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BMC Neurology
Published in: BMC Neurology 1/2020

01-12-2020 | Stroke | Research article

Regulatory T cells participate in the recovery of ischemic stroke patients

Authors: María Santamaría-Cadavid, Emilio Rodríguez-Castro, Manuel Rodríguez-Yáñez, Susana Arias-Rivas, Iria López-Dequidt, María Pérez-Mato, Manuel Rodríguez-Pérez, Ignacio López-Loureiro, Pablo Hervella, Francisco Campos, José Castillo, Ramón Iglesias-Rey, Tomás Sobrino

Published in: BMC Neurology | Issue 1/2020

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Abstract

Background

Recent preclinical studies have shown that regulatory T cells (Treg) play a key role in the immune response after ischemic stroke (IS). However, the role of Treg in human acute IS has been poorly investigated. Our aim was to study the relationship between circulating Treg and outcome in human IS patients.

Methods

A total of 204 IS patients and 22 control subjects were recruited. The main study variable was good functional outcome at 3 months (modified Rankin scale ≤2) considering infarct volume, Early Neurological Deterioration (END) and risk of infections as secondary variables. The percentage of circulating Treg was measured at admission, 48, 72 h and at day 7 after stroke onset.

Results

Circulating Treg levels were higher in IS patients compared to control subjects. Treg at 48 h were independently associated with good functional outcome (OR, 3.5; CI: 1.9–7.8) after adjusting by confounding factors. Patients with lower Treg at 48 h showed higher frequency of END and risk of infections. In addition, a negative correlation was found between circulating Treg at 48 h (r = − 0.414) and 72 h (r = − 0.418) and infarct volume.

