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image of In vivo Effects of Disease-modifying Therapies on Immunological Subsets in Patients with Relapsing-Remitting Multiple Sclerosis

Abstract

Background

Disease-modifying therapies (DMTs) are aimed at controlling Multiple Sclerosis disease by modulating or suppressing the immune system. However, there is limited data on changes in immune cell subsets induced by these treatments.

Objective

To assess differences in myeloid, T-, and B-cell subsets in the peripheral blood of relapsing-remitting MS (RR-MS) patients treated with different DMTs.

Methods

This longitudinal study enrolled all RR-MS patients treated with cladribine (CLAD), dimethyl fumarate (DMF), and natalizumab (NTZ) between July 2022 and September 2022. All patients underwent blood sample collection with flow cytometry at baseline (T0; before starting treatment) and 24 ± 3 months after treatment initiation (T1).

Results

Forty-three RR-MS patients (83.7% women; mean age 34.7 ± 11.1 years; median EDSS: 2.0, IQR: 1.0-2.8) were enrolled. Among them, 24 (55.8%) were treated with DMF, 10 (23.3%) with NTZ, and 9 (20.9%) with CLAD. At T1, patients assigned to CLAD showed a reduction in B-cell memory-switched ( = .029), B-cell memory-unswitched ( = .08), and B-cell naïve resting ( = .029). Additionally, the T and NK cell compartments showed a reduction in the percentage of CD3/CD4/CD127/CD45RA/CD161+ ( = .057). In the NTZ group, a significant decrease in the percentage of CD3/CD4/CD127/CD45RA/CD161+ ( = .029) was observed. A reduced percentage of mature naïve B cells ( = .057) and B memory-unswitched ( = .059) was observed in the DMF group. No significant differences were found in the myeloid subsets.

Conclusion

DMTs induced significant modifications in B- and T-cell compartments. Characterizing these immunologic changes could deepen our understanding of the mechanisms of action of different therapies.

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2025-07-04
2025-07-20
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References

