP53 and ATM gene alterations and chemoresistance in chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(8):1849-53.
4. Te Raa GD, Derks IA, Navrkalova V, Skowronska A, Moerland PD, van LJ, Oldreive C, Monsuur H, Trbusek M, Malcikova J, et al. The impact of SF3B1 mutations in CLL on the DNA-damage response. Leukemia. 2014.
5. Pascutti MF, Jak M, Tromp JM, Derks IA, Remmerswaal EB, Thijssen R, van Attekum MH, van Bochove GG, Luijks DM, Pals ST, et al. IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells. Blood. 2013;122(17):3010-9.
6. van Attekum M, Terpstra S, Reinen E, Kater AP, and Eldering E. Macrophage-mediated chronic lymphocytic leukemia cell survival is independent of APRIL signaling. Cell death discovery. 2016;2(16020.
7. van Attekum MH, Terpstra S, Slinger E, von Lindern M, Moerland PD, Jongejan A, Kater AP, and Eldering E. Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia. Oncogene. 2017.
8. Slinger E, Wensveen FM, Guikema JE, Kater AP, and Eldering E. Chronic lymphocytic leukemia development is accelerated in mice with deficiency of the pro-apoptotic regulator NOXA. Haematologica. 2016;101(9):e374-7.
9. Peperzak V, Slinger E, Ter Burg J, and Eldering E. Functional disparities among BCL-2 members in tonsillar and leukemic B-cell subsets assessed by BH3-mimetic profiling. Cell death and differentiation. 2016.
10. Thijssen R, Slinger E, Weller K, Geest CR, Beaumont T, van Oers MH, Kater AP, and Eldering E. Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors. Haematologica. 2015.
11. Thijssen R, Ter Burg J, Garrick B, van Bochove GG, Brown JR, Fernandes SM, Rodriguez MS, Michot JM, Hallek M, Eichhorst B, et al. Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood. 2016;128(4):574-83.
12. Te Raa GD, Pascutti MF, Garcia-Vallejo JJ, Reinen E, Remmerswaal EB, Ten Berge IJ, van Lier RA, Eldering E, van Oers MH, Tonino SH, et al. CMV-specific CD8+ T cell function is not impaired in chronic lymphocytic leukemia. Blood. 2013.
13. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, and Pearce EL. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68-78.
14. van der Windt GJ, and Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev. 2012;249(1):27-42.


For further information about our research and opportunities for work or collaborations, you can contact Prof. dr. Eric F. Eldering

+31 (0)20 566 7018

Macrophage Biology and Adhesion-GPCRs

Principal Investigator

Jörg Hamann, PhD

Macrophage Biology

Macrophages are innate immune cells with well-established roles in tissue homeostasis, primary response to pathogens, coordination of adaptive immunity, and even wound repair. Macrophages accomplish these varied roles by adapting their gene and protein expression programs in response to endogenous and exogenous environmental cues, such as cytokines and pathogen-associated molecular patterns. The ability of macrophages to change their gene and protein signatures falls under the umbrella of a developing concept: macrophage plasticity. Plasticity is naturally at the basis of macrophage heterogeneity in basal and inflammatory conditions but also at the basis of worldwide efforts to treat diseases by subverting aberrant macrophage activation. Macrophage-mediated inflammation is increasingly recognized to contribute to chronic inflammatory disorders, such as chronic obstructive pulmonary disease, severe asthma, rheumatoid arthritis, and multiple sclerosis. We are studying the cellular program and function of human tissue macrophages in health in disease. To this we collaborate with Dr. Kris Reedquist, Dr. Marco van Eijk, Dr. Rene Jonkers (all AMC, Amsterdam), Dr. Inge Huitinga (NIN, Amsterdam), and Dr. Fernando Martinez (University of Oxford, UK).


G protein-coupled receptors (GPCRs) represent the largest superfamily of receptors in the human genome. Present on every cell and responding to a plethora of stimuli, GPCRs are involved in a great variety of physiological processes. Phylogenetic comparison has led to the GRAFS classification, which divides GPCRs into five classes called Glutamate, Rhodopsin, Adhesion, Frizzled/taste, and Secretin. The adhesion class comprises 33 members in humans with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and various tumor cells.

Adhesion-GPCRs possess a juxtamembranous GPCR proteolysis site (GPS) that facilitates autocatalytic processing into an extracellular N-terminal fragment (NTF) and a 7TM/cytoplasmic C-terminal fragment (CTF), which subsequently remain associated. Only recently, it became clear that the autoproteolysis site is part of a much larger ~320-residue GAIN (GPCR autoproteolysis-inducing) domain that forms a non-covalently associated heterodimer upon proteolysis. The cartoon shows the general design and terminology of Adhesion-GPCRs based on cleavage (left) and topology (right).

Despite their wide distribution and some dramatic phenotypes resulting from lack or gain of function, Adhesion-GPCRs are ‘functional orphans’. Little is known regarding how these unusual GPCRs are activated, which is due to uncertainty about the role of the identified binding partners and the cooperation between the NTF and the CTF of the receptors. Recent studies imply that adhesion through the NTF and signaling through the CTF may be separated activities and demonstrate the ability of Adhesion-GPCRs to modulate the activity of other receptors in a ligation-independent manner.

