SKINSTRUCT – Human skin structural cells instruct T cell tissue adaptation

Grantee: Georg Stary, Associate Professor, Medical University of Vienna

Amount: DKK 3,996,806

Grant category: Research Grants in open competition

Year: 2024

Geography: Austria

Georg Stary’s project aims to investigate interactions between T cells and structural cells, including keratinocytes, in the skin and how this cellular communication may affect the function of the T cells in dermatological diseases.

Human skin is protected by specialized T cells, called tissue-resident memory T cells (TRMs), which are needed to protect against infection at the site of pathogen encounter, but can also mediate inflammation in certain conditions. The exact regulation of TRMs in human skin is not well understood, hence TRM-targeted therapies are currently unavailable.

Georg Stary and his team have discovered that T cells communicate with structural cells of the skin via certain surface molecules and acquire a TRM phenotype after interaction with keratinocytes and fibroblasts. Some of the newly described molecules that instruct T cells to become TRM have not been implicated in the regulation of T cell tissue residency before.

Georg and his team aim to explore how structural cells of the skin instruct the maintenance of human TRM, and how this cellular crosstalk changes during inflammation. Based on preliminary data, they will unravel the function of certain co-receptors in TRM regulation using modern single-cell sequencing technologies on primary tissue from patients and ex-vivo co-culture systems with genetically engineered human cells. Based on this, they will subsequently test the therapeutic potential of targeting T cell-structural cell interactions in a humanized mouse model of TRM-mediated skin inflammation.

This study will not only inform about new mechanisms of human TRM instruction in health and disease and explore options for developing clinical applications targeting interactions with structural cells, but also form the basis for designing clinical studies to treat selected TRM-mediated diseases, such as graft-versus-host disease or psoriasis.

Curing Cutaneous Calcinosis (CUCUC)

Grantee: Beate Lichtenberger, Principal Investigator, Medical University of Vienna

Amount: DKK 2,757,196

Grant category: Serendipity Grants

Year: 2023

Geography: Austria

Beate Lichtenberger investigates the mechanisms behind cutaneous calcinosis caused by over-activation of Hedgehog signaling in the dermis to improve treatment options.

Cutaneous calcinosis (CUC) is a debilitating condition characterized by the abnormal deposition of calcium salts in the skin and subcutaneous tissues, leading to pain, impaired mobility, and disfigurement. Despite its significant impact on patient quality of life, effective therapeutic interventions for CUC remain lacking, and there is no model system to study the disease. Beate Lichtenberger and her team serendipitously discovered that over-activation of Hedgehog (Hh) signaling in dermal fibroblasts leads to calcium precipitates and inflammation in limb and tail skin of mice, recapitulating the human disease

Beate Lichtenberger will elucidate the underlying mechanisms driving calcium deposition, inflammation, and tissue damage in cutaneous calcinosis. Furthermore, she will perform single cell RNA sequencing (scRNA-Seq) of human CUC tissue to assess which cell types apart from fibroblasts contribute to the pathogenesis and how

By advancing the understanding of the pathogenesis of CUC and developing targeted therapeutic strategies like repurposing of existing Hh inhibitors, Beate Lichtenberger’s project has the potential to revolutionize the treatment landscape and significantly improve the lives of individuals afflicted by this condition.

Skin barrier immune defence against the multidrug-resistant fungal pathogen Candida auris

Grantee: Adelheid Elbe-Bürger, Associate Professor, Medical University of Vienna

Amount: DKK 3,139,984

Grant category: Research Grants in open competition

Year: 2023

Geography: Austria

Adelheid Elbe-Bürger’s project investigates the pathogen:host interplay using ex-vivo skin models in relation to infections by Candida auris – a multidrug resistant fungus.

Drug-resistant microorganisms represent a serious human health threat worldwide. Candida auris (C. auris) is an emerging, multidrug-resistant human fungal pathogen. Its pronounced skin tropism (i.e., ability to infect) promotes persistent colonization of the skin and facilitates skin-skin transmission within health care facilities, leading to life-threatening infections of high mortality in immunocompromised patients.

The lack of clinically relevant primary human skin models with a disrupted barrier function has been a serious impediment to better understand the C. auris:host interplay during pathogenesis.

To counter this, Adelheid Elbe-Bürger and her team have developed unique, standardized human ex vivo skin models that allow them to study C. auris colonization and penetration as well as identify the immune cells that orchestrate both the recognition and immune defense against this fungus.

In Adelheid Elbe-Bürger’s project infected skin biopsies will be analyzed by single-cell RNA-sequencing, flow cytometry as well as confocal microscopy. Culture supernatants will be subjected to multiplex proteomics (i.e., a way to analyze many proteins simultaneously) to decipher host components governing fungal:host interactions.

