Interleukin-1 (IL-1) signaling is strongly implicated in numerous pathologies, including central nervous system (CNS) disorders such as multiple sclerosis (MS), Alzheimer's disease and Parkinson's disease. Hallmarks of MS are disseminated lesions caused by immune cell infiltration into the CNS which promotes inflammation, demyelination, gliosis and neuroaxonal degeneration. In severe cases, MS patients suffer from sensory/visual disturbances, motor impairments, fatigue, pain and cognitive deficits. Elevated levels of IL-1 have been reported within the white matter and in acute lesions of MS patients. Typically, increased IL-1 activity is associated with more severe MS symptoms. In this regard, therapeutic targeting of the IL-1 pathway is an attractive solution to pursue, which, however, requires additional experimental support.
To mimic Multiple Sclerosis in a preclinical setting, we use a murine model for CNS-directed autoimmunity, namely Experimental Autoimmune Encephalomyelitis (EAE).
The assessment of disease progression and analysis of CNS infiltrates in interleukin-1 receptor type 1 (IL-1R1) as well as interleukin-1 receptor type 2 (IL-1R2) deficient mice is our toolbox in studying the role of IL-1 in CNS-directed autoimmunity.

Interleukin-6 (IL-6) is a critical cytokine for host immune defense and its elevated levels are found in literally all inflammatory conditions. In extreme cases, such as sepsis or cytokine release syndrome (CRS) caused by SARS-CoV-2 infection or as a side effect of CAR T cell therapy, the excessive levels of IL-6 can cause life-threatening complications.
Idiopathic Multicentric Castleman Disease (iMCD) is a rare, but devastating, lymphoproliferative disorder. In this disease, IL-6 is considered to be a major pathogenic factor that causes lymphadenopathy, hepatosplenomegaly, thrombocytopenia, plasmacytosis and multiorgan dysfunction. First-line symptomatic treatment largely relies on inhibition of IL-6 signaling, however, up to 70% of patients remain refractory to IL-6 blockade. The progress on the development of alternative therapeutic interventions remains limited due to the absence of suitable preclinical models.
In this project we aim to identify novel molecular targets in iMCD and repurpose drugs, which are already approved for other inflammatory disorders. We are also fascinated by the idea of developing gene-edited adoptive cell transfer therapy for the treatment of iMCD. For that, we use mice with conditional IL-6 overexpression that display key features of iMCD and mice deficient in IL-6 signaling.

Regulatory T (Treg) cells are a specialized subset of immuno-suppressive CD4 T cells that express the lineage-specific transcription factor Foxp3. Treg cells regulate a variety of immune responses in various biological contexts, including inflammation, cancer, metabolism, tissue repair, pregnancy and more. Humans and mice with impaired Treg cell function suffer from severe-to-lethal autoimmune disorders. Although the developmental pathways leading to the generation of Treg cells are well-studied, little is known how inflammatory mediators (and in particular IL-6) impact mature Treg cells function. Filling up this gap of knowledge is a keystone for improving treatment strategies. Such treatments could modulate Treg cells in patients on-site or could be a part of fast-developing strategies of adoptive cell transfer therapies. Thanks to advances in genetic engineering, Treg cells might be isolated, modified, expanded and transferred back into the patients as living drugs.Immune responses occur at a complex in vivo environment; therefore, they cannot be fully recapitulated by in vitro systems. To study short-term and long-lasting effects of IL-6 exposure on Treg cells, we use transgenic mice with IL-6 overexpression and employ Treg cell depletion, Treg cell modulation and Treg cell transfer protocols. We are confident that our translational approach is highly relevant for the development of Treg cell based therapeutic strategies aiming at suppression of Treg cells to promote anti-tumor immunity, or in opposite, stimulation of Treg cells in autoimmune disorders.

Recent discoveries highlighted that maternal immune activation (MIA) in response to infections during pregnancy influences the development of fetal nervous and immune system. Dysregulated signaling of maternal IL-6 and IL-17A are key components of MIA and a high-risk factor for the development of autism spectrum disorders (ASD) in offspring. The core ASD symptoms, which vary in severity, are impaired communication and social skills, restricted or repetitive behaviors and intellectual disability. 

Currently, there is no definitive standard-of-care neither for already developed ASD nor for the prevention of ASD development. Progress in the field is prevented by the fact that research and therapeutic interventions during human pregnancy are extremely limited for ethical reasons.

To study the etiology of ASD in response to maternally produced cytokines, we use well-defined transgenic mouse models with IL-6 and IL-17A overexpression during pregnancy. This allows us to characterize long-lasting consequences and decipher mechanisms of prenatal imprinting to IL-6 and IL-17A. We believe that insights from our studies will be used to design novel treatment strategies to prevent the development of ASD.