Abstract
Background and Objectives Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology.
Methods A first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest.
Results Using an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4+ T cells: one corresponding to naive CD4+ T cells was increased, the other clusters corresponded to effector memory (EM) CD4+CCR6− T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8+ T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8+CCR5+ T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells.
Discussion Our study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5.
Glossary
- ANOVA=
- analysis of variance;
- ADCC=
- antibody-dependent cell-mediated cytotoxicity;
- BBB=
- blood-brain barrier;
- CCR=
- C-C chemokine receptor type;
- CCL=
- C-C motif ligand;
- CIS=
- clinically isolated syndrome;
- CM=
- central memory;
- EAE=
- experimental autoimmune encephalomyelitis;
- EM=
- effector memory;
- EOMES=
- Eomesodermin;
- FACS=
- fluorescence-activated cell sorting;
- FMO=
- fluorescence minus one;
- GZMB/K=
- granzym B or K;
- IFC=
- integrated fluidic circuit;
- LFA1=
- lymphocyte function associated antigen 1;
- MAIT=
- mucosal-associated invariant T;
- MS=
- multiple sclerosis;
- NK=
- natural killer;
- NMOSD=
- neuromyelitis optica spectrum disorder;
- OCR=
- ocrelizumab;
- OIND=
- other inflammatory neurologic diseases;
- PBMC=
- peripheral blood mononuclear cell;
- PRF1=
- perforin 1;
- qPCR=
- quantitative PCR;
- RR=
- relapsing-remitting;
- RPMI=
- Roswell Park Memorial Institute medium;
- SOM=
- self-organizing map;
- TBET=
- T-box expressed in T cells;
- t-SNE CUDA=
- t-Distributed Stochastic Neighbor Embedding Compute Unified Device Architecture;
- VLA4=
- very late antigen-4
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by CHU Nantes.
Submitted and externally peer reviewed. The handling editor was Deputy Editor Scott S. Zamvil, MD, PhD, FAAN.
- Received June 17, 2022.
- Accepted in final form December 12, 2022.
- Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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