Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0340 - High-dimensional immune profiling of dimethyl fumarate and ocrelizumab in multiple sclerosis (ID 1007)

Speakers
  • Y. Zhang
Authors
  • Y. Zhang
  • B. Lee
  • H. Xie
  • J. Rockoff
  • R. Brandstadter
  • S. Kim-Schulze
  • F. Lublin
  • A. Ntranos
Presentation Number
P0340
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) and ocrelizumab are two effective immunomodulators for multiple sclerosis (MS). Identifying overlapping mechanisms of action between the drugs may elucidate common pathways in preventing disease activity.

Objectives

In this study we analyzed cytokine and immune-profiling data to evaluate the similarities and differences between these two disease-modifying therapies in MS.

Methods

Plasma and PBMCs from MS patients were collected at baseline, 3 months and 6 months after treatment with DMF (n=16) and ocrelizumab (n=13). Immunophenotyping was performed with mass cytometry (CyTOF) and analyzed with gating based on cell surface markers. Cytokine analysis from plasma was performed with Olink assays and analyzed with linear mixed effects models.

Results

DMF reduced both effector T and memory B cell populations while increasing CD56bright natural killer (NK) cells. Ocrelizumab exerted its main immunomodulatory effect by reducing the frequency of all B cells and increasing frequency of NK cells. At 6 months, naïve B-cells began to reconstitute; however, memory B cells remain depleted. DMF treatment was associated with a significant reduction of plasma cytokines involved in inflammatory pathways, such as IL-6 and IL-12 signaling in MS and Dectin-1 signaling. In addition, DMF lowered plasma cytokines that are dysregulated in psoriasis and involved in allograft rejection pathways. Ocrelizumab treatment led to the upregulation of neurotropic proteins in the plasma of MS patients, including proteins involved in NAD biosynthesis and tryptophan metabolism.

Conclusions

Our high-dimensional immunophenotyping results suggest that DMF and ocrelizumab both increase NK cells in addition to affecting different immune cell populations and cytokine pathways to exert their effects in MS patients. Detecting similarities between the mechanisms of the two drugs may contribute to identifying more specific therapeutic targets.

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