Highlights
- •Teriflunomide increased CD39 on Tregs but decreased CXCR3 on CD4+ T helper cells.
- •Teriflunomide reduced switched memory B cells but increased naïve B cells.
- •Teriflunomide reduced absolute number of natural killer cells.
- •Teriflunomide reduced percentage and absolute number of natural killer T cells.
- •Teriflunomide decreased ratio of CD56dim/CD56hi natural killer cells.
Abstract
Background
Teriflunomide (TER) (Aubagio™) is an FDA-approved disease-modifying therapy (DMT)
for relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of TER
is thought to be related to the inhibition of dihydroorotate dehydrogenase (DHODH),
a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing lymphocytes. Several large
pivotal studies have established the efficacy and safety of TER in patients with RRMS.
Despite this, little is known about how the adaptive and innate immune cell subsets
are affected by the treatment in patients with MS.
Methods
We recruited 20 patients with RRMS who were newly started on TER and performed multicolor
flow cytometry and functional assays on peripheral blood samples. A paired t-test was used for the statistical analysis and comparison.
Results
Our data showed that TER promoted a tolerogenic environment by shifting the balance
between activated pathogenic and naïve or immunosuppressive immune cell subsets. In
our cohort, TER increased the expression of the immunosuppressive marker CD39 on regulatory
T cells (Tregs) while it decreased the expression of the activation marker CXCR3 on
CD4+ T helper cells. TER treatment also reduced switched memory (sm) B cells while it
increased naïve B cells and downregulated the expression of co-stimulatory molecules
CD80 and CD86. Additionally, TER reduced the percentage and absolute numbers of natural
killer T (NKT) cells, as well as the percentage of natural killer (NK) cells and showed
a trend toward reducing the CD56dim NK pathogenic subset.
Conclusion
TER promotes the tolerogenic immune response and suppresses the pathogenic immune
response in patients with RRMS.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Multiple Sclerosis and Related DisordersAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Randomized trial of oral teriflunomide for relapsing multiple sclerosis.N. Engl. J. Med. 2011; 365 (Oct): 1293-1303https://doi.org/10.1056/NEJMoa1014656
- The efficacy and safety of teriflunomide in patients with relapsing MS: results from TOWER, a phase III, placebo-controlled study.in: presented at: 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). 2012 (Oct)
- The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro.J. Neuroimmunol. 2013; 265 (Dec): 82-90https://doi.org/10.1016/j.jneuroim.2013.10.003
- Immune mechanisms of new therapeutic strategies in MS: teriflunomide.Clin. Immunol. 2012; 142 (Jan): 49-56https://doi.org/10.1016/j.clim.2011.02.011
- Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells.Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012; 303 (Dec): R1136-R1146https://doi.org/10.1152/ajpregu.00315.2012
- Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide–mechanisms independent of pyrimidine depletion.J. Leukoc. Biol. 2004; 76 (Nov): 950-960https://doi.org/10.1189/jlb.0504308
- Induction of regulatory T cells by leflunomide in a murine model of contact allergen sensitivity.J. Invest. Dermatol. 2006; 126 (Jul): 1524-1533https://doi.org/10.1038/sj.jid.5700228
- Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects.Sci. Transl. Med. 2019; 05 (11(490))https://doi.org/10.1126/scitranslmed.aao5563
- Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients.J. Immunol. 2017; 198 (Apr 15): 3069-3080https://doi.org/10.4049/jimmunol.1601532
- Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis.JCI Insight. 2020; 5 (Feb 13)https://doi.org/10.1172/jci.insight.134251
- Teriflunomide induces a tolerogenic bias in blood immune cells of MS patients.Ann. Clin. Transl. Neurol. 2019; 6 (Feb): 355-363https://doi.org/10.1002/acn3.711
