Immunology

Our immunological studies focus on what provokes autoimmunity. We want to decipher the deregulated cell types in multiple sclerosis and other neuroimmunological diseases and here in particular CD8+ T cells and dendritic cells. We want to understand the molecules that serve as regulators of immune cell migration and the effector molecules that invigorate an autoimmune response. In addition, learning from evolution, e.g. by understanding how pregnancy shapes immune responses, will help the quest for novel immunomodulatory treatments for neuroimmunological diseases.

Dendritic cells coordinate the innate and adaptive immune response. Therefore, they are involved in the initiation of an autoimmune response. However, many fundamental questions are still unanswered and the mechanisms how they induce an autoimmune response is ill defined. By using specific transgenically modified mouse lines and models we study how different molecular regulators coordinate the activation and function of DCs. This understanding will help us to devise approaches to treat or prevent autoimmune diseases, such as multiple sclerosis.

Friese Group

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 CD8+ T cells in the disease aetiology and pathogenesis is still not understood. Especially it is unknown what conventional CD8+ T cells infiltrating the brain recognise with their diverse T cell receptors (TCR). Furthermore, mechanisms leading to their dysregulation and brain infiltration remain to be defined. Besides conventional CD8+ T cells carrying diverse TCRs, we and others recently discovered the presence of a newly described population of mainly CD8+ T cells with an invariant, very restricted TCR repertoire in multiple sclerosis lesions. These cells are evolutionarily conserved, abundant in humans and are named due to their first discovery at sites of mucosal tissue, mucosa-associated invariant T (MAIT) cells. Here we aim to define the role of conventional CD8+ T cells and MAIT cells in multiple sclerosis and to unravel, how they are regulated and what they recognise.

Friese Group

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 these pregnancy-related effects in multiple sclerosis. We aim at deciphering these powerful, evolutionary-driven pathways of immunomodulation and exploiting them to inform novel therapeutic approaches in non-pregnant multiple sclerosis patients. We currently focus on the role of hormones, regulatory T cell induction, and shaping of the immune repertoire during pregnancy using animal models and cohort studies in female patients with multiple sclerosis and healthy women.

Friese Group Gold Group

Neurobiology

Inflammatory insults lead to progressive degeneration of axons and neurons that is key for the development of permanent neurological disability in chronic inflammatory diseases such as multiple sclerosis. Our neurobiological studies focus on the molecular mechanisms of this inflammation-induced neuronal degeneration. Stress response pathways can either 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 conserved molecular pathways that enhance neuronal resilience. Inhibiting damaging pathways or reinforcing protective pathways may lead to the development of novel interventions for neurodegenerative disorders. We aim at identifying, understanding and modulating these key pathways to ameliorate neurodegeneration in multiple sclerosis but also other neurodegenerative disease.

Inflammatory insults in multiple sclerosis determine neurodegeneration by causing axonal and neuronal mitochondrial dysfunction, energy failure and alterations of ion exchange mechanisms. Since approximately 75% of the neuronal energy is needed for ion exchange mechanisms, we study how energy shortage impacts on ion channel dysfunction. We recently discovered two neuronally expressed ion channels, acid sensing ion channel-1 (ASIC1) and transient receptor potential melastatin-4 (TRPM4), which respond to an inflamed CNS environment with alterations in cation handling thereby contributing to neurodegeneration. Currently, we study additional ion channels and their involvement in this process as well as their disturbed downstream signalling pathways that drive both neuronal resistance and injury.

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 and diet, 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 on cognitive functions of multiple sclerosis patients in a randomised clinical trial. In collaboration with the Institute of Neurophysiology and Pathophysiology at the UKE we intend to develop novel outcome parameters to decipher alterations of cognitive networks by integrating clinical, neuropsychological and MRI measures, both in the course of the disease as well as before and after exercise.

Friese Group Gold Group Heesen 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 as a partner of the consortium NEU2 with pharmaceutical (MerckSerono) and biotech companies (Evotec, Fraunhofer IME SP) and aim at identifying compounds, which we can test in pre-clinical models.

Friese Group

Systems Biology

Understanding the mechanisms by which neurons alter and maintain their molecular signatures during inflammation is fundamental in understanding their injury. Similarly autoimmunity changes cellular states by altering gene and protein expression in certain immune cell subtypes. Genomic tools such as next-generation sequencing enable us not only to analyse the complete molecular signatures of cells but also the cascade of events that induce or maintain such signatures. Therefore, we use systems biology to get a comprehensive description of molecular and cellular components and their interactions in neurons and immune cells to predict disease processes (biomarker development) but also to identify novel master regulators of molecular cascades and networks defining a cellular state, e.g. autoimmune or neurodegenerative. These could be interesting targets for future drug development.

Identification of reliable diagnostic and prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies directly from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunomodulation. Using transcriptional and microRNA profiling of circulating immune cells isolated from multiple sclerosis patients with clearly defined disease courses, we aim at identifying distinguishable biomarkers. Furthermore, we expect to identify currently unknown mechanistic pathways contributing to the dysregulation of different immune cell subsets in multiple sclerosis. Certain aspects are jointly analysed with the Fraunhofer IME SP.

Friese Group

After neuronal sensing of inflammation downstream signalling pathways will be activated that drive both neuronal resilience and injury. Thus, accessing the dynamics of gene expression programs during the course of inflammation is a promising approach to identify potentially protective or injurious signalling networks. Here we analyse the neuronal transcriptome and miRNome to decipher novel target structures for neuroprotective treatment strategies.

