Natalizumab treatment reduces endothelial activity in MS patients

Millonig, Alban; Hegen, Harald; Pauli, Franziska Di; Ehling, Rainer; Gneiss, Claudia; Hoelzl, Martina; Künz, B; Lutterotti, Andreas; Rudzki, Dagmar; Berger, Thomas; Reindl, Markus; Deisenhammer, Florian

doi:10.1016/j.jneuroim.2010.07.012

Cited by 31 publications

(33 citation statements)

References 35 publications

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“…26 Herein, sVCAM-1 in plasma collected at necropsy positively correlated to VCAM-1 expression in DRG tissue, suggesting that reduced tissue expression is not because of increased shedding (data not shown). Thus, we hypothesize that the reduced VCAM-1 expression is because of a feedback mechanism where VCAM-1 is down-regulated in natalizumab-treated animals because of the absence of its ligand.…”

Section: Anti-a4 Blocks Monocyte Traffic To Drgmentioning

confidence: 81%

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

Lakritz

Thibault

Robinson

et al. 2016

The American Journal of Pathology

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Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine þ MAC387 þ ) monocytes is associated with severe DRG pathology and loss of intraepidermal nerve fibers in SIV-infected macaques. Herein, we blocked leukocyte traffic by treating animals with natalizumab, which binds to a4-integrins. SIV-infected CD8-depleted macaques treated with natalizumab either early (the day of infection) or late (28 days after infection) were compared with untreated SIV-infected animals sacrificed at similar times. Histopathology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation, neuronophagia, and Nageotte nodules. Natalizumab treatment resulted in a decrease in the number of bromodeoxyuridine þ (early), MAC387 þ (late), CD68 þ (early and late), and SIVp28 þ (late) macrophages in DRG tissues. The number of CD3 þ T lymphocytes in DRGs was not affected by natalizumab treatment. Vascular cell adhesion molecule 1, an adhesion molecule that mediates leukocyte traffic, was diminished in DRGs of all natalizumab-treated animals. These data show that blocking monocyte, but not T lymphocyte, traffic to the DRG results in decreased inflammation and pathology, supporting a role for monocyte traffic and activation in HIV peripheral neuropathy. The primary mechanisms of HIV peripheral neuropathy include immune damage secondary to viral infection and mitochondrial toxicity from the antiretrovirals. Because HIV and SIV do not productively infect neurons or Schwann cells, damage to the dorsal root ganglia (DRG) in peripheral neuropathy is believed to be, in part, because of infected and activated macrophages. In vitro and in vivo studies suggest that both viral proteins and systemic inflammation secondary to the viral infection may damage neurons and axons. 1 Using a CD8-depleted SIV-infected rhesus macaque model of peripheral neuropathy, we have shown that accumulation of recruited [bromodeoxyuridine (BrdU) þ MAC387 þ ] monocytes/macrophages was associated with severe DRG pathology. 2 The number of BrdU þ monocytes correlated with DRG histopathology, which included neuronophagia, satellitosis, and Nageotte nodules. 2 Our data demonstrate that newly recruited MAC387 þ BrdU þ macrophages play a significant role in DRG pathogenesis.

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Section: Anti-a4 Blocks Monocyte Traffic To Drgmentioning

confidence: 81%

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

Lakritz

Thibault

Robinson

et al. 2016

The American Journal of Pathology

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“…LFA-1, the adhesion molecule for intracellular adhesion molecule, is also increased during active disease [77]. Soluble VCAM levels have been found to be decreased by treatment with natalizumab and recover in patients who develop neutralizing antibodies to natalizumab [78].…”

Section: Adhesion Molecules and Matrix Metalloproteinasesmentioning

confidence: 99%

Biomarkers of disease activity in multiple sclerosis

Graber

Dhib‐Jalbut²

2011

Journal of the Neurological Sciences

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“…MFI in vivo bound natalizumab ×100 MFI in vitro saturated natalizumab = Serum NAB were determined by the national reference laboratory (Department of Neurology, Innsbruck) and classified as low and high NAB titers in case of positive ELISA results [14] .…”

Section: Sample Processingmentioning

confidence: 99%

A routine-qualified flow cytometric method for the identification of multiple sclerosis patients with a reduced therapeutic effectiveness of natalizumab

Oppermann

Harrer

Pilz

et al. 2014

LaboratoriumsMedizin

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Background: Natalizumab-neutralizing antibodies (NABs) occur in 9% of natalizumab-treated multiple sclerosis (MS) patients. Loss of clinical and biological efficacy in patients with persisting NABs requires termination of natalizumab treatment. Because high-titer NABs are strongly associated with persistence of NABs, we investigated if determination of natalizumab saturation levels of α -4 integrins by flow cytometry has the potential to identify patients early with NABs. Methods: Cell-bound natalizumab and natalizumab saturation of α -4 integrins on T cells were detected by flow cytometry using a monoclonal anti-human IgG4 antibody. Peripheral blood mononuclear cells were enriched from venous blood collected at the start (baseline) and every 4 weeks immediately before subsequent infusions until up to 9 months from natalizumab-treated patients with NABs (n = 4) and at the start and after 1 (n = 15), 2 (n = 14), 3 (n = 9), 6 (n = 7), and 9 months (n = 3) from natalizumab-treated patients without NABs. Natalizumab saturation levels (in %) of T cells were determined by relating median fluorescence intensities (MFIs) of in vivo bound natalizumab to MFIs after in vitro incubation with saturating amounts of natalizumab. Determination of serum NABs was performed by ELISA. Results: In patients without NABs, the median natalizumab saturation level of T cells over 9 months was 75% (confidence interval of 95%: 72 -78%). In two of the four patients with NABs, the natalizumab saturation level of T cells only reached approximately 50% after the first infusion and further declined to baseline levels with the second infusion. Low-titer NABs were measured after the first infusion and development of persistent high-titer NABs led to termination of natalizumab treatment after 6 months. In another two patients, the natalizumab saturation level of T cells was 74% and 68% after the first infusion, temporarily decreased to approximately baseline levels and reincreased after approximately 6 months. Transient NABs

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Natalizumab treatment reduces endothelial activity in MS patients

Cited by 31 publications

References 35 publications

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy

Biomarkers of disease activity in multiple sclerosis

A routine-qualified flow cytometric method for the identification of multiple sclerosis patients with a reduced therapeutic effectiveness of natalizumab

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