Effects of Natalizumab Treatment on Foxp3+ T Regulatory Cells

Stenner, Max-Philipp; Waschbisch, Anne; Buck, Dorothea; Doerck, Sebastian; Einsele, Hermann; Toyka, Klaus V.; Wiendl, Heinz

doi:10.1371/journal.pone.0003319

Cited by 53 publications

(56 citation statements)

References 39 publications

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“…In addition, Tregs may be ‘recruited’ to migrate into the CNS at times of inflammation and may modulate the function of effector cells in the CNS, which suggests a role in the immune surveillance in the CNS [20]. Our finding is somewhat different from the one of Stenner et al [27] who did not find an impact of natalizumab on Treg frequency. One explanation may be that the definition of Tregs may be different – Stenner et al measured CD25 high -expressing Tregs.…”

Section: Discussioncontrasting

confidence: 79%

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Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

et al. 2010

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Background: Natalizumab is a humanized monoclonal antibody directed against very late activation antigen 4 (VLA-4) and has a potent effect on disease activity in multiple sclerosis. Blockade of VLA-4 with natalizumab may not only interfere with autoimmunological mechanisms but also with central nervous system immune surveillance. Methods: Longitudinal ex vivo and in vitro study to determine the effect of natalizumab on the frequency of distinct immune cells and on the frequency and suppressive function of natural CD4+CD25+ regulatory T cells (Tregs). Results: Natalizumab binding to VLA-4 was more marked for B cells than for T cells (49% reduction in VLA-4-expressing B cells compared to 24.5% reduction of T cells). There was an increase in circulating B cells over T cells (2.6 vs. 1.5 fold, p < 0.001). Natural killer cells increased 1.5-fold (p = 0.01). Natalizumab led to a relative decrease in CD4+CD25+ Tregs from 18.9 to 14.1% (p = 0.04). The impaired suppressive capacity of Tregs was not restored. Conclusion: Natalizumab reduces VLA-4 expression on all investigated immune cells, but changes were most marked for B cells. Further differential effects on immune cells may be relevant to opportunistic central nervous system infections during treatment with natalizumab.

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Section: Discussioncontrasting

confidence: 79%

“…One explanation may be that the definition of Tregs may be different – Stenner et al measured CD25 high -expressing Tregs. This study, however, reported on the effect of a single infusion on Tregs [27]. It is noteworthy that 5 of 15 patients had a decrease in CD4+CD25+FoxP3+ Treg frequency in this study.…”

Section: Discussionmentioning

confidence: 70%

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

et al. 2010

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“…ϩ frequency or suppressive activity either in vitro or in vivo (79). Moreover, there was no preferential blockade or permissiveness for the transmigration of Tregs into tissues compared with conventional T cells.…”

Section: Foxp3mentioning

confidence: 93%

“…Natalizumab is an ␣4 (VLA4) integrin antagonist that selectively blocks trafficking of leukocytes to inflamed tissues and that may also play a role in co-stimulatory signals for T cells (79). Major concerns were raised about this molecule in 2005 after cases of PML were reported (80 -82).…”

Section: Natalizumab (Tysabri)mentioning

confidence: 99%

Immunosuppressive Drugs and Tregs

Serres

Sayegh

Najafian

2009

Clinical Journal of the American Society of Nephrology

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To define therapeutic strategies that promote tolerance, it is of critical importance to determine the effects of immunosuppressive drugs on regulatory T cells (Tregs). This review discusses the current knowledge about the physiology of Tregs in humans, the role or Tregs in transplantation, and the impact of the different types of immunosuppressive agents on the frequency and functionality of Tregs in in vitro and in vivo systems.

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“…23f). TREG have previously been shown to express relatively low levels of VLA-4 (Stenner et al 2008), a finding supporting the observation in our study. We also observed a significant decrease in terminally differentiated, senescent CD8 + CD28 -CD57 + cells after treatment (Fig.…”

Section: Natalizumab Effects On Lymphocyte Subpopulations (Paper Iii)supporting

confidence: 93%

Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab

Edström¹

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Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) and the most common neurological cause of disability in young adults. In most cases, the disease course is characterised by the cycling of relapses and remissions, so called relapsingremitting MS (RR-MS). Although extensively studied, the underlying mechanisms are not fully elucidated, yet CD4 + T cells have been shown to be of importance in disease pathology.A range of treatments are available; the most effective to date being natalizumab, a monoclonal antibody directed against the adhesion molecule VLA-4 on the lymphocyte surface, thereby preventing entry into the CNS.The aim of this thesis was to assess the nature of lymphocyte populations in MS. This was achieved by studying CD4 + T helper cells (TH) and regulatory T cells (TREG) in peripheral blood. In addition, the influence of natalizumab was also investigated, both regarding the effect of the drug on the composition of the peripheral lymphocyte compartment as well as its effects on CD4 + T cells in vitro.We showed an imbalance in the mRNA expression of CD4 + T helper cell lineage specific transcription factors in peripheral blood. While TH1 and TH17 associated TBX21 and RORC expression was comparable in MS and healthy individuals, the TH2 and TREG associated A sizable effect of natalizumab treatment was seen in the composition of peripheral lymphocyte populations after one year of treatment. While the number of lymphocytes increased over all, the largest increase was seen in the NK and B cell compartments. ABSTRACT Furthermore, T cells from patients with MS displayed decreased responsiveness towardsantigens and mitogens in vitro. Natalizumab treatment was able to normalise the responsiveness in blood, an effect not solely dependent on the increased number of cells.The importance of CD4 + T cells in human disease, including MS, was shown by a systems biology approach; using GWAS data, genes associated with CD4 + T cell differentiation were enriched for many, not only immune-related, diseases. Furthermore, global CD4 + T cell gene expression (by microarray) could discriminate between patients and controls. Lastly, using in vitro treated CD4 + T cells, we could show that natalizumab perturbated gene expression differently in patients responding to the drug compared to those not responding.In

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Effects of Natalizumab Treatment on Foxp3+ T Regulatory Cells

Cited by 53 publications

References 39 publications

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

Effects of Natalizumab on Circulating B Cells, T Regulatory Cells and Natural Killer Cells

Immunosuppressive Drugs and Tregs

Regulation of immunity in Multiple Sclerosis : CD4+ T cells and the influence of natalizumab

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