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Published in: BMC Neurology 1/2016

Open Access 01-12-2016 | Study protocol

Natural Killer (NK) Cell Functionality after human Spinal Cord Injury (SCI): protocol of a prospective, longitudinal study

Authors: Inês Laginha, Marcel A. Kopp, Claudia Druschel, Klaus-Dieter Schaser, Benedikt Brommer, Rick C. Hellmann, Ralf Watzlawick, Ramin-Raul Ossami-Saidi, Harald Prüss, Vieri Failli, Christian Meisel, Thomas Liebscher, Erik Prilipp, Andreas Niedeggen, Axel Ekkernkamp, Ulrike Grittner, Sophie K. Piper, Ulrich Dirnagl, Monica Killig, Chiara Romagnani, Jan M. Schwab

Published in: BMC Neurology | Issue 1/2016

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Abstract

Background

Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI.

Methods and design

The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5–9) days, 14 days (11–28) days, and 10 (8–12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8–12 weeks following SCI. Secondary endpoints are the NK cell’s TNF-α and IFN-γ production by the NK cells 8–12 weeks following SCI.

Discussion

The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality.

Trial registration

Literature
1.
go back to reference Failli V, Kopp MA, Gericke C, Martus P, Klingbeil S, Brommer B, Laginha I, Chen Y, DeVivo MJ, Dirnagl U, Schwab JM. Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain. 2012;135:3238–50.CrossRefPubMed Failli V, Kopp MA, Gericke C, Martus P, Klingbeil S, Brommer B, Laginha I, Chen Y, DeVivo MJ, Dirnagl U, Schwab JM. Functional neurological recovery after spinal cord injury is impaired in patients with infections. Brain. 2012;135:3238–50.CrossRefPubMed
2.
go back to reference Soden RJ, Walsh J, Middleton JW, Craven ML, Rutkowski SB, Yeo JD. Causes of death after spinal cord injury. Spinal Cord. 2000;38:604–10.CrossRefPubMed Soden RJ, Walsh J, Middleton JW, Craven ML, Rutkowski SB, Yeo JD. Causes of death after spinal cord injury. Spinal Cord. 2000;38:604–10.CrossRefPubMed
3.
go back to reference DeVivo MJ, Kartus PL, Stover SL, Rutt RD, Fine PR. Cause of death for patients with spinal cord injuries. Arch Intern Med. 1989;149:1761–6.CrossRefPubMed DeVivo MJ, Kartus PL, Stover SL, Rutt RD, Fine PR. Cause of death for patients with spinal cord injuries. Arch Intern Med. 1989;149:1761–6.CrossRefPubMed
4.
go back to reference DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and causes of death among persons with spinal cord injury. Arch Phys Med Rehabil. 1999;80:1411–9.CrossRefPubMed DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and causes of death among persons with spinal cord injury. Arch Phys Med Rehabil. 1999;80:1411–9.CrossRefPubMed
5.
go back to reference Riegger T, Conrad S, Liu K, Schluesener HJ, Adibzahdeh M, Schwab JM. Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur J Neurosci. 2007;25:1743–7.CrossRefPubMed Riegger T, Conrad S, Liu K, Schluesener HJ, Adibzahdeh M, Schwab JM. Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur J Neurosci. 2007;25:1743–7.CrossRefPubMed
6.
go back to reference Riegger T, Conrad S, Schluesener HJ, Kaps HP, Badke A, Baron C, Gerstein J, Dietz K, Abdizahdeh M, Schwab JM. Immune depression syndrome following human spinal cord injury (SCI): a pilot study. Neuroscience. 2009;158:1194–9.CrossRefPubMed Riegger T, Conrad S, Schluesener HJ, Kaps HP, Badke A, Baron C, Gerstein J, Dietz K, Abdizahdeh M, Schwab JM. Immune depression syndrome following human spinal cord injury (SCI): a pilot study. Neuroscience. 2009;158:1194–9.CrossRefPubMed
7.
go back to reference Campagnolo DI, Keller SE, DeLisa JA, Glick TJ, Sipski ML, Schleifer SJ. Alteration of immune system function in tetraplegics. A pilot study. Am J Phys Med Rehabil. 1994;73:387–93.CrossRefPubMed Campagnolo DI, Keller SE, DeLisa JA, Glick TJ, Sipski ML, Schleifer SJ. Alteration of immune system function in tetraplegics. A pilot study. Am J Phys Med Rehabil. 1994;73:387–93.CrossRefPubMed
8.
