CNS Elevation of Vascular and Not Mucosal Addressin Cell Adhesion Molecules in Patients with Multiple Sclerosis

Allavena, Rachel; S, Noy; Andrews, M. D.; Pullen, Nick

doi:10.2353/ajpath.2010.090437

Cited by 49 publications

(43 citation statements)

References 27 publications

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“…MAdCAM represents an organ-specific target, as expression is restricted mainly to gastrointestinal tract mucosa 22. This organ specificity may translate to a favourable safety profile; in particular, the absence of MAdCAM in the brain microvasculature32 suggests that drugs acting on MAdCAM would not impact the body's ability to respond to CNS infections such as PML.…”

Section: Discussionmentioning

confidence: 99%

The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

Vermeire¹,

Ghosh

Panés

et al. 2011

Gut

128

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Background and aims Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis. Methods In this randomised, double-blind placebocontrolled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03e10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of a 4 b 7 + lymphocytes was measured to demonstrate drug activity. Results No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in a 4 b 7 + lymphocytes in patients receiving PF-00547,659. Conclusions The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.

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Section: Discussionmentioning

confidence: 99%

The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

Vermeire¹,

Ghosh

Panés

et al. 2011

Gut

128

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“…In an experimental model of multiple sclerosis, blocking VCAM-1 inhibits T cell infiltration into the brain [63]. Consistent with this, multiple sclerosis patients have elevated VCAM-1 but not MAdCAM-1 expression in brain tissue [64]. In clinical trials, blocking the VCAM-1 ligand, α4-integrin, with antibodies (natalizumab) reduces disease severity in multiple sclerosis and Crohn’s disease [65, 66].…”

Section: Vcam-1 Function In Disease and Infectionsmentioning

confidence: 94%

Isoforms of Vitamin E Differentially Regulate Inflammation

Cook‐Mills¹,

McCary²

2010

EMIDDT

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Vitamin E regulation of disease has been extensively studied in humans, animal models and cell systems. Most of these studies focus on the α-tocopherol isoform of vitamin E. These reports indicate contradictory outcomes for anti-inflammatory functions of the α-tocopherol isoform of vitamin E, especially with regards to clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with recently reported unrecognized properties of isoforms of vitamin E. Recently, it has been reported that physiological levels of purified natural forms of vitamin E have opposing regulatory functions during inflammation. These opposing regulatory functions by physiological levels of vitamin E isoforms impact interpretations of previous studies on vitamin E. Moreover, additional recent studies also indicate that the effects of vitamin E isoforms on inflammation are only partially reversible using physiological levels of a vitamin E isoform with opposing immunoregulatory function. Thus, this further influences interpretations of previous studies with vitamin E in which there was inflammation and substantial vitamin E isoforms present before the initiation of the study. In summary, this review will discuss regulation of inflammation by vitamin E, including alternative interpretations of previous studies in the literature with regards to vitamin E isoforms.

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“…This is, at least in part, a result of leukocyte specific chemokine activation of integrins to their integrin high affinity conformation [11,17,18,20]. Blocking VCAM-1 by intravenous injection of anti-VCAM-1 blocking antibodies inhibits eosinophil and mast cell precursor recruitment in asthma models [56-63], severity and onset of atopic dermatitis [64], T cell infiltration into the intestine in inflammatory bowel disease [65], T cell infiltration into the brain in an experimental model of multiple sclerosis [66,67], CD8 + T cell, monocyte and dendritic cell infiltration into the brain during lymphocytic choriomeningitis virus (LCMV) infections [68], and monocyte recruitment, carotid neointimal formation and inflammation in cardiovascular disease [69-76]. ICAM-1 is important for leukocyte recruitment in several diseases including atherosclerosis and T cell recruitment in an experimental model of multiple sclerosis [77-80].…”

Section: Vcam-1 and Icam-1 Function In Disease And Infectionsmentioning

confidence: 99%

Isoforms of Vitamin E Differentially Regulate PKCα and Inflammation: A Review

Cook‐Mills¹

2013

J Clin Cell Immunol

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Vitamin E regulation of disease has been extensively studied but most studies focus on the α-tocopherol isoform of vitamin E. These reports indicate contradictory outcomes for anti-inflammatory functions of the α-tocopherol isoform of vitamin E with regards to animal and clinical studies. These seemingly disparate results are consistent with our recent studies demonstrating that purified natural forms of vitamin E have opposing regulatory functions during inflammation. In this review, we discuss that α-tocopherol inhibits whereas γ-tocopherol elevates allergic inflammation, airway hyperresponsiveness, leukocyte transendothelial migration, and endothelial cell adhesion molecule signaling through protein kinase Cα. Moreover, we have demonstrated that α-tocopherol is an antagonist and γ-tocopherol is an agonist of PKCα through direct binding to a regulatory domain of PKCα. In summary, we have determined mechanisms for opposing regulatory functions of α-tocopherol and γ-tocopherol on inflammation. Information from our studies will have significant impact on the design of clinical studies and on vitamin E consumption.

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CNS Elevation of Vascular and Not Mucosal Addressin Cell Adhesion Molecules in Patients with Multiple Sclerosis

Cited by 49 publications

References 27 publications

The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

Isoforms of Vitamin E Differentially Regulate Inflammation

Isoforms of Vitamin E Differentially Regulate PKCα and Inflammation: A Review

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