Treatment of psoriasis during pregnancy, an immunological puzzle and a delicate balance

Grantee: Renate van der Molen, Assistant Professor, Radboud University Medical Center

Amount: DKK 2,596,390

Grant category: Research Grants in open competition

Year: 2023

Geography: Netherlands

Renate van der Molen’s project will study the effect of psoriasis and the associated treatment with biologics on the pre-pregnancy uterine immune environment and also investigate the effect on trophoblast invasion using a co-culture cellular model.

Pregnancy in patients with immune-mediated diseases like psoriasis is challenging and requires a tightly regulated immune system. The mother’s immune system must prevent rejection of the fetus that partly represents paternal characteristics and thus foreign to the mother’s immune system, while still being alert to infections threatening herself and the baby. Additionally, the immune system is important for invasion of fetal cells (trophoblast cells), into the cell lining of the womb to form a healthy placenta. Thus, a dysregulated immune system, i.e., during flares of psoriasis, can negatively affect pregnancy.

Furthermore, knowledge of the effect of biologics to treat psoriasis, anti-TNFα, anti-interleukin-17 (IL17) and anti-IL23, on pregnancy is sparse. This complicates decision making on treatment of women with psoriasis before and during pregnancy.

In this project, Renate van der Molen and her team will therefore study the effect of psoriasis and the treatment with biologics on the local uterine immune environment. In addition, using an innovative in vitro co-culture model of trophoblasts and immune cells they will study the effect of psoriasis and the treatment with anti-TNFα, anti-IL17 or anti-IL23 on trophoblast invasion.

Renate van der Molen’s project will give insights to whether and how psoriasis and the treatment with biologics can affect a future pregnancy, which is a step towards better evidence based clinical decisions on the best treatment for women with psoriasis with a child wish.

Non-Tuberculous Mycobacterial Skin and Soft Tissue Infections: Using a Site-of-Disease Approach to Understand Pathophysiology and Improve Outcome

Grantee: Arjan van Laarhoven, PhD, Radboud University Medical Center

Amount: DKK 3,987,136

Grant category: Research Grants in open competition

Year: 2023

Geography: Netherlands

Arjan van Laarhoven’s project aims to improve the treatment of patients infected with mycobacteria by looking at the patient’s individual immune responses to the infection and combining this with optimized treatment with antibiotics.

Non-tuberculous mycobacteria (NTM) can cause debilitating skin and soft tissue infections (SSTI). NTM SSTI incidence rises with an aged population and increased use of immunosuppression. These infections require treatment with multiple antibiotics for minimally 4-6 months. Still, non-response or worsening of skin lesions occurs frequently, because antibiotics fail or too much inflammation occurs.

Arjan van Laarhoven and his team hypothesize that differences in the patients’ immune systems, so-called ‘patient endotypes’, drive these diverging treatment courses. Currently, the involved immune processes in the skin are not identified for NTM SSTI. In addition, it is unknown what antibiotic concentrations in the skin are needed to kill the NTM.

In this study, the team will investigate the individual immune response in the skin of NTM SSTI patients by measuring the activity of genes in individual cells, and how these cells interact. They will compare this to the immune cells in the patients’ blood and will use the combined information to understand how patients differ in their immune response to the infection. These findings will be related to the clinical response to antibiotic treatment.

After eight weeks of antibiotic treatment, a second biopsy will be taken, in which measurement of the number of live mycobacteria and the local skin drug concentrations of azithromycin and clofazimine will be repeated.

By providing targets for optimizing treatment with both antibiotics and anti-inflammatory or immunostimulating drugs, this project aims to improve the outlook for NTM SSTI patients.

Digging deep for filaggrin’s function in regulating epidermal barrier formation

Grantee: Ellen van den Bogaard, Professor, Radboud University Medical Center

Amount: DKK 3,929,813

Grant category: Research Grants in open competition

Year: 2022

Geography: Netherlands

The aim of Ellen’s project is to improve the understanding of the role of skin protein filaggrin (FLG) in regulating and controlling epidermal keratinocyte robustness and differentiation.

Ever since the discovery that loss-of-function mutations in the FLG gene are the main risk factor for developing Atopic Dermatitis (AD), many studies have aimed to relate the presence or absence of FLG to processes involved in skin homeostasis. The filaggrin protein is comprised of several repetitive elements as well as two unique domains, A and B. While many mutations in the filaggrin monomers are known to be important in AD, the role of the A and B domains have been less studied.

Previous investigation, featuring collaborator and postdoctoral fellow Jos P.H. Smits, discovered that mutations in these domains affect the expression of genes that are important for terminal differentiation of epidermal keratinocytes. The terminal differentiation of keratinocytes is important for the formation of the skin barrier. In this project, the team want to expand initial findings into elaborate studies using 3D skin organoids, also called “human skin equivalents” combined with in-depth molecular and functional analyses. Ellen’s group has developed many of these 3D skin equivalents to resemble both the structure and environment of real skin. By exposing the skin equivalents to relevant environmental factors, they will study how mutations in the filaggrin A and B domains affect keratinocyte differentiation and terminal fate and ultimately the overall skin barrier function. The hope is to identify potential new targets for therapeutic interventions in AD by modifying the expression of filaggrin and thereby regulating the barrier function of the skin.

