Immunology
Our immunological studies focus on what provokes autoimmunity. We aim to decipher the deregulated cell types in multiple sclerosis and other neuroimmunological diseases and here in particular T cells. We want to understand the molecules that serve as regulators of immune cell function and the effector molecules that invigorate an autoimmune response. In addition, learning from evolution, e.g. by understanding how sex differences and pregnancy shape immune responses, will help the quest for novel immunomodulatory treatments for neuroimmunological diseases.
T lymphocytes can be divided into CD4+ and CD8+ T cells, of which CD8+ T cells predominate in multiple sclerosis lesions. However, the precise role of CD4+ and CD8+ T cells in the disease aetiology and pathogenesis is still not understood. Mechanisms leading to their dysregulation, central nervous system infiltration and residency remain to be defined. Another T cell subset likely involved in multiple sclerosis pathogenesis are regulatory CD4+ T cells. Their dysfunction in multiple sclerosis leads to an insufficient inhibition of auto-aggressive T cell responses. Therefore, we aim to understand the mechanisms of the T cell dysfunctional state. We ask, which functional pathways regulate T cell activation or suppression and can be exploited as therapeutic strategy to regain tolerance in multiple sclerosis.
Friese Group
Females are two to three times more often affected by multiple sclerosis than males. Moreover, pregnancy in female multiple sclerosis patients is associated with a substantial decrease in relapse rate. However, post-partum the relapse rate increases in a rebounding fashion above the rate seen before pregnancy. Currently we do not understand the biological mechanisms underlying the sexual dimorphism and pregnancy-related effects in multiple sclerosis. We aim at deciphering these powerful, evolutionary-driven regulatory pathways of immunomodulation and at exploiting them to inform novel therapeutic approaches in multiple sclerosis patients. We currently focus on the role of genetic factors, cytokines and hormones in T cell regulation, and in shaping the immune repertoire using preclinical models and cohort studies with multiple sclerosis patients and healthy individuals.
Friese Group
Neurobiology
Inflammatory insults lead to progressive degeneration of neurons and their axons that is key for the development of permanent neurological disability in chronic inflammatory diseases such as multiple sclerosis, but also in acute infections of the central nervous system. Our neurobiological studies focus on the molecular mechanisms of this inflammation-induced neuronal degeneration. Stress response pathways can determine neuronal injury, but hormetic stress also stimulates signalling pathways that enhance the abilities of neurons to resist inflammatory stressors. Thus, we aim at discovering molecular pathways that enhance neuronal resilience. Inhibiting damaging and cell death pathways or reinforcing protective pathways may lead to the development of novel interventions for neurodegenerative or neuroinfectious disorders. We aim at identifying, understanding and modulating key pathways in neurons to ameliorate neurodegeneration in multiple sclerosis and other neurodegenerative or neuroinfectious diseases.
While great progress has been made in understanding and controlling the inflammatory component of the disease, the pathophysiological mechanisms of neurodegeneration are still not understood and only poorly affected by immunomodulatory drugs. Neurons exposed to chronic inflammation initiate their own innate immune response, termed the neuronal inflammatory stress response. This includes altered ion channel activity, mitochondrial changes, production of reactive oxygen species, altered proteostasis with protein accumulations, integrated stress response, epigenetic modifications and distinct cell death pathways. We study how these pathways are interconnected and their hierarchical order to eventually identify the most tractable target to enhance neuronal resilience and counteract degeneration.
Friese Group
We study the mechanisms that drive endothelial and neuronal dysfunction in infectious diseases associated with neurological complications, such as viral encephalitis and cerebral malaria. Encephalitis, an acute inflammation of the brain that is predominantly caused by viral infections results in widespread neuronal damage. Cerebral malaria, caused by a parasite that is transmitted by mosquitos, refers to brain dysfunction in parasitaemic patients and is associated with high rates of morbidity and mortality. We focus on understanding the molecular mechanisms that drive neuronal injury in viral encephalitis and cerebral malaria, with the ultimate goal to decipher the mechanisms that govern permissiveness or resistance of the central nervous system that can be translated into novel strategies of prevention, diagnosis and/or treatment.
