Sage Journals: Discover world-class research

Abstract

Objective:

Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity.

Methods:

Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients (n = 33), untreated RRMS patients (n = 13), and healthy controls (n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients.

Results:

Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed.

Conclusion:

Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug’s mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.

Keywords

Multiple sclerosis natalizumab lymphocytes interleukin-17 magnetic resonance imaging

Get full access to this article

View all access options for this article.

References

Compston

Coles

Multiple sclerosis. Lancet 2008; 372: 1502–1517.

Kivisakk

Healy

Viglietta

. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 2009; 72: 1922–1930.

Koralnik

IJ.

New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004; 17: 365–370.

Stuve

Marra

Bar-Or

. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 2006; 63: 1383–1387.

Stuve

Marra

Jerome

. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006; 59: 743–747.

Stuve

Cravens

Frohman

. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009; 72: 396–401.

Kowarik

Pellkofer

Cepok

. Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS. Neurology 2011; 76: 1214–1221.

Luchtman

Ellwardt

Larochelle

. IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: Current and future developments. Cytokine Growth Factor Rev 2014; 25: 403–413.

Hartmann

Khademi

Aram

. Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells. Nat Commun 2014; 5: 5056.

10.

Carbajal

Mironova

Ulrich-Lewis

. Th cell diversity in experimental autoimmune encephalomyelitis and multiple sclerosis. J Immunol 2015; 195: 2552–2559.

11.

Sie

Korn

Mitsdoerffer

Th17 cells in central nervous system autoimmunity. Exp Neurol 2014; 262(Pt A): 18–27.

12.

Kebir

Kreymborg

Ifergan

. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 2007; 13: 1173–1175.

13.

Tzartos

Friese

Craner

. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008; 172: 146–155.

14.

Polman

Reingold

Banwell

. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.

15.

Godoy-Ramirez

Franck

Mahdavifar

. Optimum culture conditions for specific and nonspecific activation of whole blood and PBMC for intracellular cytokine assessment by flow cytometry. J Immunol Methods 2004; 292: 1–15.

16.

Clerico

Schiavetti

De Mercanti

. Treatment of relapsing-remitting multiple sclerosis after 24 doses of natalizumab: Evidence from an Italian spontaneous, prospective, and observational study (the TY-STOP Study). JAMA Neurol 2014; 71: 954–960.

17.

Truyen

van Waesberghe

van Walderveen

. Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996; 47: 1469–1476.

18.

Durelli

Conti

Clerico

. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 2009; 65: 499–509.

19.

Sailer

Losseff

Wang

. T1 lesion load and cerebral atrophy as a marker for clinical progression in patients with multiple sclerosis. A prospective 18 months follow-up study. Eur J Neurol 2001; 8: 37–42.

20.

Börnsen

Christensen

Ratzer

. Effect of natalizumab on circulating CD4⁺ T-cells in multiple sclerosis. PLoS ONE 2012; 7: e47578.

21.

Kappos

O’Connor

Polman

. Clinical effects of natalizumab on multiple sclerosis appear early in treatment course. J Neurol 2013; 260: 1388–1395.

22.

Fox

Rudick

RA.

Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology 2012; 78: 436–437.

23.

Bloomgren

Richman

Hotermans

. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880.

24.

O’Connor

Goodman

Kappos

. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011; 76: 1858–1865.

25.

Brucklacher-Waldert

Stuerner

Kolster

. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009; 132: 3329–3341.

26.

Gagliani

Amezcua Vesely

Iseppon

. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015; 523: 221–225.

27.

Hoppmann

Graetz

Paterka

. New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis. Brain 2015; 138: 902–917.

28.

Kebir

Ifergan

Alvarez

. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol 2009; 66: 390–402.

29.

Schneider-Hohendorf

Rossaint

Mohan

. VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells. J Exp Med 2014; 211: 1833–1846.

30.

Rothhammer

Heink

Petermann

. Th17 lymphocytes traffic to the central nervous system independently of alpha4 integrin expression during EAE. J Exp Med 2011; 208: 2465–2476.

31.

Glatigny

Duhen

Oukka

. Cutting edge: Loss of alpha4 integrin expression differentially affects the homing of Th1 and Th17 cells. J Immunol 2011; 187: 6176–6179.

32.

Larochelle

Cayrol

Kebir

. Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain 2012; 135: 2906–2924.

33.

Van Walderveen

Lycklama

ANGJ

Ader

. Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: Relation to clinical characteristics in subgroups of patients with multiple sclerosis. Arch Neurol 2001; 58: 76–81.

34.

Brex

Ciccarelli

O’Riordan

. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002; 346: 158–164.

35.

Fisniku

Brex

Altmann

. Disability and T2 MRI lesions: A 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131: 808–817.

36.

Benkert

Dietz

Hartmann

. Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis. PLoS ONE 2012; 7: e52208.

37.

Perriard

Mathias

Enz

. Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes. J Neuroinflammation 2015; 12: 119.

38.

Broux

Gowing

Prat

Glial regulation of the blood-brain barrier in health and disease. Semin Immunopathol 2015; 37: 577–590.

39.

Ramos-Cejudo

Oreja-Guevara

Stark Aroeira

. Treatment with natalizumab in relapsing-remitting multiple sclerosis patients induces changes in inflammatory mechanism. J Clin Immunol 2011; 31: 623–631.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.31 MB

Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment

Abstract

Objective:

Methods:

Results:

Conclusion:

Keywords

Get full access to this article

References

Supplementary Material