Conclusions

These findings suggest that Treg may participate in the recovery of IS patients. Therefore, Treg may be considered a potential therapeutic target in acute ischemic stroke.
Literature
1.
Mozaffarian D, Benjamin EJ, Go AS, American Heart Association Statistics Committee and Stroke Statistics Subcommittee, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–e322.PubMed
2.
Rodríguez-Castro E, López-Dequit I, Santamaría-Cadavid M, et al. Trends in stroke outcomes in the last ten years in a European tertiary hospital. BMC Neurol. 2018;18:164.PubMedPubMedCentralCrossRef
3.
Wahlgren N, Ahmed N, Dávalos A, Hacke W, Millán M, Muir K, SITS Investigators, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372:1303–9.CrossRefPubMed
4.
5.
6.
7.
8.
Chen S, Wu H, Klebe D, Hong Y, Zhang J, Tang J. Regulatory T cell in stroke: a new paradigm for immune regulation. Clin Dev Immunol. 2013;2013:689827.PubMedPubMedCentral
9.
Liesz A, Suri-Payer E, Veltkamp C, Doeer H. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med. 2009;15:192–9.CrossRefPubMed
10.
Brea D, Agulla J, Rodríguez-Yáñez M, Barral D, Ramos-Cabrer P, Campos F, et al. Regulatory T cells modulate inflammation and reduce infarct volume in experimental brain ischaemia. J Cell Mol Med. 2014;18:1571–9.PubMedPubMedCentralCrossRef
11.
Hug A, Liesz A, Muerle B, et al. Reduced efficacy of circulating costimulatory cells after focal cerebral ischemia. Stroke. 2011;42:3580–6.CrossRefPubMed
12.
Yan J, Greer JM, Etherington GP, Cadigan GP, Cavanagh H, Henderson RD, et al. Immune activation in the peripheral blood of patients with acute ischemic stroke. J Neuroimmunol. 2009;206:112–7.CrossRefPubMed
13.
Li Q, Wang Y, Yu F, Wang YM, Zhang C. Hu c. peripheral Th17/Treg imbalance in patients with atherosclerotic cerbral infarction. Int J Clin Exp Pathol. 2013;6:1015–27.PubMedPubMedCentral
14.
Yan J, Read SJ, Henderson R, Hull R, O’Sullivan J, McCombe P, Greer JM. Frecuency and function of regulatory T cells after ischemic stroke in humans. J Neuroimmunol. 2012;243:89–94.CrossRefPubMed
15.
Wrigen M, Björkbacka H, Andersson L, Ljungcrantz I, Fredrikson GN, Persson M, et al. Low levels of circulating CD4+FoxP3+ T cells are associated with an increased risk for development of myocardial infarction but not for stroke. Arterioscler Thromb Vasc Biol. 2012;32:2000–4.CrossRef
16.
Urra X, Cervera A, Villamallor M, Planas AM, Chamorro A. Harms and benefits of lymphocyte subpopulations in patients with acute stroke. Neuroscience. 2009;158:1174–83.CrossRefPubMed
17.
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA. The development and function of regulatory T cells. Cell Mol Life Sci. 2009;66:2603–22.PubMedPubMedCentralCrossRef
18.
Alonso de Leciñana M, Egido JA, Casado I, Ribó M, Dávalos A, Masjuan J, et al. Guidelines for the treatment of acute ischaemic stroke. Neurologia. 2014;29:102–22.CrossRefPubMed
19.
Adams HP Jr, Bendixen BH, Kappelle J, Biller J, Love BB, Gordon L, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke. 1993;24:35–41.CrossRefPubMed
20.
Pedraza S, Puig J, Blasco G, Daunis-Estadella J, Boada I, Bardera A, et al. Reliability of the ABC/2 method in determining acute infarct volume. J Neuroimaging. 2012;22:155–9.CrossRefPubMed
21.
Liu W, Putman AL, Xu Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+Treg cells. J Exp Med. 2006;20:1701–11.CrossRef
22.
Peters JH, Preijers FW, Woostenenik R, Hilbrands LB, Koenen HJ, Joosten I. Clinical grade Treg: GMP isolation, improvement of purity by CD127 depletion, Treg expansion, and Treg cryopreservation. PLoS One. 2008;3:e3161.PubMedPubMedCentralCrossRef
23.
Seddiki N, Santner-Nonan B, Martninson J, Zaunders J. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693–700.PubMedPubMedCentralCrossRef
24.
Perini F, Marro M, Alecci M, Galloni E, Marchi M, Tosjo V. Temporal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischemic stroke. Neurol Sci. 2001;22:289–96.CrossRefPubMed
25.
Stubbe T, Ebner F, Ritcher D, et al. Regulatory T-cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO. J Cereb Blood Flow Metab. 2013;33:37–47.CrossRefPubMed
26.
Vila N, Castillo J, Dávalos A, Esteve A, Planas AM, Chamorro A. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke. 2003;34:671–5.CrossRefPubMed
27.
