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Neuroimmunology

Research on mechanisms of inflammation in the nervous system presents a major translational focus in Düsseldorf, bridging the gap between basic and clinical sciences. This approach is best reflected by research on multiple sclerosis (MS), the most common chronic inflammatory disease of the CNS and immune mediated peripheral neuropathies.

The department and the Düsseldorf Multiple Sclerosis Center (DMSC) investigate both immunological and neurobiological processes observed in the course of autoimmune neuroinflammation of the CNS, covering molecular steps of immune cell activation, reversible and irreversible neurodegeneration, as well as mechanisms of disturbed regeneration, with a view to develop new experimental therapies.

MS is thought to be an autoimmune disease in which autoreactive T cells invade the CNS and initiate a local immune attack directed against the myelin sheaths in the CNS and in which B cells set up a compartmentalized chronic immune environment with continued generation of demyelinating autoantibodies. MS therapy research is a highly active field in neurology (Hartung et al., Ann Neurol, 2009). As current immune-based treatments suggest a quite narrow window of therapeutic opportunity and since axonal damage and fall out critically determine accumulating disability, there is an urgent need to focus on neurodegenerative and regenerative processes, considering the complex interplay between the immune and nervous system in MS. In these areas, NND researchers have a long-standing and highly successful track record.

PIs

Orhan Aktas is focusing on the molecular basis of inflammatory neurodegeneration and the identification of novel therapeutic targets. Using the MS animal model of experimental autoimmune encephalomyelitis (EAE), he showed that statins efficiently block antigen-mediated T cell proliferation (Aktas et al, J Exp Med 2003). In addition, the bradykinin system was uncovered as an endogenous control mechanism limiting encephalitogenic T cell migration (Schulze-Topphoff et al, Nat Med 2009). Moreover, work on microglia (Diestel et al, J Exp Med 2003) and T cell mediated damage mechanisms (Aktas et al, Neuron 2005) linked autoimmune demyelination to neuronal damage (Zipp & Aktas, TINS 2006). Recent work on neural progenitor cell homeostasis revealed that inflammation-associated changes may limit endogenous repair capacities via epigenetic (Prozorovski et al, Nat Cell Biol 2008) and proteasome-associated pathways (Seifert, Cell 2010). Finally, as the coordinator of the DMSC, Aktas is working on emerging clinical issues such as new measures for neurodegeneration including optic coherence tomography. Moreover, he is investigating specific MS subforms such as neuromyelitisoptica (NMO), where he is coordinating a national network and associated partner of a recently founded European FP7 initiative on NMO (together with H.-P. Hartung).

The molecular characterization of immune effector cells infiltrating the target organ is a major research area of Norbert Goebels. He identified clonally expanded, tissue invading CD8+ T cell populations in MS (Babbe J Exp Med 2000; Skulina, PNAS 2004) and myositis (Hofbauer, PNAS 2003) and investigated the role of dendritic cell homeostasis in EAE (Greter, Nat Med 2005). He also contributed as PI to several recent MS trials (Giovannoni, N Engl J Med 2010; Cohen, N Engl J Med 2010; Kappos, N Engl J Med 2010). Applying state-of-the-art reverse genetics and recombinant antibody technology, Goebels’ group reconstructed the antigen specificity of expanded plasma cell populations in the cerebrospinal fluid of patients with CNS inflammation (Künzle, Infect Immun 2007; von Büdingen, Eur J Immunol 2008; von Büdingen, J Neuroimm 2010). This genuine “bedside-to-bench” approach aims at the identification of novel targets of humoral immune responses directly from affected MS patients.

Recently, his group established and refined an experimental model of the immune-CNS interface, which allows live imaging of the interaction of defined immune components and brain resident cells and reduces the need for laboratory animals (Goebels, ALTEX 2007; Harrer, ExpNeurol 2009). Using this approach, they identified oligodendrocytes as antigen presenting cells and myelin-directed CD8+ T cells as potent drivers of “bystander” axonal damage in CNS inflammation (Sobottka, Am J Pathol 2009). They also vizualized CNS myelination itself (Sobottka et al., Glia 2011), proposinga new concept of myelination which attributes an active role to the axon, shifting the focus on mechanisms of disturbed regeneration in the inflamed nervous system.