- From leflunomide to teriflunomide: drug development and immunosuppressive oral drugs in the treatment of multiple sclerosis.Curr. Neuropharmacol. 2017; 15: 874-891https://doi.org/10.2174/1570159X14666161208151525
- TERI-DYNAMIC: exploring the impact of teriflunomide on immune cell population size, receptor repertoire, and function in patients with RRMS (P50.282).Neurology. 2016; 86 (16 SupplementP50.282)
- Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation.J. Immunol. 2002; 169 (Sep 15): 3392-3399https://doi.org/10.4049/jimmunol.169.6.3392
- Teriflunomide treatment reduces B cells in patients with MS.Neurol. Neuroimmunol. Neuroinflamm. 2017; 4 (Nov): e403https://doi.org/10.1212/NXI.0000000000000403
- Teriflunomide Treatment of Multiple Sclerosis Selectively Modulates CD8 Memory T Cells.Front. Immunol. 2021; 12730342https://doi.org/10.3389/fimmu.2021.730342
- Mitochondrial dysfunction induced by leflunomide and its active metabolite.Toxicology. 2018; (Mar 1396-397:33-45)https://doi.org/10.1016/j.tox.2018.02.003
- Mitochondrial-linked de novo pyrimidine biosynthesis dictates human T-cell proliferation but not expression of effector molecules.Front. Immunol. 2021; 12718863https://doi.org/10.3389/fimmu.2021.718863
- Induction of gut regulatory CD39(+) T cells by teriflunomide protects against EAE.Neurol. Neuroimmunol. Neuroinflamm. 2016; 3 (Dec): e291https://doi.org/10.1212/NXI.0000000000000291
- Real-world outcomes of teriflunomide in relapsing-remitting multiple sclerosis: a prospective cohort study.J. Neurol. 2022; 269 (Sep): 4808-4816https://doi.org/10.1007/s00415-022-11118-7
- Effector and regulatory B cells in multiple sclerosis.Clin. Immunol. 2017; 184 (Nov): 11-25https://doi.org/10.1016/j.clim.2017.04.014
- B-cell kinetics in humans: rapid turnover of peripheral blood memory cells.Blood. 2005; 105 (May): 3633-3640https://doi.org/10.1182/blood-2004-09-3740
- γδ T cells and NK cells - distinct pathogenic roles as innate-like immune cells in CNS autoimmunity.Front. Immunol. 2015; 6: 455https://doi.org/10.3389/fimmu.2015.00455
- Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis.J. Neuroimmunol. 2013; 265 (Dec): 124-127https://doi.org/10.1016/j.jneuroim.2013.10.004
- The role of natural killer cells in multiple sclerosis and their therapeutic implications.Front. Immunol. 2013; 4: 63https://doi.org/10.3389/fimmu.2013.00063
- Optimal response to dimethyl fumarate associates in MS with a shift from an inflammatory to a tolerogenic blood cell profile.Mult. Scler. 2017; (Jun 01)1352458517717088https://doi.org/10.1177/1352458517717088
- Glatiramer Acetate, Dimethyl Fumarate, and Monomethyl Fumarate Upregulate the Expression of CCR10 on the Surface of Natural Killer Cells and Enhance Their Chemotaxis and Cytotoxicity.Front. Immunol. 2016; 7: 437https://doi.org/10.3389/fimmu.2016.00437
- Pharmacology and clinical efficacy of dimethyl fumarate (BG-12) for treatment of relapsing-remitting multiple sclerosis.Ther. Clin. Risk Manag. 2014; 10: 229-239https://doi.org/10.2147/TCRM.S53285
- The effect of dimethyl fumarate on gene expression and the level of cytokines related to different T helper cell subsets in peripheral blood mononuclear cells of patients with psoriasis.Int. J. Dermatol. 2015; 54 (Jul): e254-e260https://doi.org/10.1111/ijd.12834
- Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a.Cell Mol. Immunol. 2016; 13 (Jan): 57-64https://doi.org/10.1038/cmi.2014.114
- The role of natural killer T cells in cancer-a phenotypical and functional approach.Front. Immunol. 2018; 9: 367https://doi.org/10.3389/fimmu.2018.00367
- The role of NK and NKT cells in the pathogenesis and improvement of multiple sclerosis following disease-modifying therapies.Health Sci. Rep. 2022; 5 (Jan): e489https://doi.org/10.1002/hsr2.489
- The peripheral blood immune cell profile in a teriflunomide-treated multiple sclerosis patient with COVID-19 pneumonia.J. Neuroimmunol. 2020; 346 (Jul 15)577323https://doi.org/10.1016/j.jneuroim.2020.577323
Article info
Publication history
Published online: April 16, 2023
Accepted:
April 15,
2023
Received in revised form:
April 2,
2023
Received:
January 30,
2023
Identification
Copyright
© 2023 Published by Elsevier B.V.