Otsubo K, Kanegane H, Kamachi Y, et al. Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clin Immunol. 2011;141:111–20.CrossRefPubMed
28.
29.
Spera PA, Ellison JA, Fenersten GZ, Barone FC. IL-10 reduces rat brain injury following focal stroke. Neurosci Lett. 1998;251:189–92.CrossRefPubMed
30.
Liesz A, Zhou W, Na S, Hammerling GJ. Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. J Neurosci. 2013;33:17350–62.PubMedPubMedCentralCrossRef
31.
Na SY, Marckso E, Liesz A, Hunig T, Velktamp R. Amplification of regulatory T-cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice. Stroke. 2015;46:212–20.CrossRefPubMed
32.
33.
Protti GG, Gagliardi RJ, Forte WC, Spravieri SR. IL-10 may protect against progressing injury during acute phase of ischemic stroke. Arq Neuropsiquiatr. 2013;71:846–51.CrossRefPubMed
34.
Singh HV, Pandey A, Shrivastova AK, Raizade A, Singh SK, Singh N. Prognostic value of neuron specific enolase and IL-10 in ischemic stroke and its correlation with degree of neurological deficit. Clin Chim Acta. 2013;419:136–8.CrossRefPubMed
35.
Chang LT, Yuen C, Lian CW, Lu CH, Chang WN, Youssef AA, et al. Link between IL-10 level and outcome after ischemic stroke. Neuroimmunomodulation. 2010;17:223–8.CrossRefPubMed
36.
Rodríguez-Yáñez M, Castellanos M, Sobrino T, Brea D, Ramos-Cabrer P, Pedraza S, et al. Interleukin-10 facilitates the selection of patients for systemic thrombolysis. BMC Neurol. 2013;13:62.PubMedPubMedCentralCrossRef
37.
Chamorro A, Urra X, Planas AM. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke. 2007;38:1097–103.CrossRefPubMed
38.
Davenport RJ, Dennis MS, Weelwood L, Warlow CP. Complications after acute stroke. Stroke. 1996;27:415–20.CrossRefPubMed
39.
Grau AJ, Buggle F, Schitrler P, Spiel M, Lichy C, Hacke W. Fever and infection early after ischemic stroke. J Neurol Sci. 1999;171:115–20.CrossRefPubMed
40.
Langhorne P, Stott DJ, Robertson L, McDonald M, Jones L, McAlpine C, et al. Medical complications after stroke: a multicenter study. Stroke. 2000;31:1223–9.CrossRefPubMed
41.
Katzan IL, Cebul RD, Husak SH, Dawson NV, Baker DW. The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology. 2003;60:620–5.CrossRefPubMed
42.
Heuschmann PU, Kolominsky-Rabas PL, Misselwitz B, Hermanek P, Leffmann C, Jauzen RW, et al. Predictors of in-hospital mortality and attributable risks of death after ischemic stroke: the German stroke registers study group. Arch Intern Med. 2004;164:1761–8.CrossRefPubMed
43.
Vargas M, Horcajada J, Obach V, Revilla M, Cervera A, Torres F, et al. Clinical consequences of infection in patients with acute stroke: is it prime time for further antibiotic trials? Stroke. 2006;37:461–5.CrossRefPubMed
44.
Wilckens T, De Rijk R. Glucocorticoids and immune function: unknown dimensions and new frontiers. Immunol Today. 1997;18:418–24.CrossRefPubMed
45.
Elenkov IJ, Wilder RL, Chrousos GD, Vizi ES. The sympathetic nerve an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.PubMed
46.
Rodríguez-Yáñez M, Castillo J. Role of inflammatory markers in brain ischemia. Curr Opin Neurol. 2008;21:353–7.CrossRefPubMed
47.
Hug A, Dalpke A, Wieczorek N, Giese T, Lorenz A, Auffarth G, Liesz A, Veltkamp R. Infarct volume is a major determiner of post-stroke immune cell function and susceptibility to infection. Stroke. 2009;40:3226–32.CrossRefPubMed
48.
O'Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. Nat Med. 2004;10:801–5.CrossRefPubMed
49.
Emsley H, Hopkins SJ. Post-stroke immunodepression and infection: an emerging concept. Infect Disord Drug Targets. 2010;10:91–7.CrossRefPubMed
50.
Li P, Mao L, Zhou G, Leak RK, Sun B, Chen J, et al. Adoptive regulatory T cell therapy preserves systemic inmmune homeostasis after cerebral ischemia. Stroke. 2013;44:3509–15.PubMedPubMedCentralCrossRef
Metadata
Title
Regulatory T cells participate in the recovery of ischemic stroke patients
Authors
María Santamaría-Cadavid
Emilio Rodríguez-Castro
Manuel Rodríguez-Yáñez
Susana Arias-Rivas
Iria López-Dequidt
María Pérez-Mato
Manuel Rodríguez-Pérez
Ignacio López-Loureiro
Pablo Hervella
Francisco Campos
José Castillo
Ramón Iglesias-Rey
Tomás Sobrino
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Stroke
Published in
BMC Neurology / Issue 1/2020
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-020-01648-w

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