go back to reference Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003;198:725–36.CrossRefPubMedPubMedCentral Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, Ruscher K, Victorov IV, Priller J, Dirnagl U, Volk HD, Meisel A. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003;198:725–36.CrossRefPubMedPubMedCentral
9.
go back to reference Mrakovcic-Sutic I, Tokmadzic VS, Laskarin G, Mahmutefendic H, Lucin P, Zupan Z, Sustic A. Early changes in frequency of peripheral blood lymphocyte subpopulations in severe traumatic brain-injured patients. Scand J Immunol. 2010;72:57–65.PubMed Mrakovcic-Sutic I, Tokmadzic VS, Laskarin G, Mahmutefendic H, Lucin P, Zupan Z, Sustic A. Early changes in frequency of peripheral blood lymphocyte subpopulations in severe traumatic brain-injured patients. Scand J Immunol. 2010;72:57–65.PubMed
10.
go back to reference Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nature reviews. Neuroscience. 2005;6:775–86.PubMed Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nature reviews. Neuroscience. 2005;6:775–86.PubMed
11.
go back to reference Cruse JM, Keith JC, Bryant Jr ML, Lewis Jr RE. Immune system-neuroendocrine dysregulation in spinal cord injury. Immunol Res. 1996;15:306–14.CrossRefPubMed Cruse JM, Keith JC, Bryant Jr ML, Lewis Jr RE. Immune system-neuroendocrine dysregulation in spinal cord injury. Immunol Res. 1996;15:306–14.CrossRefPubMed
12.
go back to reference Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S. Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol. 1985;135:755s–65s.PubMed Felten DL, Felten SY, Carlson SL, Olschowka JA, Livnat S. Noradrenergic and peptidergic innervation of lymphoid tissue. J Immunol. 1985;135:755s–65s.PubMed
13.
go back to reference Irwin M. Stress-induced immune suppression. Role of the autonomic nervous system. Ann N Y Acad Sci. 1993;697:203–18.CrossRefPubMed Irwin M. Stress-induced immune suppression. Role of the autonomic nervous system. Ann N Y Acad Sci. 1993;697:203–18.CrossRefPubMed
14.
go back to reference Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S, Huang K, Weil Z, Bratasz A, Wells J, Powell ND, Sheridan JF, Whitacre CC, Rabchevsky AG, Nash MS, Popovich PG. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J Neurosci. 2013;33:12970–81.CrossRefPubMedPubMedCentral Zhang Y, Guan Z, Reader B, Shawler T, Mandrekar-Colucci S, Huang K, Weil Z, Bratasz A, Wells J, Powell ND, Sheridan JF, Whitacre CC, Rabchevsky AG, Nash MS, Popovich PG. Autonomic dysreflexia causes chronic immune suppression after spinal cord injury. J Neurosci. 2013;33:12970–81.CrossRefPubMedPubMedCentral
15.
go back to reference Denes A, Boldogkoi Z, Uhereczky G, Hornyak A, Rusvai M, Palkovits M, Kovacs KJ. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience. 2005;134:947–63.CrossRefPubMed Denes A, Boldogkoi Z, Uhereczky G, Hornyak A, Rusvai M, Palkovits M, Kovacs KJ. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience. 2005;134:947–63.CrossRefPubMed
16.
go back to reference Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol. 2004;5:575–81.CrossRefPubMed Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol. 2004;5:575–81.CrossRefPubMed
17.
go back to reference Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.PubMed Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve–an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.PubMed
20.
go back to reference Orange JS, Ballas ZK. Natural killer cells in human health and disease. Clin Immunol. 2006;118:1–10.CrossRefPubMed Orange JS, Ballas ZK. Natural killer cells in human health and disease. Clin Immunol. 2006;118:1–10.CrossRefPubMed
21.
go back to reference Colucci F, Caligiuri MA, Di Santo JP. What does it take to make a natural killer? Nature reviews. Immunology. 2003;3:413–25.PubMed Colucci F, Caligiuri MA, Di Santo JP. What does it take to make a natural killer? Nature reviews. Immunology. 2003;3:413–25.PubMed
22.
go back to reference Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–40.CrossRefPubMed Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–40.CrossRefPubMed
23.
go back to reference Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97:3146–51.CrossRefPubMed Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA. Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood. 2001;97:3146–51.CrossRefPubMed
