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Description
A multiple sclerosis (MS) treatment is natalizumab (NAT; Tysabri®), a monoclonal antibody against the cell adhesion molecule very late antigen-4 (VLA-4), which prevents leukocytes to adhere to the blood-brain-barrier (BBB) and therefore invasion into the central nervous system (CNS). However, after NAT 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 investigated by multi-colour flow cytometry and transcriptome analysis the impact of NAT treatment on the cytokine profile and pathogenic gene expression signature of Th17 cells in relapsing-remitting MS patients. Moreover, 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. To corroborate these findings and proof-of-concept, we performed an immunohistochemical analysis of brain histology material of a NAT rebound patient.
Under long-term NAT treatment, Th17 cells acquired a pronounced pathogenic profile as illustrated by significantly increased production of proinflammatory cytokines such as IL-17A, IL-22 and GM-CSF. 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, in contrast to other CD4 T cell subsets, acquire an increased potential for endothelial barrier disruption during the course of NAT treatment. In this line, we observed a significant increase in Th17 cells in the cerebrospinal fluid under NAT compared to naïve MS patients, suggesting preferential egress of Th17 cells into the CNS. Furthermore, Th17 cells but not other CD4 T cells from NAT patients exhibited an enhanced capacity to kill oligodendrocytes. Finally, histology of a biopsy specimen from a NAT 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.
Taken together our data suggest that long-term NAT treatment is associated with an acquisition of increased pathogenicity of Th17 cells, which might explain the clinical phenomenon of enhanced disease activity upon NAT cessation.