  1. Malpas C.B. Manouchehrinia A. Sharmin S. Roos I. Horakova D. Havrdova E.K. Trojano M. Izquierdo G. Eichau S. Bergamaschi R. Sola P. Ferraro D. Lugaresi A. Prat A. Girard M. Duquette P. Grammond P. Grand’Maison F. Ozakbas S. Van Pesch V. Granella F. Hupperts R. Pucci E. Boz C. Sidhom Y. Gouider R. Spitaleri D. Soysal A. Petersen T. Verheul F. Karabudak R. Turkoglu R. Ramo-Tello C. Terzi M. Cristiano E. Slee M. McCombe P. Macdonell R. Fragoso Y. Olascoaga J. Altintas A. Olsson T. Butzkueven H. Hillert J. Kalincik T. Early clinical markers of aggressive multiple sclerosis. Brain 2020 143 5 1400 1413 10.1093/brain/awaa081 32386427
    [Google Scholar]
  2. Filippi M. Agosta F. Imaging biomarkers in multiple sclerosis. J. Magn. Reson. Imaging 2010 31 4 770 788 10.1002/jmri.22102 20373420
    [Google Scholar]
  3. Jones A.P. Kermode A.G. Lucas R.M. Carroll W.M. Nolan D. Hart P.H. Circulating immune cells in multiple sclerosis. Clin. Exp. Immunol. 2017 187 2 193 203 10.1111/cei.12878 27689339
    [Google Scholar]
  4. Dai J. El Gazzar M. Li G.Y. Moorman J.P. Yao Z.Q. Myeloid-derived suppressor cells: Paradoxical roles in infection and immunity. J. Innate Immun. 2015 7 2 116 126 10.1159/000368233 25401944
    [Google Scholar]
  5. Bronte V. Brandau S. Chen S.H. Colombo M.P. Frey A.B. Greten T.F. Mandruzzato S. Murray P.J. Ochoa A. Ostrand-Rosenberg S. Rodriguez P.C. Sica A. Umansky V. Vonderheide R.H. Gabrilovich D.I. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 2016 7 1 12150 10.1038/ncomms12150 27381735
    [Google Scholar]
  6. Gabrilovich D.I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 2017 5 1 3 8 10.1158/2326‑6066.CIR‑16‑0297 28052991
    [Google Scholar]
  7. Reder A.T. Genç K. Byskosh P.V. Porrini A.M. Monocyte activation in multiple sclerosis. Mult. Scler. 1998 4 3 162 168 10.1177/135245859800400314 9762667
    [Google Scholar]
  8. González-Oria M.C. Márquez-Coello M. Girón-Ortega J.A. Argente J. Moya M. Girón-González J.A. Monocyte and lymphocyte activation and regulation in multiple sclerosis patients. therapy effects. J. Neuroimm. Pharmacol. 2019 14 3 413 422 10.1007/s11481‑018‑09832‑z 30649665
    [Google Scholar]
  9. Parisi L. Gini E. Baci D. Tremolati M. Fanuli M. Bassani B. Farronato G. Bruno A. Mortara L. Macrophage polarization in chronic inflammatory diseases: Killers or builders? J. Immunol. Res. 2018 2018 1 25 10.1155/2018/8917804 29507865
    [Google Scholar]
  10. Gjelstrup M.C. Stilund M. Petersen T. Møller H.J. Petersen E.L. Christensen T. Subsets of activated monocytes and markers of inflammation in incipient and progressed multiple sclerosis. Immunol. Cell Biol. 2018 96 2 160 174 10.1111/imcb.1025 29363161
    [Google Scholar]
  11. Ziegler-Heitbrock L. Blood monocytes and their subsets: Established features and open questions. Front. Immunol. 2015 6 423 10.3389/fimmu.2015.00423 26347746
    [Google Scholar]
  12. D’Amico E. Zanghì A. Parrinello N.L. Romano A. Palumbo G.A. Chisari C.G. Toscano S. Raimondo F.D. Zappia M. Patti F. Immunological subsets characterization in newly diagnosed relapsing–remitting multiple sclerosis. Front. Immunol. 2022 13 819136 10.3389/fimmu.2022.819136 35273601
    [Google Scholar]
  13. Schweitzer F. Laurent S. Fink G.R. Barnett M.H. Hartung H.P. Warnke C. Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis. J. Neurol. 2021 268 7 2379 2389 10.1007/s00415‑019‑09690‑6 32036423
    [Google Scholar]
  14. Longbrake E.E. Cross A.H. Effect of multiple sclerosis disease-modifying therapies on B cells and humoral immunity. JAMA Neurol. 2016 73 2 219 225 10.1001/jamaneurol.2015.3977 26720195
    [Google Scholar]
  15. Canto-Gomes J. Boleixa D. Teixeira C. Martins da Silva A. González-Suárez I. Cerqueira J. Correia-Neves M. Nobrega C. Distinct disease-modifying therapies are associated with different blood immune cell profiles in people with relapsing-remitting multiple sclerosis. Int. Immunopharmacol. 2024 131 111826 10.1016/j.intimp.2024.111826 38461632