Psoriasis: a microbiome-driven disease?

Grantee: Patrick Zeeuwen, Radboud University Medical Center, Nijmegen

Amount: DKK 2,545,944

Grant category: Research Grants in open competition

Year: 2018

Geography: Netherlands

Psoriasis is highly prevalent and has a significant medical and socio-economic impact.

The prevailing dogma has been that abnormalities of the adaptive immune system were primary, but genetic studies have highlighted the importance of local skin-specific factors. We and others have identified epidermis-specific innate immunity genes, like beta-defensins and Late Cornified Envelope (LCE) genes, to be associated with disease development.

We recently made two exciting observations. First, deletion of LCE3B and LCE3C does not merely imply the loss of two genes but has a genomic effect that leads to a strong induction of the flanking LCE3A gene. Secondly, we found that LCE proteins, and LCE3A in particular, have broad-spectrum antimicrobial activity. We hypothesize that the LCE3B/C-del status affects the cutaneous host defense repertoire thereby shaping the skin microbiome. We aim to investigate the biology of LCE genes and to translate these findings to our understanding of psoriasis pathogenesis.

Key objectives are to:

  1. assess the antimicrobial activity and specificity of all LCEs and their synergy with other antimicrobial proteins. This will be investigated by metagenomic approaches and classical in vitro microbiological assays, using recombinant and synthetic LCE proteins and peptides derived thereof
  2. investigate LCE3B/C-del in isogenic 3D-skin equivalents in vitro generated from the immortalized human keratinocyte N/TERT cell line. Deletions of other LCE genes or their regulatory sequences will be made using CRISPR/Cas9 technology. Effects on epidermal biology relevant to psoriasis will be studied and include antimicrobial host defense, innate immune response and skin barrier function

Skin barrier dysfunction and thymus size during the first year of life as predictors for atopic dermatitis

Grantee: Jacob P. Thyssen MD PhD DmSci, Trine Danvad Nilausen MD, Lone Skov MD PhD DmSci, Dep. Dermatology and Allergology, Herlev-Gentofte Hospital, Hellerup, Denmark, Caroline Ewertsen MD PhD, Department of Radiology, Rigshospitalet, Copenhagen, Denmark, Charlotte Bonefeld PhD, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Pal Szecsi MD DmSci, Department of Clinical Biochemistry, Herlev-Gentofte Hospital, Hellerup , Denmark, Sanja Kezic PhD, Coronel Institute, AMC, University of Amsterdam, The Netherlands, and Christoph Riethmüller PhD, nAnostic Institute, Centre for Nanotechnology, University of Münster, Germany

Amount: DKK 2,558,500

Grant category: Research Grants in open competition

Year: 2016

Geography: Denmark, Germany, Netherlands

The study is foreseen to increase the understanding of the skin barrier and immune system in atopic dermatitis.

Through international collaboration with scientists who perform state of the art and pioneering analyses on skin samples as well as national collaboration with immunologists and radiologists, the team will seek to evaluate non-invasive and easily collectable biomarkers that can predict the risk for atopic dermatitis.

The study has the potential to provide insight in atopic dermatitis pathogenesis and the value of promising pre-atopic dermatitis biomarkers that indicate both inflammation and skin barrier barriers dysfunction. This could be used to develop an algorithm that can better predict the onset of atopic dermatitis.

The team’s work may thus substantially increase the understanding of skin biology in neonates, both normal and diseased. The study will also provide a basis for not only future large-scale observational studies, but also randomised controlled studies evaluating the efficacy of preventive skin barrier restoration or anti-inflammatory treatment in selected groups, potentially reducing the incidence and complications of the most common skin disease in childhood.

Depletion, UV Exposure and Relation between Ozone and Skin Cancer

Grantee: Dr. Harry Slaper, Laboratory for Radiation Research, RIVM, Holland

Amount: DKK 200,000

Grant category: Research Grants in open competition

Year: 2012

Geography: Netherlands

Dr. Harry Slaper, Laboratory for Radiation Research, RIVM, Holland, has developed a unique model, the AMOUR 2.0, for relating ozone depletion scenarios and UV to changes in skin cancer incidence (melanoma, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). This model has been used since 2008 as a reference for other researchers in Europe.

The model, however, does not factor in age. Apart from cumulated UV Radiation, age is the major risk factor for the development of Non Melanoma Skin Cancer (NMSC), and an ageing population will contribute to the increasing incidence of NMSCs.

The LEO Foundation has funded a development of the model to also incorporate the effects of population aging in Europe in order to obtain a more precise picture of the projected incidence of NMSC in Europe.

Based on the Dutch Cancer registry and the enhanced model, then, Dr. Slaper has estimated age and gender specific incidence rates, incorporated them into the model as well as UN Population forecasts to forecast the incidence of NMSC in Europe and the contribution of both cumulated UV radiation and age and gender.

The results are expected to play a key role in raising awareness among decision makers in the health care sector on the increasing incidences of non-melanoma skin cancer, an awareness which will also benefit patients as the long-term aim is to increase the political prioritisation of non-melanoma skin cancer.