After having cloned and deorphanized CD97 in the mid 90th, work on Adhesion-GPCRs expressed by cells of the immune system became a major research focus at our laboratory. We have studied the structure, expression, evolution, ligand specificity, and function of these receptors in humans and mice, thereby using molecular tools and mouse models developed in our laboratory. Using the CD97-CD55 interaction as a model, we recently proved the interaction of an Adhesion-GPCR with its endogenous binding partner in vivo. Our findings strengthen the hypothesis that Adhesion-GPCRs adhere and signal independently through their two subunits.

Our current work focuses on the function and mechanism of action of Adhesion-GPCRs on immune cells, thereby exploring CD97 and GPR56 as models. We have close and long-lasting collaborations with Prof. Siamon Gordon (University of Oxford, UK), Prof. Gabriela Aust (University of Leipzig, Germany), Prof. Hsi-Hsien Lin (Chang Gung University, Taiwan), Dr. Martin Stacey (University of Leeds, UK), Dr. Tobias Langenhan (University of Würzburg, Germany), and other members of the international Adhesion-GPCR Consortium (AGC, Our final goal is to utilize the potential of Adhesion-GPCRs for human health.

Group members

Jörg Hamann, PhD
Kirstin Heutinck, PhD
Cheng-Chih Hsiao, MSc
Hanneke de Kort, PhD

Former group members:
Martijn van de Garde, MSc
Dennis Flierman, PhD
Robert Hoek, PhD
Else Kop, MD, PhD
Olga Karpus, PhD
Mark Kwakkenbos, PhD
Mourad Matmati, PhD
Henrike Veninga, PhD
Walter Pouwels, Ing

Current undergraduate students:

Students are welcome to perform research internships within our group. We permanently have projects available for medical students and students in the master programs Immunology, Medical Biochemistry, Medical Biology and Biology.

Selected publications

Hamann, J., G. Aust, D. Araç, F.B. Engel, C. Formstone, R. Fredriksson, R.A. Hall, B.L. Harty, C. Kirchhoff, B. Knapp, A. Krishnan, I. Liebscher, H.H. Lin, D.C. Martinelli, K.R. Monk, M.C. Peeters, X. Piao, S. Prömel, T. Schöneberg, T.W. Schwartz, K. Singer, M. Stacey, Y.A. Ushkaryov, M. Vallon, U. Wolfrum, M.W. Wright, L. Xu, T. Langenhan, H.B. Schiöth (2015). International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharm. Rev. 67: 338-67.

Van de Garde, M.D.B., F.O. Martinez, B.N. Melgert, M.N. Hylkema, R.E. Jonkers and J. Hamann (2014). Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction. J. Immunol. 192: 1196-208. Highlighted in Nature Rev. Immunol. 14: 66 (2014).

Melief, J., K.G. Schuurman, M.D. van de Garde, J. Smolders, M. van Eijk, J. Hamann and I. Huitinga (2013). Microglia in normal appearing white matter of multiple sclerosis are alerted but immunosuppressed. Glia 61: 1848-61.

Smolders, J., E.B.M. Remmerswaal, K.G. Schuurman, J. Melief, C.G. van Eden, R.A.W. van Lier, I. Huitinga and J. Hamann (2013). Characteristics of differentiated CD8+ and CD4+ T cells present in the human brain. Acta Neuropathol. 126: 525-35.

Aust, G., C. Kerner, S. Gonsior, D. Sittig, H. Schneider, P. Buske, M. Scholz, N. Dietrich, S. Oldenburg, O.N. Karpus, J. Galle, S. Amasheh and J. Hamann (2013). Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth. Mol. Biol. Cell 24: 2256-68.

Langenhan, T., G. Aust and J. Hamann (2013) Sticky signaling – Adhesion class G protein-coupled receptors take the stage. Sci. Signal. 6: re3.

Karpus, O.N., H. Veninga, R.M. Hoek, D. Flierman, J.D. van Buul, C.C. vandenAkker, E. vanBavel, M.E. Medof, R.A.W. van Lier, K.A. Reedquist and J. Hamann (2013). Shear stress-dependent downregulation of the adhesion-G protein-coupled receptor CD97 on circulating leukocytes upon contact with its ligand CD55. J. Immunol. 190: 3740-8.

Heutinck, K.M., A.T. Rowshani, J. Kassies, N. Claessen, F.J. Bemelman, E. Eldering, R.A.W. van Lier, S. Florquin, I.J.M. ten Berge and J. Hamann (2012). The viral dsRNA sensors TLR3, MDA5 and RIG-I induce pro-inflammatory, anti-viral and pro-apoptotic responses in human renal tubular epithelial cells. Kidney Int. 82: 664-75.

Melief, J., N. Koning, K.G. Schuurman, M.D. van de Garde, J. Smolders, R.M. Hoek, M. van Eijk, J. Hamann and I. Huitinga (2012). Phenotyping primary human microglia: Tight regulation of LPS responsiveness. Glia 60: 1506-17.

Gordon, S., J. Hamann, H.H. Lin and M. Stacey (2011). Celebrating 30 years: F4/80 and the related adhesion-GPCRs. Eur. J. Immunol. 41: 2470–525.

Hoek, R.M., D. de Launay, E.N. Kop, A.S. Yilmaz-Ellis, F. Lin, K.A. Reedquist, J.S. Verbeek, M.E. Medof, P.P. Tak and J. Hamann (2010). Deletion of either CD55 or CD97 ameliorates arthritis in mouse models. Arthritis Rheum. 62: 1036-42.

