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NK and NKT cell dynamics after rituximab therapy for systemic lupus erythematosus and rheumatoid arthritis

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Abstract

Biomarkers of clinical response to rituximab (RTX) therapy and early predictors of outcome are still under investigation. We report a flow cytometric immunophenotyping analysis from peripheral blood leukocyte subpopulations of two patients with systemic lupus erythematosus (SLE) associated thrombocytopenia and one patient with rheumatoid arthritis (RA), before and after 6 weeks of treatment with RTX. Our results show a reduced population of CD19+ expressing cells (B cells) after RTX treatment in all three patients. Increased frequency of peripheral regulatory CD4+CD25high T cell subset and the CD3−CD16−CD56bright NK cell subset after RTX therapy were also observed in all patients, the latter being more pronounced in the SLE patient with sustained clinical response. In addition, an increased population of NKT cell subsets was observed in the patients with clinical response. This is the first evaluation of NK and NKT cells as biomarkers of clinical response after rituximab therapy in rheumatic diseases.

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References

  1. Stohl W, Looney RJ (2006) B cell depletion therapy in systemic rheumatic diseases: different strokes for different folks? Clin Immunol 121:1–12. doi:10.1016/j.clim.2006.03.010

    Article  PubMed  CAS  Google Scholar 

  2. Strand V, Kimberly R, Isaacs JD (2007) Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev Drug Discov 6:75–92. doi:10.1038/nrd2196

    Article  PubMed  CAS  Google Scholar 

  3. Sfikakis PP, Boletis JN, Lionaki S et al (2005) Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum 52:501–513. doi:10.1002/art.20858

    Article  PubMed  CAS  Google Scholar 

  4. Tanaka Y, Yamamoto K, Takeuchi T et al (2007) A multicenter phase I/II trial of rituximab for refractory systemic lupus erythematosus. Mod Rheumatol 17:191–197. doi:10.1007/s10165-007-0565-z

    Article  PubMed  CAS  Google Scholar 

  5. Kavanaugh A, Rosengren S, Lee SJ et al (2007) Assessment of rituximab’s immunomodulatory synovial effects (the ARISE trial). I: clinical and synovial biomarker results. Ann Rheum Dis 67:402–428. doi:10.1136/ard.2007.074229

    Article  PubMed  Google Scholar 

  6. Smolen JS, Keystone EC, Emery P et al (2007) Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 66:143–150. doi:10.1136/ard.2006.061002

    Article  PubMed  CAS  Google Scholar 

  7. Browning JL (2006) B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5:564–576. doi:10.1038/nrd2085

    Article  PubMed  CAS  Google Scholar 

  8. Sfikakis PP, Souliotis VL, Fragiadaki KG et al (2007) Increased expression of the FoxP3 functional marker of regulatory T cells following B cell depletion with rituximab in patients with lupus nephritis. Clin Immunol 123:66–73. doi:10.1016/j.clim.2006.12.006

    Article  PubMed  CAS  Google Scholar 

  9. Toubi E, Kessel A, Slobodin G et al (2007) Changes in macrophage function after rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 66:818–820. doi:10.1136/ard.2006.062505

    Article  PubMed  CAS  Google Scholar 

  10. Shi FD, Van Kaer F (2006) Reciprocal regulation between natural killer cells and autoreactive T cells. Nat Rev Immunol 6:751–760. doi:10.1038/nri1935

    Article  PubMed  CAS  Google Scholar 

  11. Miyake S, Yamamura T (2007) NKT cells and autoimmune diseases: unraveling the complexity. Curr Top Microbiol Immunol 314:251–267. doi:10.1007/978-3-540-69511-0_10

    Article  PubMed  CAS  Google Scholar 

  12. Green MR, Kennell AS, Larche MJ et al (2005) Natural killer cell activity in families of patients with systemic lupus erythematosus: demonstration of a killing defect in patients. Clin Exp Immunol 141:165–173. doi:10.1111/j.1365-2249.2005.02822.x

    Article  PubMed  CAS  Google Scholar 

  13. Green MR, Kennell AS, Larche MJ et al (2007) Natural killer T cells in families of patients with systemic lupus erythematosus: their possible role in regulation of IGG production. Arthritis Rheum 56:303–310. doi:10.1002/art.22326

