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TRR 43:  The Brain as a Target of Inflammatory Processes

Subject Area Medicine
Term from 2008 to 2016
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 29837756
 
Final Report Year 2017

Final Report Abstract

During its two funding periods, the focus of the Collaborative Research Centre TRR 43 (SFB TRR 43) was to substantiate the hypothesis that immune actions are not only involved in prototypical inflammatory brain diseases such as multiple sclerosis (MS) or encephalitides, but also play an important role in the pathogenesis and pathology of central nervous system (CNS) disorders that are generally considered to be primarily noninflammatory, such as stroke, brain tumors and neurodegenerative disorders. In any of these conditions or disorders, immune cells interact with cells of the nervous system via complex signalling cascades. Besides local cross talk between cells of the nervous and the immune systems, there is increasing evidence that CNS alterations also impact systemic immune responses which in turn may facilitate systemic infections or protect CNS tissue by modulating local CNS actions. Although the initiating events may differ considerably between various CNS diseases, they seem, at least in some instances, to utilize common pathways for the cross talk between the immune and the nervous systems. Deciphering these common - or divergent - pathways was a common denominator for the research of the SFB TRR 43 consortium. While insights into immune functions in certain CNS diseases have already opened up new avenues for preventing or treating these diseases, the SFB TRR 43 envisaged transferring knowledge of immune actions in a given CNS disease to CNS disorders with different origins but similar immune actions. Recent insights have led to a discrimination of CNS disorders as having either an innate-immune or an adaptive-immune component. The translational implication of this distinction will be a therapeutic focus on the respective immune process active in the disease; it is noteworthy that it does not matter whether the immune contribution is primary and disease-causing or secondary and disease-maintaining or - exacerbating. Our collaborative efforts have resulted in the description and characterisation of hitherto unknown roles of both the innate and the adaptive immune system in various CNS conditions or disorders. A few of the “highlights” include the delineation of new pathophysiological aspects of myeloid cells/microglia in neurodegenerative settings such as Alzheimer’s disease (AD) and also in stroke, subarachnoidal hemorrhage and brain tumors, as well as the finding that microRNA can act as signal molecules and thus promote neurodegeneration. We also discovered new mechanisms relevant to inflammatory demyelinating diseases with respect to myelin assembly, the support of axonal energy metabolism by myelinating oligodendrocytes and the cure of hypomyelination by neuroinflammation-dependent transfer of dietary cholesterol. Data provided by SFB TRR 43 principle investigators also enabled a better understanding of crucial steps involved in the initiation of disease-inducing T cells and their recruitment to and interactions within the brain in CNS autoimmunity, thus contributing to a better understanding of the pathogenesis and disease progression in MS and neuromyelitis optica. Moreover, principle investigators of the SFB TRR 43 provided first evidence for a therapeutic intervention in AD, utilizing blockers against a defined immune molecule, namely interleukin (IL)-12 and -23, which appears to be a promising target in AD. During the second funding period, the SFB TRR 43 researchers from Berlin and Göttingen profited from the established close ties and synergistic cooperations, thus considerably expanding the existing joint research. By combining the efforts of clinicians and basic scientists, among others neuroimmunologists and neurobiologists, in a network approach, the SFB TRR 43 consortium has taken up the challenges of the emerging field of translational research. In addition, the SFB TRR 43 has served to further shape the profile and scope of the ongoing neuroimmunological research at both sites insofar as our research focused on processes inside rather than outside the CNS. Particularly in light of emerging novel neuroimmunological concepts to distinguish immune driven CNS diseases mainly by their innate-immune or adaptive-immune predominance, our initial organizational basis for the SFB TRR 43 with its focus on the interaction of the immune system with the nervous system can be seen in retrospect as visionary and imaginative.

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