Veninga, H., S. Becker, R.M. Hoek, M. Wobus, E. Wandel, J. van der Kaa, M. van der Valk, A.F. de Vos, H. Haase, B. Owens, T. van der Poll, R.A.W. van Lier, J.S. Verbeek, G. Aust and J. Hamann (2008). Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration. J. Immunol. 181: 6574-83.

Hamann, J., N. Koning, W. Pouwels, L. Ulfman, M. van Eijk, M. Stacey, H.H. Lin, S. Gordon and M.J. Kwakkenbos (2007). EMR1, the human homolog of F4/80, is an eosinophil-specific receptor. Eur. J. Immunol. 37: 2797-2802.

Kwakkenbos, M.J., M. Matmati, O. Madsen, W. Pouwels, Y. Wang, R. Bontrop, P.J. Heidt, R.M. Hoek and J. Hamann (2006). An unusual mode of concerted evolution of the EGF-TM7 receptor chimera EMR2. FASEB J. 20: 2582-4.

Kop, E.N., M.J. Kwakkenbos, G.J.D.Teske, M.C. Kraan, T.J. Smeets, M. Stacey, H.H. Lin, P.P. Tak and J. Hamann (2005). Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue. Arthritis Rheum. 52: 442-50.

Leemans, J.C., A.A. te Velde, S. Florquin, R.J. Bennink, K. de Bruin, R.A.W. van Lier, T. van der Poll and J. Hamann (2004). The EGF-TM7 receptor CD97 is required for neutrophil migration and host defense. J. Immunol. 172: 1125-31.

Hamann, J., M.J. Kwakkenbos, E.C. de Jong, H. Heus, A.S. Olsen and R.A.W. van Lier (2003). Inactivation of the EGF-TM7 receptor EMR4 after the Pan-Homo divergence. Eur. J. Immunol. 33: 1365-71.

Hamann, J., J.O. Wishaupt, R.A.W. van Lier, T.J. Smeets, F. Breedveld and P.P. Tak (1999). Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum. 42: 650-8.

Hamann, J., C. Stortelers, E. Kiss‑Toth, B. Vogel, W. Eichler and R.A.W. van Lier (1998). Characterization of the CD55 (DAF)‑binding site on the seven‑span transmembrane receptor CD97. Eur. J. Immunol. 28: 1701-7.

Hamann, J., B. Vogel, G.M.W. van Schijndel and R.A.W. van Lier (1996). The seven‑span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J. Exp. Med. 184: 1185-9.

Hamann, J., W. Eichler, D. Hamann, H.M.J. Kerstens, P.J. Poddighe, J.M.N. Hoovers, E. Hartmann, M. Strauss and R.A.W. van Lier (1995). Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven‑span transmembrane molecule of the secretin receptor superfamily with an unusual extracellular domain. J. Immunol. 155: 1942-50.

Hamann, J., H. Fiebig and M. Strauss (1993). Expression cloning of the early activation antigen CD69, a type II integral membrane protein with a C‑type lectin domain. J. Immunol. 150: 4920-7.

For a full list with publication klick here.


For further information about our research and opportunities for work or collaborations, you can contact Dr. Jörg Hamann

+31 (0)20 566 6080

Viral Immune Pathogenesis

The research group of Dr. Neeltje Kootstra (Head Laboratory of Viral Immune Pathogenesis) focuses mainly on virus-host interactions in HIV-1, HBV and HCV infection and pathogenesis. We also participate in the Amsterdam Cohort studies, the AGEhIV cohort study and COBRA and as part of these studies, we maintain the biobanks and perform cohort-related research (Clinical monitoring).

HIV-1 evolution

HIV-1 has a high genetic variability and can vary with respect to biological properties such as coreceptor usage, cell tropism, and replication rate. The reverse transcriptase machinery of the virus creates mutations and mutant viruses may be selected if they have an advantage over coexisting virus variants that lack the mutation. For instance, in the presence of CTL, virus variants will be selected that accidentally have mutations in the CTL epitope, providing the virus with an escape mechanism.

In the past, we have focused on the evolution of virus variants that differed with respect to co-receptor usage. Early in infection, HIV-1 variants that only use C-C chemokine receptor 5 (CCR5; R5 variants) predominate. With progression of disease, virus variants that use C-X-C receptor 4 (CXCR4; X4 variants) emerge in about 50% of individuals.

Our current research focuses on the effect of the adaptive (e.g. CTL, antibodies) and innate immunity (e.g. restriction factors) on HIV-1 evolution and the effect of escape mutations on viral replication fitness.

Host cell factors involved in HIV-1 infection

The natural course of HIV-1 infection is widely variable with extremes of disease progression within 2 years (rapid progressors, RP) or continuous asymptomatic infection for more than 15 years (long term non progressors, LTNP). We have studied several reported polymorphisms in relation to HIV susceptibility and disease progression in the Amsterdam cohort. For example, a 32 base pair deletion in the CCR5 gene correlated with delayed disease progression, whereas a polymorphism in the tripartite interaction motif 5 gene (Trim5), that affects the antiviral activity of the Trim5a protein, was associated with an accelerated disease progression.

Recently, a number of new host factors have been identified by our group in 1.) a genome wide single nucleotide polymorphism (SNP) analysis on associations with HIV-1 pathogenesis; 2.) genome wide SNP analysis on HIV-1 susceptibility of macrophages; 3.) genome wide transcriptional analysis of macrophages in association with HIV-1 susceptibility; and 4.) genome wide miRNA-analysis on HIV-1 susceptibility of macrophages. The identified host factors (HIV-1 dependency and restriction factors) are currently under study for their role in HIV-1 replication and HIV-1 pathogenesis.