The overarching aim is that the results will advance the understanding of tissue-specific mechanisms of anti-C. auris defense and may help to pave the way for improved therapeutic options.

Unravelling the Link Between Past Infections, the Microbiome, and Therapy Resistant Psoriasis

Grantee: Johannes Griss, MD PhD, Medical University of Vienna

Amount: DKK 3,975,754

Grant category: Research Grants in open competition

Year: 2023

Geography: Austria

Johannes Griss’ project aims to elucidate the immunological memory of biologics-resistant psoriasis patients using advanced screening methodology. This, coupled with identifying immune composition in lesions, may reveal new treatment options.

Efficient treatment of cutaneous psoriasis is an example of the great success of modern biologicals. Nevertheless, a subset of patients remain that do not respond to most biologic treatments. This group remains in high need of efficient treatment options. It has been speculated that therapy-resistant psoriasis is caused by either specific compositions of the microbiome or unique previous viral infections.

Viral infections can trigger autoimmune diseases and dysregulated immune responses against the microbiome may trigger inflammatory and autoimmune diseases. However, to date it has not been possible to cover the vast space of antigens represented by the microbiome. Johannes Griss and his team recently showed that phage display libraries (PhIP-Seq, a high-troughput screening method utilizing bacteria-infecting viruses) can be used to identify and characterize antibodies against several 100,000s of antigens simultaneously instead of several 100s with conventional methods. This method can reveal both previous viral infections as well as the composition of the microbiome at large scale and low cost.

In this project, the team will use their novel PhIP-seq approach to characterize the immunologic state of a large in-house cohort of psoriasis patients. They will pair this with an in-depth characterization of the lesional immune composition. In this way, they aim to be able to test whether a patient’s immune memory alters psoriatic inflammation and influences therapy response.

If successful, their findings may reveal novel treatment approaches and biomarkers to allow optimal matching of biologic treatments.

T-cell – keratinocyte interactions as therapeutic targets in lichenoid and interphase dermatoses

Grantee: Georg Stary, Associate Professor, Medical University of Vienna

Amount: DKK 3,136,390

Grant category: Research Grants in open competition

Year: 2021

Geography: Austria

The aim of this project is to investigate the crosstalk between T-cells (TC) and keratinocytes (KC) and its role in two less explored inflammatory skin diseases, namely cutaneous lupus erythematosus and lichen planus. Specifically, the role of co-receptor stimulation or inhibition of T-cells will be investigated. 

The researchers hypothesize that skin diseases with prominent infiltration of pathogenic CD8+ T cells (cells that attack and kill other cells – including keratinocytes in autoimmune diseases) are related to an imbalance of activating and inhibitory signals on T cells determining the extent of the T-cell–keratinocyte (TC–KC) crosstalk. 

The team will investigate this using skin biopsies from patients to map TC–KC receptor-ligand interactions by single-cell and spatial transcriptomics. They will then assess the properties of candidate receptors and decipher their mechanism of action by immunofluorescent imaging. 

While inhibitory T-cell co-receptors are already targeted for cancer immunotherapy, their therapeutic potential in T-cell-driven inflammatory disorders remains to be established. This study may provide the rationale to design T-cell-targeting therapies in inflammation and is particularly strong with its basis on patient material. 

The LEO Foundation Award 2021 – Region EMEA

Grantee: Dr. Beate Lichtenberger, Assistant Professor, Medical University of Vienna

Amount: USD 100,000

Grant category: LEO Foundation Awards

Year: 2021

Geography: Austria

Dr. Beate Lichtenberger is Assistant Professor at the Medical University of Vienna, Austria.

She receives the award for her excellent research aimed at a better understanding of how fibroblasts affect skin cancer, skin regeneration and skin diseases like scleroderma and keloid scars.

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Deciphering the pathogenic immune infiltrate in atopic dermatitis subtypes

Grantee: Patrick Brunner, Associate Professor, Medical University of Vienna

Amount: DKK 3,447,335

Grant category: Research Grants in open competition

Year: 2020

Geography: Austria

The aim of this project is to address the challenge that current treatments for atopic dermatitis (AD) only work as long as they are given.  

A subgroup of the so-called tissue-resident memory (Trm) T-cells appears to be absent in healthy controls and in patients, who have outgrown their AD, but is still present at least a year after a successful clinical outcome following treatment with dupilumab.  