Friese Group
Evolutionary drive of physical abilities has resulted in optimized brain function by exercise and dietary energy restriction. Such energetic challenges result in an adaptation of neuronal stress-response pathways with mitochondrial biogenesis and increased neuronal resistance to stressors. Since chronic inflammation during multiple sclerosis results in an overload of neuronal stressors and dysfunction of mitochondria, we explore how behavioural interventions like exercise, diet and exposure to high-altitude hypoxia can ameliorate neurodegeneration during multiple sclerosis and possibly other neurodegenerative diseases. Besides studying these processes on a molecular level, we analyse the impact of exercise and high-altitude hypoxia on clinical outcomes in multiple sclerosis patients in clinical trials.
Rosenkranz Group
Target identification is a critical step in the drug discovery and development process, however even more critical is the development of lead compounds inhibiting the target molecule. In order to expedite development of new drugs with neuroprotective potentials by targeting newly identified neuronal pathways leading to inflammation-induced neurodegeneration, we teamed up with pharmaceutical and biotech companies and aim at identifying compounds, which we can test in preclinical models. This has led to promising compounds with preclinical neuroprotective activity that will be further developed.
Friese Group
Clinical Research
Clinical research at the INIMS aims to develop treatments with a comprehensive translational approach. This includes assessment and consideration of psychosocial aspects of multiple sclerosis as well as educational, behavioural and lifestyle interventions in investigator-initiated trials. Moreover, we pursue pharmaceutical trials in the area of unmet clinical needs such as safe treatments in early multiple sclerosis, highly immunosuppressive approaches for aggressive multiple sclerosis but also new neuroprotective concepts. Complementing this approach, we conduct research to improve assessment tools, develop novel outcome parameters with clinical relevance, and optimize study designs.
Autonomy preferences, risk perception, risk knowledge and factors relevant for medical decision making differ between different patient groups. We study approaches of decision support in a European network to enhance patient autonomy. Online tools are increasingly used; upcoming projects focus on education about the relevance of MRI, motherhood choice and pregnancy management. Moreover, we pursue adherence determining factors and interventions as well as illness narratives as decision support factors.
Heesen Group
Behavioural interventions that target aspects of well-being and lifestyle can be effective in increasing quality of life, reducing neuropsychiatric symptoms and may also have some effects on pathobiological processes in multiple sclerosis. However, they often require highly trained specialists and are thus strongly limited in their scalability and are not available to most patients with multiple sclerosis. We are developing novel, internet-based eHealth applications that can be tailored to the individual patient’s needs and preferences and test their efficacy on psychological as well as biological outcomes in randomised controlled trials.
Heesen Group
Exercise has beneficial effects on the physical fitness in multiple sclerosis patients such as strength, endurance and balance and also improves several multiple sclerosis symptoms such as fatigue, depression, and the quality of life. Early evidence suggests that exercise may also have disease-modifying effects. However, physical activity recommendations for pwMS are not sufficiently implemented in clinical routine. Furthermore, a direct link between an exercise-induced mechanism and a disease-modifying effect in multiple sclerosis has not been identified and studies investigating the long-term effects of exercise in multiple sclerosis patients are currently lacking. We investigate the potential immunomodulatory and neuroprotective effects of exercise in multiple sclerosis by translational approaches and perform clinical studies to improve the motivational aspects and adherence to exercise in multiple sclerosis patients.
Heesen Group Rosenkranz Group
We evaluate molecular approaches by conducting investigator-initiated trials for presumably safe but also for aggressive therapies. Immune tolerance induction is a focus in early disease, while autologous stem cell transplantation and CAR T cell therapy is investigated in early highly aggressive multiple sclerosis.
Heesen Group
Understanding and counteracting neurodegenerative processes are major unmet needs for all multiple sclerosis subtypes. However, detecting disability worsening in relatively short-term interventional trials (up to 2-3 years) is very difficult. The current clinical study outcomes mainly rely on neurological exams. Furthermore, longitudinal neurodegenerative biomarkers in multiple sclerosis that predict clinical progression are lacking. Our outcome and biomarker research aims at improving the sensitivity and clinical meaningfulness of study endpoints and prediction of disease activity by following triangulation of measurements: objective (e.g. MRI, accelerometry), rater-based (e.g. walking tests) and patient-reported (eg. Quality of life). Our research further focuses on the visual system as it has a direct link to a specific clinical outcome and is easy to access without causing any harm to the patient. We combine different methods to develop a responsive outcome set ranging from visual quality of life to visual fMRT tasks and optical coherence tomography.
Heesen Group Rosenkranz Group