Viral hepatitis

HBV is a small enveloped DNA virus belonging to the Hepadnaviridae group. It replicates through an intermediate RNA molecule that is reversely transcribed into a partially double-stranded circular DNA genome. The HBV-encoded polymerase is error prone, theoretically enabling the virus to quickly evolve under selection pressure, such as the adaptive immune response and antiviral therapy. This mechanism is limited by the fact that the HBV genome largely consists of overlapping genes. People with chronic HBV infection are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Current treatment of chronic HBV infection consists of nucleoside analogues, which inhibit virus replication at the step of reverse transcription, and interferon alpha, which has both an antiviral and immunomodulatory effect.

HCV is a small enveloped single-stranded RNA virus belonging to the Flaviviridae family. Due to the high error rate of the viral RNA-dependent RNApolymerase, HCV has a high mutations rate and rapidly adapts to host immune responses and suboptimal treatment regiments. The current treatment for patients with HCV consist of combination therapy with interferon alpha, a nucleoside inhibitor and an HCV protease inhibitor. The success rate of the treatment is highly dependent on the HCV genotype and on the response to previous treatment. New insights in the HCV life cycle, has resulted in the development of many promising antiviral agents that interfere with HCV infection and replication. Some of these agents act directly on viral proteins, such as NS3/4A protease and NS5B RNA-dependent polymerase, whereas others target host factors that are essential for HCV replication, such as miR-122 or cyclophilin A.

In collaboration with Prof. H. L. Zaaijer (Blood-borne Infections, Sanquin Amsterdam) and Dr. H. Reesink (Gastro-enterology Dept., AMC, Amsterdam), we study the role of viral and host factors (e.g. genetics and immunological) in viral replication and in response to antiviral therapy in chronic hepatitis patients.


For further information please contact

Dr. Neeltje Kootstra (Head LVIP)

+31 (0)20 566 8298

Host Defense

Principal Investigators

Prof. Dr. Teunis Geijtenbeek, PhD
Dr. Sonja Gringhuis, PhD

Host Defense

The research in our group is focused on identifying the molecular mechanisms involved in the human host defense against pathogens.

We focus on specific professional antigen presenting cells called dendritic cells (DCs), which are present at critical barriers in our body, such as skin and mucosa, to survey the surrounding environment for invading pathogens. These DCs are not only crucial in inducing adaptive immunity but are also involved in innate immunity. DCs recognize pathogens through innate receptors and the subsequent signaling dictates the induction of adaptive immune responses by T cells. However, several pathogens, such as HIV-1, have subverted the function of DCs for their own dissemination in the host.

Therefore, elucidation of the molecular mechanisms involved in pathogen recognition and subsequent adaptive immunity will be instrumental in identifying general molecular processes as well as helping to counteract infections, such as preventing HIV-1 from hijacking DCs.

Our multidisciplinary research involves identification of pattern recognition receptors and intracellular signaling pathways that control infection and innate and adaptive immune responses to pathogens. In particular we investigate the role of C-type lectin receptors expressed by DC subsets in the interaction with pathogens.

We study the human immune system and therefore use primary DCs to perform our experiments. We generate monocyte-derived DCs from blood and isolate different DC subsets from skin that we obtain from plastic surgery via a long standing collaboration with the Boerhaave Medical Center Amsterdam ( Recently we have started to investigate mucosal DC subsets in vaginal tissues that we obtain from plastic surgery. The use of ex vivo tissue infection models as well as primary DC subsets allows us to create models that closely resemble the in vivo situation.

We use a great variety of techniques from the fields of virology, biochemistry, molecular biology, cell biology and immunology.

Group members

Prof. Dr. Teunis Geijtenbeek (Principal investigator)
Dr. Sonja Gringhuis (Associate Professor)
Dr. Carla Ribeiro (Assistent Professor)
Ramin Sarrami-Forooshani (PhD student)
Joris Sprokholt (PhD student)
Maartje Nijmeijer (PhD student)
Nienke van Teijlingen (PhD student)
Nina Hertoghs (PhD student)
Melissa Stunnenberg (PhD student)
Leane Helgers (PhD student)
Tanja Kaptein (technician)
Ester Zijlstra-Willems (technician)
John van Hamme (technician)

Former lab members
Dr. Michiel van der Vlist
Sietske Galama
Dr. Alex Nabatov
Dr. Annemarie Lekkerkerker
Dr. Irene Ludwig
Dr. Jeroen van Dunnen
Dr. Lot de Witte
Manja Litjens
Dr. Marein de Jong
Dr. Stella Koppel
Dr. Angelic van der Aar
Annelies Mesman
Dr. Brigitte Wevers
Dr. Daniele Amadio

Selected publications

Top 5 selected publications as senior author.