    Article  PubMed  Google Scholar 

  14. Shevach EM, Piccirillo CA, Thornton AM et al. (2003) Control of T cell activation by CD4+CD25+ suppressor T cells. Novartis Found Symp 252:24–36, discussion 36–44, 106–114

    Google Scholar 

  15. Barath S, Aleksza M, Tarr T et al (2007) Measurement of natural (CD4+CD25high) and inducible (CD4+IL-10+) regulatory T cells in patients with systemic lupus erythematosus. Lupus 16:489–496. doi:10.1177/0961203307080226

    Article  PubMed  CAS  Google Scholar 

  16. Crispin JC, Martinez A, Alcocer-Varela J (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273–276. doi:10.1016/S0896-8411(03)00121-5

    Article  PubMed  Google Scholar 

  17. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640. doi:10.1016/S1471-4906(01)02060-9

    Article  PubMed  CAS  Google Scholar 

  18. Vitelli-Avelar DM, Sathler-Avelar R, Dias JC et al (2005) Chagasic patients with indeterminate clinical form of the disease have high frequencies of circulating CD3+CD16-CD56+ natural killer T cells and CD4+CD25High regulatory T lymphocytes. Scand J Immunol 62:297–308. doi:10.1111/j.1365-3083.2005.01668.x

    Article  PubMed  CAS  Google Scholar 

  19. Jonsdottir T, Gunnarsson I, Risselada A et al (2007) Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann Rheum Dis 56:1263–1272

    Google Scholar 

  20. McMillan R (2007) The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol 44:S3–S11. doi:10.1053/j.seminhematol.2007.11.002

    Article  PubMed  CAS  Google Scholar 

  21. Moretta A, Bottino C, Mingari MC et al (2002) What is a natural killer cell? Nat Immunol 3:6–8. doi:10.1038/ni0102-6

    Article  PubMed  CAS  Google Scholar 

  22. Bowles JA, Wang SY, Link BK et al (2006) Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood 108:2648–2654. doi:10.1182/blood-2006-04-020057

    Article  PubMed  CAS  Google Scholar 

  23. Bonelli M, von Dalwigk K, Savitskaya A et al (2008) Foxp3 expression in CD4+ T cells of patients with systemic lupus erythematosus (SLE): a comparative phenotypic analysis. Ann Rheum Dis 67:664–671. doi:10.1136/ard.2007.074690

    Article  PubMed  CAS  Google Scholar 

  24. Vallerskog T, Gunnarsson I, Widhe M et al (2007) Treatment with rituximab affects both the cellular and the humoral arm of the immune system in patients with SLE. Clin Immunol 122:62–74. doi:10.1016/j.clim.2006.08.016

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by Grant 304713/2002-3 (M.G.R) by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). M.S. is currently receiving a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Conflict of interest statement

The authors have no conflict of interest.

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Authors and Affiliations

  1. Oswaldo Cruz Foundation, Salvador, Brazil

    Eliana A. G. Reis, Daniel A. Athanazio, Jorge Clarencio S. Andrade, Ronden N. Jesus, Lúcio M. Barbosa & Mitermayer G. Reis

  2. Federal University of Bahia, Salvador, Brazil

    Daniel A. Athanazio, Ronden N. Jesus & Mitermayer G. Reis

  3. Serviço de Reumatologia do Hospital Santa Izabel, Praça Almeida Couto 500, Nazaré, Salvador, Bahia, CEP 40050-001, Brazil

    Isabella Lima & Mittermayer B. Santiago

  4. Escola Bahiana de Medicina e Saúde Pública (Medical School), Salvador, Brazil

    Natália Oliveira e Silva, Mitermayer G. Reis & Mittermayer B. Santiago

Authors
  1. Eliana A. G. Reis
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  2. Daniel A. Athanazio
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  3. Isabella Lima
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  4. Natália Oliveira e Silva
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  5. Jorge Clarencio S. Andrade
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  6. Ronden N. Jesus
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  7. Lúcio M. Barbosa
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  8. Mitermayer G. Reis
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  9. Mittermayer B. Santiago
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Correspondence to Mittermayer B. Santiago.

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Reis, E.A.G., Athanazio, D.A., Lima, I. et al. NK and NKT cell dynamics after rituximab therapy for systemic lupus erythematosus and rheumatoid arthritis. Rheumatol Int 29, 469–475 (2009). https://doi.org/10.1007/s00296-008-0719-0

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  • DOI: https://doi.org/10.1007/s00296-008-0719-0

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