Friese Group

Clinical Research

Based on the concept of health as an ability to adapt to changing personal and environmental settings, clinical research at the INIMS aims to develop treatments with a comprehensive approach. Therefore, clinical care and research includes assessment and consideration of psychological and psychosocial aspects of multiple sclerosis as well as educational (i.e. evidence-based patient information), behavioural (i.e. psychological) and lifestyle (i.e. exercise) interventions. Moreover, we pursue phase I and phase II treatment trials combined with mechanistic laboratory studies in the area of unmet clinical needs such as safe treatments in early MS (i.e. boswellic acids, immunological tolerance induction), highly immunosuppressive approaches for aggressive MS (i.e. autologous hematopoietic stem cell transplantation) but also neuroprotective concepts (i.e. erythropoietin). 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

Patients with multiple sclerosis have a high risk for depression and cognitive problems including difficulties with memory and information processing. We study the role of inflammatory and neurodegenerative processes for the pathogenesis of these symptoms by combining clinical assessments with neuroimaging of relevant brain circuits and laboratory studies using techniques from molecular biology, immunology, and endocrinology. We focus on how the brain communicates with the immune system (brain-immune-endocrine networks) and how disturbances in these networks can give rise to impairment of higher-order brain functions such as cognition and mood regulation.

Gold Group

Neuropsychiatric symptoms such as depression have a considerable impact on activity and participation. However, few therapeutic options are available to effectively treat them. Thus, there is an urgent but unmet need to develop novel approaches including highly standardized psychological interventions that can be implemented at a large scale in MS. We develop online and group education programmes based on a framework of complex interventions and conduct randomised controlled trials to test their efficacy.

Heesen Group Gold Group

Currently exercise is the most effective neuroprotective treatment but disease-stage adapted format and dosing as well as mechanisms and long-term effectiveness are ill defined. We study exercise with clinical, imaging, neurophysiologic and molecular approaches.

Heesen Group Gold Group Friese 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 is investigated in early highly aggressive multiple sclerosis. Development of clinical trial designs (baseline-to-treatment and adaptive study designs) addresses the problem of recruitment to studies while licensed treatment already exists. Outcome research aims at improving the sensitivity and clinical meaningfulness of study endpoints by following triangulation of measurements: objective (e.g. MRI, OCT), rate-based (e.g. walking test) and patient-reported (e.g. quality of life). Every clinical study is accompanied by elaborated mechanistic cellular and/or molecular studies to identify mechanisms of effectiveness or failure.

Heesen Group

Clinical research has a strong commitment to engage in early trials for neuroprotective treatments especially from investigator-initiated trials. We work on improvement of outcomes and designs for these approaches with a focus on structural MRI, OCT and elaborated clinical outcome such as accelerometry and computer-based contrast sensitivity but also new cognitive measures such as social cognition.

Heesen Group

Imaging Research

SeMSI is a division of the Department of Diagnostic and Interventional Neuroradiology at the University Medical Centre Hamburg-Eppendorf (UKE), which is specialized in multiple sclerosis imaging. We aim to develop and implement new MR sequences to detect early structural alterations that might serve as prognostic parameters and to identify MR parameters to monitor treatment effects even in small treatment cohorts, particularly with regard to functional, vascular and degenerative processes in brain tissue. Research activities include the development of new post-processing algorithms and image-analysis software, as well as the investigation of Optical Coherence Tomography (OCT) as biomarker for brain network integrity.

In general, standard MRI techniques only provide information on gross pathology in multiple sclerosis and allow us to visualize e.g. multiple sclerosis lesions within the brain and spine. Nevertheless, it is known that there are also more subtle changes within the brain parenchyma that cannot be detected with these standard techniques. We therefore aim to develop and test new MRI techniques that might increase the sensitivity to detect and visualize changes beyond the tip of the iceberg. In the future, this might enable us to better estimate and monitor disease progression and treatment effects.

Siemonsen Group

One aim of our research is to better detect, understand and classify pathologic changes within the brain parenchyma in vivo – e.g. in a prospective cohort of PPMS patients. We are currently testing a number of new MRI techniques that might provide further insight into metabolic and pathophysiologic processes and therefore might provide information beyond the structural information provided by standard techniques and histopathology studies.

Siemonsen Group

Due to the heterogeneity of multiple sclerosis, monitoring of disease activity and neurodegeneration needs to combine different measures. E.g. impairment of the visual system is investigated with visual functioning questionnaires, vision testing, retinal atrophy in the OCT and MRI measures of network integrity or brain atrophy. We aim to identify and understand functional and structural networks of outcomes that are relevant to patients and have a high ecologic validity.

Siemonsen Group Heesen Group

Biobanking

Since 2008 the INIMS is running a biobank in which biomaterial such as peripheral blood mononuclear cells (PBMCs), serum, cerebrospinal fluid (CSF) as well as CSF-derived T cells are systematically stored. Patients are recruited and samples are drawn at the multiple sclerosis outpatient clinic and processed and stored at the INIMS laboratory. This also involves well established electronic database systems for pseudonymous storage of clinical and laboratory data in accordance with ethical approval, which have been developed by the ZMNH IT department. Until 2014, about 9,000 samples from more than 2,000 MS patients and 500 healthy individuals as well as more than two million MRI images have been collected. This exceptional resource of biomaterial together with clinical data enables fast and independent research in many areas of activities at the INIMS – from basic immunology to mechanistic studies substantiating clinical trials, as well as biomarker development and systems biology.
Copyright 2015. Institute of Neuroimmunology and Multiple Sclerosis. Impressum