1. Ribeiro CM, Sarrami-Forooshani R, Setiawan LC, Zijlstra-Willems EM, van Hamme JL, Tigchelaar W, van der Wel NN, Kootstra NA, Gringhuis SI, Geijtenbeek TB. (2016). Receptor usage dictates HIV-1 restriction by human TRIM5alpha in dendritic cell subsets. Nature 540: 448-52 . (IF 38.1)

2. Gringhuis SI, Hertoghs N, Kaptein TM, Zijlstra-Willems EM, Sarrami-Fooroshani R, Sprokholt JK, van Teijlingen NH, Kootstra NA, Booiman T, van Dort KA, Ribeiro CM, Drewniak A, Geijtenbeek TB. (2017). HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3. Nat Immunol 18: 225-35. (IF 19.4)

3. Geijtenbeek TB, Gringhuis SI. 2016. C-type lectin receptors in the control of T helper cell differentiation. Nat Rev Immunol 16: 433-48 . (IF 39.4)

4. Gringhuis,S.I., Kaptein,T.M., Wevers,B.A., Theelen,B., van,d., V, Boekhout,T., and Geijtenbeek,T.B. (2012). Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1beta via a noncanonical caspase-8 inflammasome. Nat. Immunol. 13, 246-254; . (IF 26.2).

5. Gringhuis,S.I., van de Vlist, M., van den Berg,L.M., den,Dunnen, J., Litjens,M., and Geijtenbeek,T.B. (2010). HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat. Immunol. 11, 419-426. (IF 26.2)


For further information about our research and opportunities for work or collaborations, you can contact Prof. Teunis Geijtenbeek

+31 (0)20 566 6063

Lung Immunology

Principal Investigator

René Lutter, PhD


Asthma and chronic obstructive pulmonary disease (COPD) are major inflammatory lung diseases. The outstanding issues in relation to treatment, prognosis and cure of asthma and COPD are:

  1. no adequate treatment of acute worsening of symptoms (exacerbation),
  2. unresponsiveness to mainstay of treatment, i.e. corticosteroids, and
  3. tissue remodelling as a consequence of chronic, severe inflammation.

Our basic research efforts are aimed at understanding the molecular mechanisms in inflammation that underlie the exaggerated inflammatory response during an exacerbation, unresponsiveness to corticosteroids and the chronicity of inflammation.

Sarcoidosis is a relatively rare granulomatous disease that in about 25% of diagnoses develops into a chronic or progressive disease. It is unclear which molecular mechanisms determine resolution or perseverance of granulomas. In that context we are addressing the involvement of the immuno-regulatory enzyme indoleamine 2,3-dioxygenase.

Details on these basic research lines are provided below (click on Controlling Inflammation). There are opportunities within our basic research projects for university students (Medical Biology, Medicine) and HLO students (lab technicians) to perform an internship (click on Internships). Our research efforts constitute an integral part of the main research interests of the Department of Respiratory Medicine and thus there is a close collaboration with clinicians and the lung function lab. For these studies we are continuously seeking volunteers (healthy or with mild to moderate asthma) to participate in these studies (if you are interested, please click on Inflammation during an exacerbation). In addition to the basic research we guide and facilitate the laboratory part of clinical studies and we contribute to the diagnosis of interstitial lung diseases and severe asthma. These activities are performed within our CCKL-accredited lab LONI.

The team. From right to left: Saheli Chowdhury, Kimberley Saman, Lara Ravanetti, Suzanne Bal, Marianne van de Pol, Barbara Dierdorp, Annemiek Dijkhuis, Elske van den Berg, Tamara Dekker and René Lutter.
The team. From right to left: Saheli Chowdhury, Kimberley Saman, Lara Ravanetti, Suzanne Bal, Marianne van de Pol, Barbara Dierdorp, Annemiek Dijkhuis, Elske van den Berg, Tamara Dekker and René Lutter.

Controlling Inflammation

The inflammatory process is critical for eradicating endogenous and exogenous challenges and thus for maintaining health. When, however, the extent of inflammation is not in balance with the challenge, inflammation can turn into a potential threat. Too much inflammation can cause tissue destruction whereas too little inflammation may lead to the persistence of the inflammatory stimulus. In either case, this may lead to more inflammation. To balance the inflammatory process, every aspect of inflammation is tightly regulated. This starts at the level of the production of inflammatory mediators that drive inflammation, till the resolution of inflammation by down-regulating inflammatory cell numbers.

IL-17-mediated inflammation

Cells within the lungs such as epithelial cells and fibroblasts are key players in producing inflammatory mediators. The expression of inflammatory mediators is tailored to ensure an adequate but limited inflammatory response, causing as little collateral tissue damage as possible. To that end, expression of inflammatory mediators is controlled transcriptionally as well as post-transcriptionally, which involves mRNA degradation and translational control. Our previous studies have indicated that post-transcriptional control (particularly mRNA degradation) of inflammatory mediator expression by lung structural cells is easily disturbed. In fact, interleukin(IL)-17, which has been implicated in chronic and severe inflammation in several inflammatory diseases among which asthma, directly attenuates degradation of mRNAs that encode for inflammatory mediators. This leads to hyperresponsive inflammatory mediator production and under certain conditions even to unresponsiveness to corticosteroids. Dr. Saheli Chowdhury's studies have revealed that mRNA decay of a number of key inflammatory mediators depends on two pathways, the ARE-mediated mRNA decay pathway and that directed by microRNAs. IL-17 attenuates both mRNA decay pathways by reducing the contribution of the microRNA pathway and changing the relative contribution of various proteins (AUBp) that bind to the AU-rich (AUUUA) elements, preventing its degradation (Figure 1).