    [Google Scholar]
  16. Orrù V. Serra V. Marongiu M. Lai S. Lodde V. Zoledziewska M. Steri M. Loizedda A. Lobina M. Piras M.G. Virdis F. Delogu G. Marini M.G. Mingoia M. Floris M. Masala M. Castelli M.P. Mostallino R. Frau J. Lorefice L. Farina G. Fronza M. Carmagnini D. Carta E. Pilotto S. Chessa P. Devoto M. Castiglia P. Solla P. Zarbo R.I. Idda M.L. Pitzalis M. Cocco E. Fiorillo E. Cucca F. Implications of disease-modifying therapies for multiple sclerosis on immune cells and response to COVID-19 vaccination. Front. Immunol. 2024 15 1416464 10.3389/fimmu.2024.1416464 39076966
    [Google Scholar]
  17. Höpner L. Proschmann U. Inojosa H. Ziemssen T. Akgün K. Corticosteroid-depending effects on peripheral immune cell subsets vary according to disease modifying strategies in multiple sclerosis. Front. Immunol. 2024 15 1404316 10.3389/fimmu.2024.1404316 38938576
    [Google Scholar]
  18. Traub J.W. Pellkofer H.L. Grondey K. Seeger I. Rowold C. Brück W. Husseini L. Häusser-Kinzel S. Weber M.S. Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients. J. Neuroinflammation 2019 16 1 228 10.1186/s12974‑019‑1593‑2 31733652
    [Google Scholar]
  19. Daei Sorkhabi A. Komijani E. Sarkesh A. Ghaderi Shadbad P. Aghebati-Maleki A. Aghebati-Maleki L. Advances in immune checkpoint-based immunotherapies for multiple sclerosis: Rationale and practice. Cell Commun. Signal. 2023 21 1 321 10.1186/s12964‑023‑01289‑9 37946301
    [Google Scholar]
  20. Mills E.A. Ogrodnik M.A. Plave A. Mao-Draayer Y. Emerging understanding of the mechanism of action for dimethyl fumarate in the treatment of multiple sclerosis. Front. Neurol. 2018 9 5 10.3389/fneur.2018.00005 29410647
    [Google Scholar]
  21. Leist T.P. Weissert R. Cladribine. Clin. Neuropharmacol. 2011 34 1 28 35 10.1097/WNF.0b013e318204cd90 21242742
    [Google Scholar]
  22. Botta C. Maia C. Garcés J.J. Termini R. Perez C. Manrique I. Burgos L. Zabaleta A. Alignani D. Sarvide S. Merino J. Puig N. Cedena M.T. Rossi M. Tassone P. Gentile M. Correale P. Borrello I. Terpos E. Jelinek T. Paiva A. Roccaro A. Goldschmidt H. Avet-Loiseau H. Rosinol L. Mateos M.V. Martinez-Lopez J. Lahuerta J.J. Bladé J. San-Miguel J.F. Paiva B. FlowCT for the analysis of large immunophenotypic data sets and biomarker discovery in cancer immunology. Blood Adv. 2022 6 2 690 703 10.1182/bloodadvances.2021005198 34587246
    [Google Scholar]
  23. Botta C. Perez C. Larrayoz M. Puig N. Cedena M.T. Termini R. Goicoechea I. Rodriguez S. Zabaleta A. Lopez A. Sarvide S. Blanco L. Papetti D.M. Nobile M.S. Besozzi D. Gentile M. Correale P. Siragusa S. Oriol A. González-Garcia M.E. Sureda A. de Arriba F. Rios Tamayo R. Moraleda J.M. Gironella M. Hernandez M.T. Bargay J. Palomera L. Pérez-Montaña A. Goldschmidt H. Avet-Loiseau H. Roccaro A. Orfao A. Martinez-Lopez J. Rosiñol L. Lahuerta J.J. Blade J. Mateos M.V. San-Miguel J.F. Martinez Climent J.A. Paiva B. Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance. Nat. Commun. 2023 14 1 5825 10.1038/s41467‑023‑41562‑6 37730678
    [Google Scholar]
  24. Romano A. Parrinello N.L. Barchitta M. Manuele R. Puglisi F. Maugeri A. Barbato A. Triolo A.M. Giallongo C. Tibullo D. La Ferla L. Botta C. Siragusa S. Iacobello C. Montineri A. Volti G.L. Agodi A. Palumbo G.A. Di Raimondo F. In-vitro NET-osis induced by COVID-19 sera is associated to severe clinical course in not vaccinated patients and immune-dysregulation in breakthrough infection. Sci. Rep. 2022 12 1 7237 10.1038/s41598‑022‑11157‑0 35508575
    [Google Scholar]
