Spinal Cord Injury
The workgroup covers the research topics like risk factors and damage Spinal Cord Injury Research.
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- Group Leader - Reserach Spinal Cord Injury
- Research Team
- Spinal Cord Injury Research
- Clinical trials
- Experimental models
- Cell- and molecular biology
- Topics and ongoing projects
- Spinal Cord Injury (SCI): Regeneration
- Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS)
- Resolution of inflammation in the lesioned CNS
- Can resolution of inflammation be propagated?
- Cooperation partners
Spinal Cord Injury Research
Spinal cord injury (SCI) is a tremendous incident in everyone's life. The patients suffer from neurologic deficits such as sensory and/or motor paralysis but also disorders of the vegetative nervous system (Schwab et al., 2006). Even though some of the predominantly young patients recover and return to a mostly independent life, in most cases a lifelong handicap remains. Despite fundamental progress in basic, cellular and molecular research in the last years only little is known about pathophysiological processes following spinal cord injury in humans (Schwab et al., 2006). Given the translational character the Spinal Cord Injury group is an associated member of the "European Multicenter Study about Spinal Cord Injury (EMSCI)".
Design and conduction of diagnostic and interventional mono-/and multicentric randomized trials in patients following spinal cord injury
- SCI-models (contusion, transection)
- Pneumonia model (Streptococcus pneumoniae)
- Peritonitis model
Cell- and molecular biology
- Gene expression analysis (qPCR, Western Blot)
- FACS analysis
- Immunohistochemistry (single and double labeling)
Topics and ongoing projects
Spinal Cord Injury (SCI): Regeneration
The main cause of the severity of SCI is the failure of axonal regeneration and restricted plasticity. It is well known, that the inhibitory environment repulses the axonal outgrowth following SCI.
Identification and blockade of these inhibitors may lead to axonal regeneration and gain of neurological function (Schwab et al., 2006). In addition, we investigate pathophysiological degenerative processes in in vivo models of SCI. Given distinct post-injury tissue responses putatively leading to differing therapeutic time frames.
These findings will be compared to humans. One aspect is the secondary subacute inflammatory process. Another aim is to protect the intrinsic recovery potential of injured nerve fibers following SCI, which is jeopardized by extrinsic factors such as infections (see below). In addition, visualizing the translational character, a prospective multicenter diagnostic trial but also a randomized placebo-controlled interventional trial is conducted.
Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS)
Infections, i.e. pneumonia and urinary tract infections, are a leading cause of morbidity and mortality but also may dampen the intrinsic recovery potential in patients with acute spinal cord injury. It has recently become clear that SCI might increase susceptibility to infections by central nervous system (CNS)-specific mechanisms: CNS-injury induces a disturbance of the normally well-balanced interplay between the immune system and the CNS (Meisel et al., 2005).
As a result, also SCI may lead to a secondary immunodeficiency, referred to as SCI injury-induced immunodepression syndrome (Riegger et al., 2007, 2009). Our research team investigates the qualitative and quantitative aspects of immune depression triggered by SCI, referring to functional impairment of innate and specific immune functions. Here different experimental models of SCI and pneumonia are used. This enables the detection of underlying SCI-specific "neurogenic" mechanisms of the elicited immune depression and ways of pharmacological intervention. The impact of fascilitated infections on secondary damage and intrinsic recovery potential is under investigation.
Furthermore, for the identification of novel clinical strategies we are realizing a SCI-IDS clinical trial as a bedside to bench and to bedside project in order to characterize the SCI-IDS pathoimmunology and phenotype in humans in more detail. These strategies aim to provide novel targets for future pharmacological interventions in order to prevent infections limiting the intrinsic recovery potential.
Resolution of inflammation in the lesioned CNS
Resolution of acute inflammation is an active process essential for appropriate host responses, tissue protection and the return to homeostasis. Resolution of inflammation is defective following SCI (Schwab et al., 2001). During intact resolution, specific omega-3 polyunsaturated fatty-acid derived mediators are generated within resolving exudates (e.g., resolvin E1, protectin D1) acting as agonists for resolution (Schwab et al., 2007). Further investigations demonstrated, that these mediators promote phagocyte removal during acute inflammation by regulating leukocyte efflux, increasing macrophage ingestion of apoptotic polymorphonuclear leukocytes (PMNs) in vitro and in vivo and are therefore potent agonists for resolution of inflamed tissues (Schwab et al., 2007).
We translate the concept of resolution "behind" the blood brain barrier and its role in SCI pathophysiology and tissue remodeling. Sustained inflammation and/or impaired resolution may enhance secondary damage and degenerative processes ("tertiary damage") following SCI.