Using state-of-the-art single-cell sequencing methods combined with advanced flow cytometry and so-called suction blistering for collecting sample material, the project will characterize the composition of cells and proteins within skin lesions of AD patients. Compared to most other approaches, this multi-omics approach is expected to provide a much more accurate reflection of what is going on in this complex disease which shows considerable heterogeneity from patient to patient.  

The present project is an extension of a project previously supported by the LEO Foundation (LF18098) where Patrick Brunner successfully refined and validated his sample collection methods. The present project may guide future targeted AD treatment approaches in a more personalized and stratified manner and may offer a relatively short way from bench to bedside.

In vivo gene editing for genodermatoses

Grantee: Thomas Kocher, Postdoc, EB House Austria, Salzburg

Amount: DKK 1,389,845

Grant category: Research Grants in open competition

Year: 2020

Geography: Austria

The goal of this project is to evaluate the translational and therapeutic potential of two in vivo CRISPR/Cas9 delivery methods. CRISPR/Cas9 is a gene-editing technology that enables researchers to edit parts of the genome by removing, adding or altering sections of a specific DNA sequence. Although CRISPR/Cas-based technologies hold great promise as genome editing tools in many genetic diseases, its clinical application, especially in genodermatoses, remains a big challenge.

To challenge this hurdle, CRISPR/Cas9 molecules will be delivered into the skin of a suitable animal model via two application methods: laser microporation and gene gun bombardment. The first method uses a laser to make micropores into the skin to allow the CRISPR/Cas9 constructs to enter the outer skin barrier and subsequently the target skin cells. The second method uses a “gene gun”, where gold particles covered with CRISPR/Cas9 constructs are shot directly into the skin/cells.

These constructs can then restore genetic defects in e.g. epidermolysis bullosa (EB) – a genetic condition that results in easy blistering of the skin and mucous membranes – which is used in this project as a model, and potentially cure the disease.

The project will investigate the potential of these two delivery methods in a mouse model using grafted human skin equivalents from expanded recessive dystrophic epidermolysis bullosa (RDEB) patient-derived fibroblasts and keratinocytes. If either delivery method proves efficient, it may hold the potential for development of future treatments, or even cure, of genetic skin diseases.

Characterizing the disease memory in atopic dermatitis

Grantee: Patrick M. Brunner, Medical University of Vienna

Amount: DKK 2,920,541

Grant category: Research Grants in open competition

Year: 2018

Geography: Austria

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, typically starts very early in life.

While many patients outgrow their disease, some develop chronic disease for the rest of their lives. Mechanisms responsible, however, are completely unknown, and no biomarker exists that can predict the course of the disease.

Thus, we want to compare skin from young adults that have outgrown their AD, with skin from patients with active disease (namely normal appearing AD under topical glucocorticoid treatment, which can be expected to flare up again after cessation of treatment, thus harbouring a “disease memory”).

Skin from healthy control subjects will serve as baseline comparators. Due to low immune cell numbers in this type of tissue, we want to use in vivo suction blistering of AD patients to obtain (i) skin resident immune cells and (ii) skin proteins. Suction blister fluid will be analysed with low cytometry and single cell RNAseq (for cells) as well as a proteomic multiplex assays (OLINK) for soluble proteins. The blister roof (i.e. the epidermis) will also be harvested, and keratinocytes will be stored in liquid nitrogen for functional experiments.

Results obtained from flow cytometry, single cell RNAseq and proteomic approaches will then be used for such functional in vitro experiments (e.g. co-culturing, skin equivalents, stimulation experiments) in future research projects.

Overall, we hope that the identification of cellular and/or molecular factors influencing the natural course of AD could possibly identify targets for novel therapeutic approaches in AD, that could induce long term remission – or even lead to a cure – of AD.

The LEO Foundation Award 2016 – Silver Award

Grantee: Dr. Thomas Wiesner

Amount: DKK 500,000

Grant category: LEO Foundation Awards

Year: 2016

Geography: Austria

Presented to Dr. Thomas Wiesner. Dr. Wiesner is breaking new ground to find new mechanism-based cancer therapies. Following medical school, Dr. Wiesner wrote his thesis on the genomic aberrations of cutaneous lymphoma and completed his residency in dermatology at the Medical University of Graz in Austria. Dr. Wiesner spent five years conducting basic and translational research using cutting-edge techniques within high-throughput sequencing techniques in particular. His work within skin cancer research resulted in key discoveries, in particular concerning the genomic landscape of skin tumours.

Based on his experience as a physician-scientist and his access to high-quality clinical samples, Dr. Wiesner plans to combine high-throughput sequencing technologies, computational approaches and functional assays in order to define the relevant genomic and epigenomic aberrations in skin cancer and pave the way for new mechanism-based cancer therapies.