24.
go back to reference Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol. 2009;254:149–54.CrossRefPubMed Aktas E, Kucuksezer UC, Bilgic S, Erten G, Deniz G. Relationship between CD107a expression and cytotoxic activity. Cell Immunol. 2009;254:149–54.CrossRefPubMed
25.
go back to reference Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Knosalla I, Romagnani C. CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood. 2010;116:1299–307.CrossRefPubMed Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Knosalla I, Romagnani C. CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood. 2010;116:1299–307.CrossRefPubMed
26.
go back to reference Shakhar G, Ben-Eliyahu S. In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J Immunol. 1998;160:3251–8.PubMed Shakhar G, Ben-Eliyahu S. In vivo beta-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J Immunol. 1998;160:3251–8.PubMed
27.
go back to reference Takamoto T, Hori Y, Koga Y, Toshima H, Hara A, Yokoyama MM. Norepinephrine inhibits human natural killer cell activity in vitro. Int J Neurosci. 1991;58:127–31.CrossRefPubMed Takamoto T, Hori Y, Koga Y, Toshima H, Hara A, Yokoyama MM. Norepinephrine inhibits human natural killer cell activity in vitro. Int J Neurosci. 1991;58:127–31.CrossRefPubMed
28.
go back to reference Kappel M, Tvede N, Galbo H, Haahr PM, Kjaer M, Linstow M, Klarlund K, Pedersen BK. Evidence that the effect of physical exercise on NK cell activity is mediated by epinephrine. J Appl Physiol (1985). 1991;70:2530–4. Kappel M, Tvede N, Galbo H, Haahr PM, Kjaer M, Linstow M, Klarlund K, Pedersen BK. Evidence that the effect of physical exercise on NK cell activity is mediated by epinephrine. J Appl Physiol (1985). 1991;70:2530–4.
29.
go back to reference Shakhar G, Blumenfeld B. Glucocorticoid involvement in suppression of NK activity following surgery in rats. J Neuroimmunol. 2003;138:83–91.CrossRefPubMed Shakhar G, Blumenfeld B. Glucocorticoid involvement in suppression of NK activity following surgery in rats. J Neuroimmunol. 2003;138:83–91.CrossRefPubMed
30.
go back to reference Kliesch WF, Cruse JM, Lewis RE, Bishop GR, Brackin B, Lampton JA. Restoration of depressed immune function in spinal cord injury patients receiving rehabilitation therapy. Paraplegia. 1996;34:82–90.CrossRefPubMed Kliesch WF, Cruse JM, Lewis RE, Bishop GR, Brackin B, Lampton JA. Restoration of depressed immune function in spinal cord injury patients receiving rehabilitation therapy. Paraplegia. 1996;34:82–90.CrossRefPubMed
31.
go back to reference Iversen PO, Hjeltnes N, Holm B, Flatebo T, Strom-Gundersen I, Ronning W, Stanghelle J, Benestad HB. Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury. Blood. 2000;96:2081–3.PubMed Iversen PO, Hjeltnes N, Holm B, Flatebo T, Strom-Gundersen I, Ronning W, Stanghelle J, Benestad HB. Depressed immunity and impaired proliferation of hematopoietic progenitor cells in patients with complete spinal cord injury. Blood. 2000;96:2081–3.PubMed
32.
go back to reference Held KS, Steward O, Blanc C, Lane TE. Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection. Exp Neurol. 2010;226:242–53.CrossRefPubMedPubMedCentral Held KS, Steward O, Blanc C, Lane TE. Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection. Exp Neurol. 2010;226:242–53.CrossRefPubMedPubMedCentral
33.
go back to reference Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer. 1999;80:880–8.CrossRefPubMed Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer. 1999;80:880–8.CrossRefPubMed
34.
