Spinal Cord Injury Research

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)".

Topics and ongoing projects

1. 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.

Impermissive mileu for axonal outgrowth

Impermissive mileu for axonal outgrowth is composed by stop signs located in the scar and in the CNS myelin. Schwab et al., 2006. Prog Neurobiol

 

 

Substrate for regeneration: dystrophic axons following SCI (axonal tracing, BDA).

Substrate for regeneration: dystrophic axons following SCI (axonal tracing, BDA)

Substrate for regeneration: dystrophic axons (dark bulbs) at the lesion site following SCI (axonal tracing, BDA). Schwab et al., 2006. Prog Neurobiol

 

 

Pathophysiology after spinal cord injury: Induction of secondary damage, regeneration failure and demyelination.

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2. 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.

Neurogenic immune deficiency following SCI

Neurogenic immune deficiency following SCI (i) occurs early within 24h, (ii) affects cells of the adaptive and innate immune system, and (iii) is most pronounced during the first week after SCI.
Schwab et al., 2006. Prog Neurobiol, 78, 91-116

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3. 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 (lesion)

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, 892-99

 

 

„Smouldering“ parenchymal monocytosis following cerebral ischaemia

„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?

Leucocyte traffic from zymosan-inflamed tissue by way of lymph nodes and spleen, qualitative

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

 

 

Leucocyte traffic from zymosan-inflamed tissue by way of lymph nodes and spleen, quantitative

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

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Methods

Clinical trials

  • Design and conduction of diagnostic and interventional mono-/and multicentric randomized trials in patients following spinal cord injury.

Experimental models

  • 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)

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Cooperations

Clinical

Prof. Wolfgang Ertel, MD, Klinik für Unfallchirurgie, Charité Berlin
Dr. Christian Meisel, MD, Institut für medizinische Immunologie, Charité Berlin
Andreas Niedeggen, MD, Unfallkrankenhaus Berlin
Prof. Peter Vajkoczy, MD, Klinik für Neurochirurgie, Charité Berlin
Prof. Yuying Chen, MDPhD, University of Alabama at Birmingham, U.S.A.

Scientific

Prof. Samuel David, PhD, McGill University, Montreal, Canada
Prof. Nan Chiang, PhD, Harvard University, Boston, U.S.A.
Prof. Karsten Gronert, PhD, University of California, Berkeley, U.S.A.
Prof. Zhigang He, PhD, Harvard University, Boston, U.S.A.
Prof. Peter Rosenberger, MD, University of Tuebingen, Germany
Prof. Charles N. Serhan, PhD, Harvard University, Boston, U.S.A.
Prof. Stephen M. Strittmatter, MD, PhD, Yale University, New Haven, U.S.A.

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Selected references

Mirakaj V, Brown S, Laucher S, Steinl C, Klein G, Köhler D, Skutella T, Meisel C, Brommer B, Rosenberger P, Schwab JM (2011) RGM-A inhibits leukocyte migration and mitigates inflammation. Proc Natl Acad Sci USA, 108:6555-60

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    

Rosenberger P, Schwab JM, Mirakaj V, Masekowsky E, Mager A, Morote-Garcia JC, Unertl K, Eltzschig HK. 2009. Hypoxia-inducible factor-dependent induction of netrin-1 dampens inflammation caused by hypoxia. Nat Immunol 10:195-202

Schwab JM, Chiang N, Arita M, Serhan CN. 2007. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447:869-874

Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. 2005. Central nervous system injury-induced immune deficiency syndrom. Nat Rev Neurosci 6:675-686

Schwab JM, Brechtel K, Mueller CA, Failli V, Kaps HP, Tuli SK, Schluesener HJ. 2006. Experimental strategies to promote spinal cord regeneration-an integrative perspective. Prog Neurobiol 78:91-116

Riegger T, Conrad S, Schluesener HJ, Kaps HP, Badke A, Baron C, Gerstein J, Dietz K, Abdizahdeh M, Schwab JM. 2008. Immune depression syndrome following human spinal cord injury: A pilot study. Neuroscience 158:1194-1199

Riegger T, Conrad S, Liu K, Schluesener HJ, Abdibzahdeh M, Schwab JM. 2007. Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur J Neurosci 25:1743-1747

Schwab JM, Conrad S, Monnier PP, Julien S, Mueller BK, Schluesener HJ. 2005. Spinal cord injury induced lesional expression of the repulsive guidance molecule (RGM). Eur J Neurosci 21:1569-1576

Schwab JM, Failli V, Chédotal A. 2005. Injury-related dynamic myelin/oligodendrocyte axon-outgrowth inhibition in the central nervous system. Lancet 365: 2055-2057.

Schwab JM, Schluesener HJ, Laufer S. 2003. COX-3: just another COX or the solitary elusive target of paracetamol. Lancet 361:981-982

Schwab JM, Frei E, Klusmann I, Schnell L, Schwab ME, Schluesener HJ. 2001. AIF-expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. J Neuroimmunol 119:214-222

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Funding

IFP - Internationale Stiftung für Forschung in Paraplegie (Zürich)

 

 

Berlin Center for Regenerative Therapies

 

 



in cooperation with

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Team Schwab

Project Leader
Jan Schwab, MD PhD

Project Team
Marcel Kopp, MD
Benedikt Brommer, MSc
Harald Prüß, MD
Inês Laginha, MD
Cand. med. Ralf Waclawczyk