  25. Wiendl H. Schmierer K. Hodgkinson S. Derfuss T. Chan A. Sellebjerg F. Achiron A. Montalban X. Prat A. De Stefano N. Barkhof F. Leocani L. Vermersch P. Chudecka A. Mwape C. Holmberg K.H. Boschert U. Roy S. Specific patterns of immune cell dynamics may explain the early onset and prolonged efficacy of cladribine tablets. Neurol. Neuroimmunol. Neuroinflamm. 2023 10 1 e200048 10.1212/NXI.0000000000200048 36411081
    [Google Scholar]
  26. Peterson L. Fujinami R. Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J. Neuroimmunol. 2007 184 1-2 37 44 10.1016/j.jneuroim.2006.11.015 17196667
    [Google Scholar]
  27. Moser T. Schwenker K. Seiberl M. Feige J. Akgün K. Haschke-Becher E. Ziemssen T. Sellner J. Long‐term peripheral immune cell profiling reveals further targets of oral cladribine in MS. Ann. Clin. Transl. Neurol. 2020 7 11 2199 2212 10.1002/acn3.51206 33002321
    [Google Scholar]
  28. Dobreanu M. Manu D.R. Mănescu I.B. Gabor M.R. Huţanu A. Bărcuţean L. Bălaşa R. Treatment with cladribine selects IFNγ+IL17+ T cells in RRMS patients – An in vitro study. Front. Immunol. 2021 12 743010 10.3389/fimmu.2021.743010 34970256
    [Google Scholar]
  29. Kemmerer C.L. Pernpeintner V. Ruschil C. Abdelhak A. Scholl M. Ziemann U. Krumbholz M. Hemmer B. Kowarik M.C. Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab. PLoS One 2020 15 7 e0235449 10.1371/journal.pone.0235449 32716916
    [Google Scholar]
  30. Montes Diaz G. Fraussen J. Van Wijmeersch B. Hupperts R. Somers V. Dimethyl fumarate induces a persistent change in the composition of the innate and adaptive immune system in multiple sclerosis patients. Sci. Rep. 2018 8 1 8194 10.1038/s41598‑018‑26519‑w 29844361
    [Google Scholar]
  31. Nakhaei-Nejad M. Barilla D. Lee C.H. Blevins G. Giuliani F. Characterization of lymphopenia in patients with MS treated with dimethyl fumarate and fingolimod. Neurol. Neuroimmunol. Neuroinflamm. 2018 5 2 e432 10.1212/NXI.0000000000000432 29296636
    [Google Scholar]
  32. Lundy S.K. Wu Q. Wang Q. Dowling C.A. Taitano S.H. Mao G. Mao-Draayer Y. Dimethyl fumarate treatment of relapsing-remitting multiple sclerosis influences B-cell subsets. Neurol. Neuroimmunol. Neuroinflamm. 2016 3 2 e211 10.1212/NXI.0000000000000211 27006972
    [Google Scholar]
  33. Smith M.D. Martin K.A. Calabresi P.A. Bhargava P. Dimethyl fumarate alters B‐cell memory and cytokine production in MS patients. Ann. Clin. Transl. Neurol. 2017 4 5 351 355 10.1002/acn3.411 28491903
    [Google Scholar]
  34. Sainz de la Maza S. Medina S. Villarrubia N. Costa-Frossard L. Monreal E. Tejeda-Velarde A. Rodríguez-Martín E. Roldán E. Álvarez-Cermeño J.C. Villar L.M. Factors associated with dimethyl fumarate-induced lymphopenia. J. Neurol. Sci. 2019 398 4 8 10.1016/j.jns.2019.01.007 30658226
    [Google Scholar]
  35. Hofmann K. Clauder A.K. Manz R.A. Targeting B cells and plasma cells in autoimmune diseases. Front. Immunol. 2018 9 835 10.3389/fimmu.2018.00835 29740441
    [Google Scholar]
  36. Spencer C.M. Crabtree-Hartman E.C. Lehmann-Horn K. Cree B.A.C. Zamvil S.S. Reduction of CD8 + T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate. Neurol. Neuroimmunol. Neuroinflamm. 2015 2 3 e76 10.1212/NXI.0000000000000076 25738172
    [Google Scholar]
  37. Fleischer V. Friedrich M. Rezk A. Bühler U. Witsch E. Uphaus T. Bittner S. Groppa S. Tackenberg B. Bar-Or A. Zipp F. Luessi F. Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS. Mult. Scler. 2018 24 5 632 641 10.1177/1352458517703799 28436295
    [Google Scholar]
  38. Wright K. Winkler M.D. Newton B.D. Sormani M.P. Okuda D.T. Patient outcomes influenced by reduced lymphocyte counts after dimethyl fumarate initiation. Neurol. Neuroimmunol. Neuroinflamm. 2017 4 6 e397 10.1212/NXI.0000000000000397 28959705
    [Google Scholar]
  39. Wu Q. Wang Q. Mao G. Dowling C.A. Lundy S.K. Mao-Draayer Y. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. J. Immunol. 2017 198 8 3069 3080 10.4049/jimmunol.1601532 28258191