Figure 1: How IL-17 attenuates, for example, IL-8 mRNA degradation. In the presence of TNF- IL-8 mRNA is generated which is degraded by destabilizing AUBps (KHSRP, TTP) and microRNA16 (in red). When IL-17 is added, a stabilizing AUBp (AUF-1) binds the majority of IL-8 mRNA and the expression of microRNA16 is reduced. Together this limits IL-8 mRNA degradation.
Figure 1: How IL-17 attenuates, for example, IL-8 mRNA degradation. In the presence of TNF- IL-8 mRNA is generated which is degraded by destabilizing AUBps (KHSRP, TTP) and microRNA16 (in red). When IL-17 is added, a stabilizing AUBp (AUF-1) binds the majority of IL-8 mRNA and the expression of microRNA16 is reduced. Together this limits IL-8 mRNA degradation.

More recent studies have revealed that there may be a defect in these regulatory pathways in bronchial epithelial cells from patients with asthma. Current studies are aimed at delineating this defect and at unravelling the molecular machinery involved in these pathways.

Inflammation during an exacerbation

Respiratory viral infections are a major cause of acute worsening (exacerbation) of asthma and COPD symptoms. In addition, inflammatory responses tend to be corticosteroid unresponsive during an exacerbation. The underlying mechanisms are still unclear although we assume that there is a relation with the defect observed in bronchial epithelial cells from patients with asthma, described above. We exploit a human challenge model in which human volunteers are exposed to a common cold virus (Rhinovirus 16) to induce a mild cold in healthy individuals and a mild exacerbation in patients with asthma. In combination with relevant experimental animal and in vitro studies we aim to delineate the cause for these excerbations and focus on the role of eosinophilic granulocytes and the underlying process that leads to corticosteroid unresponsiveness. These studies are performed by Dr. Suzanne Bal and Dr. Lara Ravanetti, part of which involves an intervention with anti-IL-5. Patients with mild to moderate asthma and healthy controls who are interested to participate in these highly relevant clinical studies can find more information here.

Resolution of inflammation

Foreign (non-self) material that the immune system fails to eradicate, typically will be walled off in well-organized inflammatory tissue structures called granulomas. These granulomas protect the host by containing the enclosed antigen and limiting inflammation.

Granulomas are manifest in various infectious and non-infectious diseases, like tuberculosis, leprosy, sarcoidosis, chronic granulomatous disease (CGD) and Crohn’s disease. The mechanisms that control resolution, persistence and progression of granulomas are still largely unknown.

The inducible enzyme indoleamine 2,3-dioxygenase (IDO) depletes tryptophan and produces kynurenine. The depletion of tryptophan and the generation of kynurenine and related metabolites have been implicated in dampening T cell responses by promoting apoptosis or preventing activation of T cells. We and others have found that IDO activity also dampens responses by neutrophils and macrophages. Since tryptophan is also an essential amino acid for most micro-organisms, IDO-mediated depletion of tryptophan can also affect microbial metabolism and even kill microbes. This led us to propose that granulomatous IDO may limit local inflammation and may prevent bacterial growth/dissemination.

Based upon studies in murine tuberculosis and analyses of clinical specimens from patients with CGD, sarcoidosis or tuberculosis, we conclude that IDO activity determines whether granuloma resolve, are stable or become progressive. High granulomatous IDO activity induces moderate to severe apoptosis of immune and inflammatory cells that may prevent the clearance of the micro-organisms/antigen and leading to persistent and progressive granuloma. Low IDO activity leads to resolution of the granulomas. If, however, these granulomas enclose live pathogens this also causes dissemination of pathogens and aggravate inflammation. Our current studies are aimed at exploring this concept (Figure 2) further.

Figure 2: Schematic representation of the working hypothesis for granulomatous IDO.
Figure 2: Schematic representation of the working hypothesis for granulomatous IDO.

Selected references:

Kuijpers T, Lutter R. Inflammation and repeated infections in CGD: two sides of a coin. Cell Mol Life Sci. 2012 Jan;69(1):7-15.

Wösten-van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, van Goor H, Kamilic J, Florquin S, Bos AP. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011 Dec;225(4):618-27.

Fan XY, van den Berg A, Snoek M, van der Flier LG, Smids B, Jansen HM, Liu RY, Lutter R. Arginine deficiency augments inflammatory mediator production by airway epithelial cells in vitro. Respir Res. 2009 Jul 3;10:62

van der Sluijs KF, Nijhuis M, Levels JH, Florquin S, Mellor AL, Jansen HM, van der Poll T, Lutter R. Influenza-induced expression of indoleamine 2,3-dioxygenase enhances interleukin-10 production and bacterial outgrowth during secondary pneumococcal pneumonia. J Infect Dis. 2006;193(2):214-22.

van den Berg A, Freitas J, Keles F, Snoek M, van Marle J, Jansen HM, Lutter R. Cytoskeletal architecture differentially controls post-transcriptional processing of IL-6 and IL-8 mRNA in airway epithelial-like cells. Exp Cell Res. 2006;312(9):1496-506.

van den Berg A, Snoek M, Jansen HM, Lutter R. E1A expression dysregulates IL-8 production and suppresses IL-6 production by lung epithelial cells. Respir Res. 2005;6:111.

van den Berg A, Kuiper M, Snoek M, Timens W, Postma DS, Jansen HM, Lutter R. IL-17 induces hyperresponsive interleukin-8 and interleukin-6 production to tumor necrosis factor-alpha in structural lung cells. Am J Respir Cell Mol Biol. 2005;33(1):97-104.

