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Long-term natalizumab treatment enhances the pathogenic signature of Th17 cells - potential implications for treatment cessation?
Author(s): ,
C. Janoschka
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
A. Schulte-Mecklenbeck
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
L. Starost
Affiliations:
Institute for Neuropathology, University of Münster, Münster, Germany
,
D. Schafflick
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
T. Schneider-Hohendorf
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
G. Meyer zu Hörste
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
C.C. Gross
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
N. Schwab
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
,
T. Kuhlmann
Affiliations:
Institute for Neuropathology, University of Münster, Münster, Germany
,
H. Wiendl
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
L. Klotz
Affiliations:
Department of Neurology with Institute of Translational Neurology, University Hospital Münster
ECTRIMS Online Library. Janoschka C. Oct 12, 2018; 229029
Claudia Janoschka
Claudia Janoschka
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Abstract: P1189

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

A current multiple sclerosis (MS) treatment is natalizumab (Tysabri®), a monoclonal antibody against the cell adhesion molecule very late antigen-4 (VLA-4) on leukocytes, which inhibits adhesion to the blood-brain-barrier (BBB) and therefore invasion into the central nervous system (CNS). However, after natalizumab cessation, MS patients frequently experience a disease rebound, often exceeding pretreatment levels of disease activity. It has been suggested that the pathophysiology of this rebound syndrome may be linked to interleukin (IL)-17 producing T helper (Th17) cells.
We addressed the impact of natalizumab treatment on the cytokine profile and pathogenic gene expression signature of Th17 cells in relapsing-remitting MS patients by multi-colour flow cytometry and transcriptome analysis. Furthermore, we evaluated the functional characteristics of Th17 cells on human brain endothelial cell barrier properties as well as human oligodendrocyte survival in co-culture assays. As proof-of-concept, we corroborated these findings by immunohistochemical analysis of brain histology material of a natalizumab rebound patient.
Under long-term natalizumab treatment, Th17 cells acquired a pronounced pathogenic profile as illustrated by significantly increased production of proinflammatory cytokines such as IL-17A, GM-CSF and IL-22. Furthermore, these Th17 cells exhibited transcriptional network changes associated with enhanced pathogenicity. In an in vitro model mirroring the brain endothelial barrier properties we observed that Th17 cells but not other CD4 T cells acquire an increased potential for endothelial barrier disruption during the course of natalizumab treatment. In this line, we observed a significant increase in Th17 cells in the cerebrospinal fluid under natalizumab compared to naïve MS patients, suggesting preferential egress of Th17 cells into the CNS. Also, Th17 cells but not other CD4 T cells from natalizumab patients exhibited an enhanced capacity to kill oligodendrocytes. Finally, histology of a biopsy specimen from a natalizumab rebound patient revealed a striking predominance of Th17 cells within an inflammatory lesion, hence corroborating the relevance of Th17 cells in the pathogenesis of disease rebound.
Together our data suggest that long-term natalizumab treatment is associated with an acquisition of increased pathogenicity of Th17 cells, which might explain the clinical phenomenon of enhanced disease activity upon natalizumab cessation.
Disclosure: This work is partly funded by the Kompetenznetz Multiple Sklerose (ReboundMS) and Novartis as part of the investigator initiated trial ToFingo -Successor (NCT: 02325440).
A.S-M; L.S; D.S: have nothing to disclose.
C.J: received travel support from Novartis Pharma.
TS-H: received travel support from Biogen, Bayer Healthcare and Novartis Pharma.
G.MzH: has received research funding from the Deutsche Forschungsgemeinschaft (DFG; ME4050/4-1), from the Gemeinnützige Hertie Stiftung,, and from the Ministerium für Innovation, Wissenschaft und Forschung (MIWF) des Landes Nordrhein-Westfalen and he has received speaker honoraria from Alexion pharma and acts as a member of Scientific Advisory Boards for LFB Pharma.
C.C.G: has received grants from the German Ministry for Education and Research (BMBF; 01GI1603A), the German Research Foundation (DFG; GR3946/3-1 and SFB/Transregio 128 A09), and the European Union (Horizon2020, RESTORE). She has also received speaker honoraria and travel expenses for attending meetings from Biogen, Genzyme, Novartis Pharma and Bayer Health Care.
NS: received travel support from Biogen, Sanofi-Genzyme and Novartis Pharma.
T.K: received honoraria for lectures from Novartis and EXCEMED and has a registered patent for the oligodendroglial differentiation protocol
HW: receives honoraria for acting as a member of Scientific Advisory Boards for Biogen, Sanofi-Genzyme, Merck Serono, Novartis Pharma, Evgen, MedDay Pharmaceuticals, Roche Pharma AG); speaker honoraria and travel support (Biogen, Sanofi-Genzyme, Merck Serono, Novartis Pharma, Roche Pharma AG, Alexion, Cognomed, F.Hoffmann-LA Roche Ltd, TEVA, WebMD Global, Gemeinnützige Hertie-Stiftung, Peervoice, Swiss Multiple Sclerosis Society); compensation as consultant (Biogen, Novartis Pharma, Sanofi-Genzyme, Abbvie, Actelion, IGES, GlaxoSmithKline GmbH, Roche Pharma AG, Swiss Multiple Sclerosis Society) an received research support by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme and Novartis Pharma.
L.K: Compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Novartis Pharma); research support (Biogen, Novartis Pharma).

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