go back to reference Kopp MA, Druschel C, Meisel C, Liebscher T, Prilipp E, Watzlawick R, Cinelli P, Niedeggen A, Schaser KD, Wanner GA, Curt A, Lindemann G, Nugaeva N, Fehlings MG, Vajkoczy P, Cabraja M, Dengler J, Ertel W, Ekkernkamp A, Martus P, Volk HD, Unterwalder N, Kolsch U, Brommer B, Hellmann RC, Saidy RR, Laginha I, Pruss H, Failli V, Dirnagl U, Schwab JM. The SCIentinel study–prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS)–study protocol and interim feasibility data. BMC Neurol. 2013;13:168.CrossRefPubMedPubMedCentral Kopp MA, Druschel C, Meisel C, Liebscher T, Prilipp E, Watzlawick R, Cinelli P, Niedeggen A, Schaser KD, Wanner GA, Curt A, Lindemann G, Nugaeva N, Fehlings MG, Vajkoczy P, Cabraja M, Dengler J, Ertel W, Ekkernkamp A, Martus P, Volk HD, Unterwalder N, Kolsch U, Brommer B, Hellmann RC, Saidy RR, Laginha I, Pruss H, Failli V, Dirnagl U, Schwab JM. The SCIentinel study–prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS)–study protocol and interim feasibility data. BMC Neurol. 2013;13:168.CrossRefPubMedPubMedCentral
35.
go back to reference Schedlowski M, Jacobs R, Stratmann G, Richter S, Hadicke A, Tewes U, Wagner TO, Schmidt RE. Changes of natural killer cells during acute psychological stress. J Clin Immunol. 1993;13:119–26.CrossRefPubMed Schedlowski M, Jacobs R, Stratmann G, Richter S, Hadicke A, Tewes U, Wagner TO, Schmidt RE. Changes of natural killer cells during acute psychological stress. J Clin Immunol. 1993;13:119–26.CrossRefPubMed
36.
go back to reference Cruse JM, Lewis Jr RE, Bishop GR, Kliesch WF, Gaitan E, Britt R. Decreased immune reactivity and neuroendocrine alterations related to chronic stress in spinal cord injury and stroke patients. Pathobiology. 1993;61:183–92.CrossRefPubMed Cruse JM, Lewis Jr RE, Bishop GR, Kliesch WF, Gaitan E, Britt R. Decreased immune reactivity and neuroendocrine alterations related to chronic stress in spinal cord injury and stroke patients. Pathobiology. 1993;61:183–92.CrossRefPubMed
37.
go back to reference Walden K, Belanger LM, Biering-Sorensen F, Burns SP, Echeverria E, Kirshblum S, Marino RJ, Noonan VK, Park SE, Reeves RK, Waring W, Dvorak MF. Development and validation of a computerized algorithm for International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Spinal Cord. 2016;54(3):197–203. Walden K, Belanger LM, Biering-Sorensen F, Burns SP, Echeverria E, Kirshblum S, Marino RJ, Noonan VK, Park SE, Reeves RK, Waring W, Dvorak MF. Development and validation of a computerized algorithm for International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Spinal Cord. 2016;54(3):197–203.
38.
go back to reference Burgdörfer H, Heidler H, Madersbacher H, Kutzenberger J, Palmtag H, Pannek J, Sauerwein, D, Stöhrer M. Manual Neuro-Urologie und Querschnittlähmung. Leitlinien zur urologischen Betreuung Querschnittgelähmter. Querschnittgelähmter, A.U.R. (ed). 2007 Burgdörfer H, Heidler H, Madersbacher H, Kutzenberger J, Palmtag H, Pannek J, Sauerwein, D, Stöhrer M. Manual Neuro-Urologie und Querschnittlähmung. Leitlinien zur urologischen Betreuung Querschnittgelähmter. Querschnittgelähmter, A.U.R. (ed). 2007
39.
go back to reference Mann G, Hankey GJ, Cameron D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke. 1999;30:744–8.CrossRefPubMed Mann G, Hankey GJ, Cameron D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke. 1999;30:744–8.CrossRefPubMed
40.
go back to reference Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294:15–22.CrossRefPubMed Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294:15–22.CrossRefPubMed
41.
go back to reference Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, Koup RA. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods. 2003;281:65–78.CrossRefPubMed Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, Koup RA. Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods. 2003;281:65–78.CrossRefPubMed
Metadata
Title
Natural Killer (NK) Cell Functionality after human Spinal Cord Injury (SCI): protocol of a prospective, longitudinal study
Authors
Inês Laginha
Marcel A. Kopp
Claudia Druschel
Klaus-Dieter Schaser
Benedikt Brommer
Rick C. Hellmann
Ralf Watzlawick
Ramin-Raul Ossami-Saidi
Harald Prüss
Vieri Failli
Christian Meisel
Thomas Liebscher
Erik Prilipp
Andreas Niedeggen
Axel Ekkernkamp
Ulrike Grittner
Sophie K. Piper
Ulrich Dirnagl
Monica Killig
Chiara Romagnani
Jan M. Schwab
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2016
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-016-0681-5

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