"Resolution-deficit" following acute traumatic CNS-injury
Kinetics of COX-1+ cells following CNS injury illustrating a persisting accumulation of activated microglia/macrophages at the lesion site (dark bars) for up to several month following CNS injury. Schwab et al., 2002. J Neurosurgery, 96, 892-899
„Smouldering“ parenchymal monocytosis following cerebral ischaemia (CD68+, COX-1+, CD14+) at the lesion site month after human CNS injury. Schwab et al., 2001. J Neurotrauma, 18, 881-90. Beschorner et al., 2002. J Neuroimmunol, 126, 107-115
Can resolution of inflammation be propagated?
Can resolution of inflammation be propagated?
Leukocyte traffic from zymosan-inflamed tissue towards afferent lymph nodes nd spleen, qualitative. Proof of principle-experiments demonstrated that, complementary to orthodox anti-inflammatory treatment aiming to limit cell influx, resolution agonists foster effective cell traffic out of the inflammatory site and migration forward afferent lyphatics. Schwab, J.M., Chiang, N., Arita, M., Serhan, C.N. (2007) Nature, 447, 869-74
Leukocyte traffic from zymosan-inflamed tissue towards lymph nodes and spleen, quantitative. Schwab, J.M., Chiang, N., Arita, M., Serhan, C.N. (2007) Nature, 447, 869-874
Fouad K, Popovich PG, Kopp MA, Schwab JM. The neuroanatomical-functional paradox in spinal cord injury. Nat Rev Neurol. 2021 Jan;17(1):53-62.
Watzlawick R, Antonic A, Sena ES, Kopp MA, Rind J, Dirnagl U, Macleod M, Howells DW, Schwab JM. Outcome heterogeneity and bias in acute experimental spinal cord injury: A meta-analysis. Neurology. 2019 Jul 2;93(1):e40-e51.
Prüss H, Tedeschi A, Thiriot A, Lynch L, Loughhead SM, Stutte S, Mazo IB, Kopp MA, Brommer B, Blex C, Geurtz LC, Liebscher T, Niedeggen A, Dirnagl U, Bradke F, Volz MS, DeVivo MJ, Chen Y, von Andrian UH, Schwab JM. Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex. Nat Neurosci. 2017 Nov;20(11):1549-1559.
Kopp MA, Watzlawick R, Martus P, Failli V, Finkenstaedt FW, Chen Y, DeVivo MJ, Dirnagl U, Schwab JM. Long-term functional outcome in patients with acquired infections after acute spinal cord injury. Neurology. 2017 Feb 28;88(9):892-900.
Kopp MA, Liebscher T, Watzlawick R, Martus P, Laufer S, Blex C, Schindler R, Jungehulsing GJ, Knüppel S, Kreutzträger M, Ekkernkamp A, Dirnagl U, Strittmatter SM, Niedeggen A, Schwab JM. SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol. BMJ Open. 2016 Jul 26;6(7):e010651.
Brommer B, Engel O, Kopp MA, Watzlawick R, Müller S, Prüss H, Chen Y, DeVivo MJ, Finkenstaedt FW, Dirnagl U, Liebscher T, Meisel A, Schwab JM. Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level. Brain. 2016 Mar;139(Pt 3):692-707.
Watzlawick R., Sena E.S., Dirnagl U., Brommer B., Kopp M.A., Macleod M.R., Howells D.W., Schwab J.M. (2014) Effect and Reporting Bias of RhoA/ROCK-Blockade Intervention on Locomotor Recovery After Spinal Cord Injury: A Systematic Review and Meta-analysis. JAMA Neurol., 71:91-9.
Failli V., Kopp M.A., Gericke C., Martus P., Klingbeil S., Brommer B., Laginha I., Chen Y., DeVivo M.J., Dirnagl U., Schwab J.M. (2012) Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain, 135:3238-50.
Prüss H., Iggena D., Baldinger T., Prinz V., Meisel A., Endres M., Dirnagl U., Schwab J.M. (2012) Evidence for intrathecal antibody synthesis in stroke – a cohort study. Arch. Neurol., 69:714-7.
Prüss H, Kopp M, Brommer B, Gatzemeier N, Laginha I, Dirnagl U, Schwab JM (2011) Non-resolving aspects of acute inflammation after spinal cord injury (SCI): indices and resolution plateau. Brain Pathol, 21:652-60
Schwab JM, Chiang N, Arita M, Serhan CN. 2007. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447:869-874