Natalizumab therapy decreases surface expression of both VLA-heterodimer subunits on peripheral blood mononuclear cells

Harrer, Andrea; Wipfler, Peter; Einhaeupl, Max; Pilz, Georg; Oppermann, Katrin; Hitzl, Wolfgang; Afazel, Shahrzad; Haschke-Becher, Elisabeth; Strasser, Peter; Trinka, Eugen; Kraus, J.

doi:10.1016/j.jneuroim.2011.03.001

Cited by 27 publications

(29 citation statements)

References 24 publications

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“…The most significant finding of this study is the observation that after anti-VLA-4 exposure there is a decrease in apha-4 integrin surface expression on NK cells, CD4 + T cells, CD8 + T cells, and CD19 + B cells. In line with our results, recent clinical investigations have demonstrated that the levels of surface-bound natalizumab correlate with diminished alpha-4 expression on T, B, NK, and NKT subsets of peripheral blood mononuclear cells from patients on natalizumab therapy (Harrer et al, 2011; Skarica et al, 2011; Stüve et al, 2006). Moreover, we found that while the expression levels on NK cells recovered in the spleen and lymph nodes 5 days after the last antibody injection, they continued to be suppressed throughout the observation period in NK cells extracted from the CNS.…”

Section: Discussionsupporting

confidence: 92%

“…We speculate that with the rising titers of the blocking antibody coinciding with the external administrations, the expression of the integrin molecule is downregulated, whereas clearance of the antibody allows recover of the adhesion molecule expression. In support of this view, are an in vitro binding assay on CD3 + T cells that showed an inverse correlation between increased amounts of cell-bound natalizumab and surface expression of VLA subunits (Harrer et al, 2011) and a clinical study that demonstrated how after the typical initial decrease, unblocked alpha-4 integrin expression levels tended to recover and were similar to baseline 14 weeks after the last natalizumab infusion (Wipfler et al, 2011). It is then fair to conclude that natalizumab diminishes the functional surface expression of the alpha-4 integrin hence the migratory capacity of the circulating immune cells and a threshold of unbound VLA-4 may be required for the capacity to migrate across the endothelial barrier thus explaining the impaired circulation of NK cells and other lymphocytes into the CNS.…”

Section: Discussionmentioning

confidence: 94%

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Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis

Gan

Liu

et al. 2012

Journal of Neuroimmunology

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Natalizumab inhibits the influx of leukocytes into the central nervous system (CNS) via blockade of alpha-4 subunit of very late activation antigen (VLA)-4. The association of natalizumab therapy with progressive multifocal leukoencephalopathy (PML) suggests a disturbance of CNS immune surveillance in a small percentage of Multiple Sclerosis (MS) patients exposed to the medication. Natural killer (NK) cells are known to play an important role in modulating the evolution of different phases of this lymphocyte mediated disease, and we investigated the effects of natalizumab on the NK cell phenotype and infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Our data show that both resting (from naïve mice) and activated (from EAE mice) NK cells express high levels of VLA-4, and anti-VLA-4 antibody treatment significantly decreases NK cells frequency in the CNS of EAE mice. Moreover, we find that anti-VLA-4 possibly impairs NK cells migratory potential, since unblocked VLA-4 expression levels were downregulated on those NK cells that penetrate the CNS. These data suggest that treatment with antibody to VLA-4 may alter immune surveillance of the CNS by impacting NK cell functions and might contribute to the understanding of the mechanisms leading to the development of PML in some MS patients.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis

Gan

Liu

et al. 2012

Journal of Neuroimmunology

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“…Increases in anti-natalizumab rfi levels were accompanied by a sharp decline of about 80% in mean α 4 rfi levels (p<0.001, Figure 1B). Both, the increase in anti-natalizumab rfi levels, and as shown before [23], the decrease in anti-α 4 rfi levels were stable from the week 12 through the week 72 measurements.…”

Section: Resultssupporting

confidence: 71%

Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

et al. 2012

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Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α4 subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α4 and α4 integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α4 integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α4. Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety.

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“…Together with transferrin receptor, these two highly expressed molecules contribute to increased viral insertion into host cells of future JCV switchers (Caruso et al 2003;Komagome et al 2002). We would like to note that in a previous report by Harrer et al that examined gene expression effects of natalizumab treatment, in contrast to our findings, VLA-4 was found to be down-regulated (Harrer et al 2011). However, as this was found in a mixed population of JCV switchers and nonswitchers, it is possible that the over activation of VLA 4 in JCV switchers was not registered in that study because seroconverters represent only a small proportion of natalizumabtreated MS patients.…”

Section: Discussioncontrasting

confidence: 96%

Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients

et al. 2016

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Estimating the individual risk for the development of progressive multifocal leukoencephalopathy (PML) in anti-John Cunningham virus (JCV) antibody-negative patients with multiple sclerosis (MS) treated with natalizumab is a major challenge. A serological conversion occurring under treatment from anti-JCV antibody-negative to positive status may significantly increase this risk. We investigated changes in peripheral blood cells' gene expression induced by natalizumab treatment in anti-JCV antibody-negative MS patients and tested blood transcriptional profile that characterizes patients predisposed to antibody switch under natalizumab treatment. After 3 years of natalizumab treatment, 24.6 % of anti-JCV antibody-negative MS patients switched to become anti-JCV antibody-positive (JCV switchers). Natalizumab induced 946 and 1186 significantly differentiating genes in JCV switchers and non-switchers, respectively. In JCV switchers, the signature was enriched by over-expression of genes associated with the first stages of viral entry to host cells including macropinocytosis (p = 1.82E-06), virus entry via endocytosis (p = 1.60E-06), clathrin-mediated endocytosis (p = 1.13E-04), and caveolar-mediated endocytosis (p = 4.50E-04) pathways. Further analysis to identify pre-existing transcriptional differences that characterize future JCV switchers prior to treatment initiation also demonstrated a transcriptional signature enriched by similar viral entry mechanisms. These findings, verified in an additional independent cohort of natalizumab-treated patients, could lead to future identification of patients that remain anti-JCV antibody-negative thus allowing safe continuation of treatment, as well as the development of future targeted therapeutic interventions to reduce the risk of PML.

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Natalizumab therapy decreases surface expression of both VLA-heterodimer subunits on peripheral blood mononuclear cells

Cited by 27 publications

References 24 publications

Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis

Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis

Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

Host cell virus entry mechanisms enhance anti-JCV-antibody switch in natalizumab-treated multiple sclerosis patients

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