Roger T, Bresser P, Snoek M, Van Der Sluijs K, Van Den Berg A, Nijhuis M, Jansen HM, Lutter R. Exaggerated IL-8 and IL-6 responses to TNF-a by parainfluenza virus type 4-infected NCI-H292 cells. Am J Physiol Lung Cell Mol Physiol. 2004;287(5):L1048-55.

van der Sluijs KF, van Elden LJ, Nijhuis M, Schuurman R, Pater JM, Florquin S, Goldman M, Jansen HM, Lutter R, van der Poll T. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J Immunol. 2004;172(12):7603-9.

van Wissen M, Snoek M, Smids B, Jansen HM, Lutter R. IFN-gamma amplifies IL-6 and IL-8 responses by airway epithelial-like cells via indoleamine 2,3-dioxygenase. J Immunol. 2002;169(12):7039-44.

Some older key papers:

Bresser P, van Alphen L, Lutter R. New strains of bacteria and exacerbations of COPD. N Engl J Med. 2002;347(25):2077-9;

Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria. Abrahams JP, Leslie AG, Lutter R, Walker JE. Nature. 1994;370(6491):621-8

Crystallization of F1-ATPase from bovine heart mitochondria. Lutter R, Abrahams JP, van Raaij MJ, Todd RJ, Lundqvist T, Buchanan SK, Leslie AG, Walker JE. J Mol Biol. 1993;229(3):787-90

A new method for detecting endocytosed proteins. EMBO J. 1988;7(13):4087-92. Bretscher MS, Lutter R.

For a full list with publication click here.


Our group has a long track record of supervising national and international (Socrates, Erasmus) students with their research projects. We have excellent lab facilities, a broad experience with cell and molecular biology approaches (see references), and pay attention to interpreting and presenting data and setting up experiments. Besides work discussions and a journal club discussing recent articles, there are a number of meetings each week giving you the opportunity to meet more leading, national and international scientists. If you are interested in our topics and would like to do a research project, please contact Dr. René Lutter (E-mail: ; Phone: +31-20-5668753) for further information. We have also developed a broad expertise on the analyses of material from clinical studies (bronchoalveolar lavage fluid, sputum (spontaneous and induced), breath condensate and of blood) using ELISA's, multiplex assays and other immunological assays (Elispot), enzymatic assays, quantitative mRNA assays and the detection of cell surface and intracellular markers (FACS, intracellular detection).


Rene Lutter:

or telephone +31-20-5668753


Transplantation Immunology

Principal Investigator

Ineke ten Berge, PhD

Transplantation Immunology

After renal transplantation, acute rejection may occur which most often takes place in the first three months after transplantation. This is - in general - reversible after intensifying immunosuppressive therapy. However, the treatment with immunosuppressive drugs may be complicated by viral infections such as cytomegalovirus (CMV) and BK virus (BKV) infection. Study of the immune response to CMV and BKV infection in these immuno-compromised patients provides insights that are also applicable to patients who are immuno-compromised for other reasons.

The research program Transplantation Immunology is focused on:

1) The presence and significance of virus-specific CD8+ T cells with cross-reactivity to alloantigen in kidney transplant recipients. First, we developed methods to detect cross-reactive cells and to characterize them functionally. Next, we studied their presence and function in healthy individuals and in renal transplant recipients. Our results indicate that circulating virus-specific T cells can indeed cross-react to alloantigens. In cytomegalovirus (CMV) seropositive recipients, cross-reactive T cells can exist prior to transplantation or emerge after viral reactivation. Donor-specific cross-reactive T cells appeared to be present in the circulation transiently, suggesting that they home to the graft. Therefore, we will study not only the peripheral-blood compartment, but also lymphocytes eluted from graft biopsies. Obtained data will be correlated to the clinical course of patients.

2) The immune response against CMV-infection in renal transplant recipients. Lymph nodes (LN) obtained from surgically removed iliac tissue of recipients of a kidney transplant appeared to contain CMV-specific CD8+ T cells resembling central memory cells, which are infrequent in peripheral blood (PB). Using next generation sequencing, the LN CMV-pp65-specific CD8+ T cell pool appeared to contain clones not found in PB. Since it is unknown if human LN CMV-specific CD8+ T cells contribute to the PB pool upon viral recall, we studied the possible appearance of these clones in the circulation during CMV reactivation. A diverse picture emerged, from which it could not be determined if the LN cells contributed to the vigorous expansion of the CMV-specific pool during reactivation. These studies will be continued and focus on heterogeneity of the T cell response in several lymphoid compartments during latency.

3) The immune response against BKV-infection in renal transplant recipients. Using different HLA-A02-tetramers, we developed methods to characterize circulating BKV-specific CD8+ T cells, essential in the defence against the virus. Phenotypic analysis showed that BKV-specific T cells in healthy individuals are mainly VP1-specific and can be considered as non-activated ‘effector memory’ T cells that express granzyme-K, but no other cytotoxic molecules. To assess the influence of BKV-specific cellular immune responses on the risk and development of BKV-nephropathy following renal transplantation, BKV-specific CD8+ T cells will be phenotypically and functionally characterized in renal transplant patients with or without this complication.

4) We previously showed that BKV-viremia is associated with induction of TLR3, MDA5, and RIG-I in tubular epithelium and that these dsRNA-sensors trigger an anti-viral and pro-apoptotic program in primary human tubular epithelial cells. Next, we aim to clarify the recognition of - and overall innate immune response to BKV, and to elucidate immune-evasive strategies of the virus. In addition, we will identify factors that facilitate viral (re)activation in renal epithelium and contribute to the development of BKV-nephropathy.

