The effect of Natalizumab on functional properties of monocytes in patients with Multiple Sclerosis

by Esther Shirin Frisch
Doctoral thesis
Date of Examination:2024-02-08
Date of issue:2024-01-12
Advisor:Prof. Dr. Martin Weber
Referee:Prof. Dr. Martin Weber
Referee:Prof. Dr. Francesca Odoardi
Persistent Address: http://dx.doi.org/10.53846/goediss-10282

 

 

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Abstract

English

Natalizumab (NTZ), a monoclonal antibody against very late antigen-4 (VLA-4), is one of the most efficient therapies to prevent acute relapses in multiple sclerosis (MS). Since VLA-4 is a vital adhesion molecule for peripheral immune cells, its blockage inhibits the migration of leukocytes into the central nervous system. It is widely acknowledged that NTZ affects peripheral immune cells. Leukocytosis, a disproportional increase in B cells and B cell activation are alterations reported upon NTZ treatment. Although myeloid cells play a crucial role in the pathogenesis of MS, the effect of NTZ on peripheral monocytes is poorly investigated. Therefore, the impact of NTZ on the immune cell composition and functional properties of monocytes was evaluated. Peripheral blood mononuclear cells (PBMCs) of NTZ treated MS patients were analyzed and compared to an untreated MS control group. In addition to fluorescence-activated cell sorting analysis, the supernatant of stimulated PBMCs was analyzed using enzyme-linked immunosorbent assay. The analysis of the immune cell composition revealed a decreased frequency of monocytes within all PBMCs. In order to assess whether this decrease is caused by the widely acknowledged disproportionate increase in B cells, which was confirmed by this study, the absolute monocyte count was determined. In contrast, this analysis even detected a trend toward an increased absolute number of monocytes (p = 0.0841). Furthermore, a decreased frequency of CD4+ T cells was measured, while no alterations regarding the frequency of CD8+ T cells and NK cells were observed. Remarkably, the study revealed an association of NTZ treatment with an enhanced activation status of peripheral monocytes. The expression of two independent activation markers, CD69 and CD150, was significantly upregulated upon NTZ treatment compared to untreated controls. Other properties, however, namely antigen presentation and cytokine production, did not alter significantly upon NTZ treatment. The robust changes in the cell composition and the increased monocytic activation failed to be reflected in the longitudinal analysis, possibly caused by a low number of longitudinally observed patients. As myeloid cells are assumed to play a prominent role in chronic MS progression, the identified monocytic activation upon NTZ treatment could implicate that NTZ exerts non-desirable effects on MS pathogenesis. Yet it remains uncertain whether NTZ causes the observed activation of monocytes itself or only indirectly, exemplarily through an NTZ-induced activation of B cells.
Keywords: Multiple Sclerosis; monocytes; Natalizumab
 
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