    [Google Scholar]
  40. Kim J.M. Rasmussen J.P. Rudensky A.Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 2007 8 2 191 197 10.1038/ni1428 17136045
    [Google Scholar]
  41. Haas J. Hug A. Viehöver A. Fritzsching B. Falk C.S. Filser A. Vetter T. Milkova L. Korporal M. Fritz B. Storch-Hagenlocher B. Krammer P.H. Suri-Payer E. Wildemann B. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. Eur. J. Immunol. 2005 35 11 3343 3352 10.1002/eji.200526065 16206232
    [Google Scholar]
  42. Venken K. Hellings N. Broekmans T. Hensen K. Rummens J.L. Stinissen P. Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: Recovery of memory Treg homeostasis during disease progression. J. Immunol. 2008 180 9 6411 6420 10.4049/jimmunol.180.9.6411 18424765
    [Google Scholar]
  43. Fletcher J.M. Lalor S.J. Sweeney C.M. Tubridy N. Mills K.H.G. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin. Exp. Immunol. 2010 162 1 1 11 10.1111/j.1365‑2249.2010.04143.x 20682002
    [Google Scholar]
  44. Bierhansl L. Hartung H.P. Aktas O. Ruck T. Roden M. Meuth S.G. Thinking outside the box: Non-canonical targets in multiple sclerosis. Nat. Rev. Drug Discov. 2022 21 8 578 600 10.1038/s41573‑022‑00477‑5 35668103
    [Google Scholar]
  45. van Langelaar J. Rijvers L. Smolders J. van Luijn M.M. B and T cells driving multiple sclerosis: Identity, mechanisms and potential triggers. Front. Immunol. 2020 11 760 10.3389/fimmu.2020.00760 32457742
    [Google Scholar]
  46. Krumbholz M. Meinl I. Kümpfel T. Hohlfeld R. Meinl E. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 2008 71 17 1350 1354 10.1212/01.wnl.0000327671.91357.96 18936427
    [Google Scholar]
  47. Zanotti C. Chiarini M. Serana F. Sottini A. Garrafa E. Torri F. Caimi L. Rasia S. Capra R. Imberti L. Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients. Clin. Immunol. 2012 145 1 19 26 10.1016/j.clim.2012.07.007 22892399
    [Google Scholar]
  48. Planas R. Jelc̆ić I. Schippling S. Martin R. Sospedra M. Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis. Eur. J. Immunol. 2012 42 3 790 798 10.1002/eji.201142108 22144343
    [Google Scholar]
  49. Ramos-Cejudo J. Oreja-Guevara C. Stark Aroeira L. Rodriguez de Antonio L. Chamorro B. Diez-Tejedor E. Treatment with natalizumab in relapsing-remitting multiple sclerosis patients induces changes in inflammatory mechanism. J. Clin. Immunol. 2011 31 4 623 631 10.1007/s10875‑011‑9522‑x 21491095
    [Google Scholar]
  50. Kunicki M.A. Amaya Hernandez L.C. Davis K.L. Bacchetta R. Roncarolo M.G. Identity and diversity of human peripheral Th and T regulatory cells defined by single-cell mass cytometry. J. Immunol. 2018 200 1 336 346 10.4049/jimmunol.1701025 29180490
    [Google Scholar]
  51. Haschka D. Tymoszuk P. Bsteh G. Petzer V. Berek K. Theurl I. Berger T. Weiss G. Expansion of neutrophils and classical and nonclassical monocytes as a hallmark in relapsing-remitting multiple sclerosis. Front. Immunol. 2020 11 594 10.3389/fimmu.2020.00594 32411125
    [Google Scholar]
  52. Waschbisch A. Schröder S. Schraudner D. Sammet L. Weksler B. Melms A. Pfeifenbring S. Stadelmann C. Schwab S. Linker R.A. Pivotal role for CD16+ monocytes in immune surveillance of the central nervous system. J. Immunol. 2016 196 4 1558 1567 10.4049/jimmunol.1501960 26746191
    [Google Scholar]
  53. Chuluundorj D. Harding S.A. Abernethy D. La Flamme A.C. Expansion and preferential activation of the CD14 + CD16 + monocyte subset during multiple sclerosis. Immunol. Cell Biol. 2014 92 6 509 517 10.1038/icb.2014.15 24638064
    [Google Scholar]
  54. Ajami B. Steinman L. Nonclassical monocytes: Are they the next therapeutic targets in multiple sclerosis? Immunol. Cell Biol. 2018 96 2 125 127 10.1111/imcb.12004 29352485
    [Google Scholar]
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