5) Optimization of immunosuppressive drug therapy in renal transplantation. As part of a new recently started clinical trial, immunological, vascular and pharmacological studies will be performed.

Group members

R.J.M. ten Berge, MD, PhD
F.J. Bemelman, MD, PhD
K.A.M.I. van Donselaar, MD
K.M. Heutinck, MSc, postdoc
H. de Kort, postdoc
M.C. van Aalderen, MD, PhD
M. Nijland, MD, PhD
G.H. Struijk, MD, PhD
E.B.M. Remmerswaal Ing, PhD
S.L. Yong

Selected publications

van Aalderen MC, Remmerswaal EB, Heutinck KM, ten Brinke A, Pircher H, van Lier RA, ten Berge IJ. Phenotypic and functional characterization of circulating polyomavirus BK VP1-specific CD8+ T cells in healthy adults. J Virol. 2013;87:10263-72.

Havenith SH, Yong SL, Henson SM, Piet B, Idu MM, Koch SD, Jonkers RE, Kragten NA, Akbar AN, van Lier RA, ten Berge IJ. Analysis of stem-cell-like properties of human CD161++IL-18Rα+ memory CD8+ T cells. Int Immunol. 2012;24:625-36.

Heutinck KM, Rowshani AT, Kassies J, Claessen N, van Donselaar-van der Pant KAMI, Bemelman FJ, Eldering E, van Lier RAW, Florquin S, ten Berge IJM, Hamann J, Viral double-stranded RNA sensors induce antiviral, pro-inflammatory, and pro-apoptotic responses in human renal tubular epithelial cells. Kidney Int 2012; 82: 664-75.

Remmerswaal EB, Havenith SH, Idu MM, van Leeuwen EM, van Donselaar KA, Ten Brinke A, van der Bom-Baylon N, Bemelman FJ, van Lier RA, Ten Berge IJ. Human virus-specific effector-type T cells accumulate in blood but not in lymph nodes. Blood 2012;119:1702-12.

Hertoghs KM, Moerland PD, van Stijn A, Remmerswaal EB, Yong SL, van de Berg PJ, van Ham SM, Baas F, ten Berge IJ, van Lier RA. Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. J Clin Invest 2010;120:4077-90.

Van de Berg PJ, Heutinck KM, Raabe R, Minnee RC, Young SL, van Donselaar-van der Pant KA, Bemelman FJ, van Lier RA, ten Berge IJ. Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature. J Infect Dis 2010;202:690-9.

Van Leeuwen EM, Koning JJ, Remmerswaal EB, van Baarle D, van Lier RA, ten Berge IJ. Differential usage of cellular niches by cytomegalovirus versus EBV-and influenza virus-specific CD8+ T cells. J Immunol 2006;177:4998-5005.

Uss E, Rowshani AT, Hooibrink B, Lardy NM, van Lier RA, ten Berge IJ. CD103 is a marker for alloantigen-induced regulatory CD8+ T cells. J Immunol 2006;177:2775-83.

Rowshani AT, Florquin S, Bemelman F, Kummer JA, Hack CE, Ten Berge IJ. Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: a potential mechanism for stable renal function in patients with subclinical rejection. Kidney Int 2004;66:1417-22.

Van Leeuwen EM, Remmerswaal EB, Vossen MT, Rowshani AT, Wertheim-van Dillen PM, van Lier RA, ten Berge IJ. Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. J Immunol 2004;173:1834-41.

Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 2003;101:2686-92.

Gamadia LE, ten Berge IJ, Picker LJ, van Lier RA. Skewed maturation of virus-specific CTLs? Nat Immunol 2002;3:203.

Rentenaar RJ, Gamadia LE, van DerHoek N, van Diepen FN, Boom R, Weel JF, Wertheim-van Dillen PM, van Lier RA, ten Berge IJ. Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection. J Clin Invest 2000;105:541-8.

Wever PC, Spaeny LH, van der Vliet HJ, Rentenaar RJ, Wolbink AM, Surachno J, Wertheim PM, Schellekens PT, Hack CE, ten Berge IJ. Expression of granzyme B during primary cytomegalovirus infection after renal transplantation. J Infect Dis 1999;179:693-6.

Buysmann S, Bemelman FJ, Schellekens PT, van Kooyk Y, Figdor CG, ten Berge IJ. Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3. Blood 1996;87:404-11.

Bemelman FJ, Buysmann S, Surachno J, Wilmink JM, Schellekens PT, ten Berge IJ. Pretreatment with divided doses of steroids strongly decreases side effects of OKT3. Kidney Int 1994;46:1674-9.

Parlevliet KJ, ten Berge IJ, Yong SL, Surachno J, Wilmink JM, Schellekens PT. In vivo effects of IgA and IgG2a anti-CD3 isotype switch variants. J Clin Invest 1994;93:2519-25.

Raasveld MH, Surachno S, Hack CE, ten Berge RJ. Thromboembolic complications and dose of monoclonal OKT3 antibody. Lancet 1992;339:1363-4.

Van Twuyver E, Mooijaart RJ, ten Berge IJ, van der Horst AR, Wilmink JM, Kast WM, Melief CJ, de Waal LP. Pretransplantation blood transfusion revisited. N Engl J Med 1991;325:1210-3.


For further information about our research and opportunities for work or collaborations, you can contact Prof. Ineke ten Berge

+31 (0)20 566 5990

Rheumatoid Arthritis

Snel naar: