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EP39530
Abstract: Introduction: The major determinant of neurological impairment during multiple sclerosis (MS) is axonal degeneration, represented as MS lesions and brain atrophy. One of commonly used biomarkers of axonal degeneration is neurofilament light protein (Nfl) elevation in cerebrospinal fluid (CSF) and plasma [1]. Modulation of lymphocyte dynamics demonstrated efficacy on several biomarkers.
Objectives: Mechanistic description of lymphocyte dynamics and neurodegeneration is warranted. Quantitative Systems Pharmacology (QSP) model of MS biomarkers would allow for therapy optimization.
Aims: To develop and verify QSP model describing Nfl dynamics and neurodegeneration in MS progression and during lymphocyte targeting therapy.
Methods: The model includes cell apoptosis, proliferation, migration and B-T cells interaction with subsequent T-cell activation, based on the data for selfreactive brain-homing effector-memory CD4+ T cells proliferation upon interaction with memory B cells [2]. Cytoskeletal processes are represented by synthesis of neurofilaments and their degradation, phosphorylation, formation of pathological aggregates, and the release of Nfl from degenerating axons into the extracellular space with distribution to the CSF. Proinflammatory cytokines, expressed by activated lymphocytes influence on neuronal cytoskeletal
dynamics through intracellular signals (Ca, kinases) activation. For calibration we used literature data on the concentration of Nfl in brain, CSF and plasma, phosphorylation level, numbers of lymphocyte subtypes in blood and CSF in healthy and MS patients and cell proliferation assay.
Results: The model describes the difference between CNS T-cell accumulation in healthy and MS subjects. It correctly captures the increase of the Nfl concentration in CSF and plasma, as well as brain and T2 lesions volume change due to MS progression. It describes natalizumab, rituximab, alemtuzumab and fingolimod treatment effects on lymphocytes and Nfl. Thus, natalizumab treatment leads to reduction of Nfl in CSF by 35%. Model also captures the dynamics of recovery of Nfl after treatment discontinuation [3].
Conclusions: The model describes major contributors to MS progression and couldbe applied for analysis of therapeutic interventions.
Summary: The model describes major contributors to MS progression and couldbe applied for analysis of therapeutic interventions.
References: [1] Martin, S-J et al. J neurol, neurosurg, and psychiatry vol. 90,9 (2019):1059-1067.
[2] Jelcic, I. et al. Cell 175, 85-100.e23 (2018).
[3] Proschmann, U. et al. Front. immunol. Vol.12 715195. (2021).
Objectives: Mechanistic description of lymphocyte dynamics and neurodegeneration is warranted. Quantitative Systems Pharmacology (QSP) model of MS biomarkers would allow for therapy optimization.
Aims: To develop and verify QSP model describing Nfl dynamics and neurodegeneration in MS progression and during lymphocyte targeting therapy.
Methods: The model includes cell apoptosis, proliferation, migration and B-T cells interaction with subsequent T-cell activation, based on the data for selfreactive brain-homing effector-memory CD4+ T cells proliferation upon interaction with memory B cells [2]. Cytoskeletal processes are represented by synthesis of neurofilaments and their degradation, phosphorylation, formation of pathological aggregates, and the release of Nfl from degenerating axons into the extracellular space with distribution to the CSF. Proinflammatory cytokines, expressed by activated lymphocytes influence on neuronal cytoskeletal
dynamics through intracellular signals (Ca, kinases) activation. For calibration we used literature data on the concentration of Nfl in brain, CSF and plasma, phosphorylation level, numbers of lymphocyte subtypes in blood and CSF in healthy and MS patients and cell proliferation assay.
Results: The model describes the difference between CNS T-cell accumulation in healthy and MS subjects. It correctly captures the increase of the Nfl concentration in CSF and plasma, as well as brain and T2 lesions volume change due to MS progression. It describes natalizumab, rituximab, alemtuzumab and fingolimod treatment effects on lymphocytes and Nfl. Thus, natalizumab treatment leads to reduction of Nfl in CSF by 35%. Model also captures the dynamics of recovery of Nfl after treatment discontinuation [3].
Conclusions: The model describes major contributors to MS progression and couldbe applied for analysis of therapeutic interventions.
Summary: The model describes major contributors to MS progression and couldbe applied for analysis of therapeutic interventions.
References: [1] Martin, S-J et al. J neurol, neurosurg, and psychiatry vol. 90,9 (2019):1059-1067.
[2] Jelcic, I. et al. Cell 175, 85-100.e23 (2018).
[3] Proschmann, U. et al. Front. immunol. Vol.12 715195. (2021).
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