Hans-Peter Hartung was Chair of the Department of Neurology and the Düsseldorf Multiple Sclerosis Center and has a track record in basic and clinical neuroimmunology. He designed and performed important approval studies for the therapy of MS, ranging from mitoxantrone treatment in secondary progressive disease courses (Hartung et al , Lancet 2002;360:2018) to new oral drugs for relapsing-remitting MS (Cohen et al, N Engl J Med 2010; Comi et al, Lancet 2009; Freedman et al, Neurol 2011; Kappos et al, LancNeurol 2009; Khatri et al, LancNeurol 2011Aktas et al, TINS 2010).

Prof. Hartung is interested in the evolution of clinical trial methodology, such as state-of-the-art response criteria for MS therapy studies (Hartung and Aktas, Lancet Neurol 2011), and in the assessment and implementation of biomarkers for established immunomodulatory therapies in MS, such as neutralizing antibodies against interferon (IFN)-β (Hartung et al, Neurology 2011; Polman et al, Lancet Neurol 2010).

Together with Patrick Küry and Hans W. Müller he is interested in exploring reparative strategies in the context of immune, traumatic and ischemic neural injury (Kotter et al, Brain 2011; Dihne et al, Stroke 2011; Kremer at al, Ann Neurol 2011Schira et al, Brain 2011).

Moreover, his longstanding research crucially contributed to our current understanding of the immunopathogenesis of inflammatory disease of the peripheral nervous system, including Guillain-Barré syndrome (GBS) (Hartung et al, Ann Neurol 1993) as well as chronic inflammatory demyelinating polyneuropathy (CIDP) (Köller et al, N Engl J Med 2005). These studies paved the way to successful conduct of pivotal approval trials with his participation, such as treatment of CIDP with polyclonal immunoglobulins (Donofrio et al, Arch Neurol 2010; Hughes et al , Lancet Neurol 2008; Merkies et al, Neurol 2009).

Regarding regeneration in the inflamed CNS, the group of Patrick Küry is focusing on the contribution of local progenitor and stem cells, investigating endogenous inhibitors of remyelination (Kremer et al, Ann Neurol 2011). His group was able to identify p57kip2 as an important regulator of the differentiation capacity of myelinating cells in both, the PNS and the CNS (Heinen et al , PNAS 2008; Kremer et al., PNAS 2009). In addition, his group identified the CXCR7 chemokine receptor as novel differentiation promoting factor for oligodendroglial precursor cells (Göttle et al., Ann Neurol 2010). Both signals appear to act independently since p57kip2 suppression and CXCL12 stimulation can be combined in order to further promote the oligodendroglial differentiation process.

Apart from resident oligodendroglial precursor cells adult neural stem/progenitor cells can also be activated in order to generate new oligodendrocytes  which is why the Küry group investigates the role of p57kip2 in directing and regulating adult stem cell differentiation (Jadasz et al., submitted). This study revealed that p57kip2 levels influence a neural stem cell’s decision to become either astrocyte or oligodendrocyte. The generation of oligodendroglial precursor cell characteristics was found to be enhanced following suppression of the p57kip2 gene and found to dominate strong astrocytic differentiation/gliosis mediating stimuli such as the presence of bone morphogenetic proteins (BMPs).

Klaus Pfeffer is interested in the characterisation of immunological effector systems involved in the elimination of intracellular pathogens, including mechanisms triggered by classical proinflammatory cytokines, such as the interferons or members of the TNF family (Scheu et al, J Exp Med 2002; Ehlers et al , J Immunol. 2003). His lab identified a family of IFN-induced GTPases, called mGBPs, that are highly induced under proinflammatory conditions (Degrandi et al, J Immunol 2007).

Stefanie Scheu leads an Emmy Noether group in Pfeffer’s department and generated “knock-in” animals reporting endogenous IFN-beta production by fluorescence in vivo (Scheu et al, PNAS 2008). In the light of the undisputed role of IFN-ß as an immunomodulatory MS treatment, ongoing EAE experiments will shed light on the precise mode of action of this approved MS drug.

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