The effect of anti-α4 integrin antibody on brain lesion activity in MS

Tubridy, Niall; Behan, P. O.; Capildeo, Rudy; Chaudhuri, Abhijit; Forbes, Raeburn B; Hawkins, C. P.; Hughes, Richard A.; Palace, J; Sharrack, Basil; Swingler, Robert; Young, Carolyn; Moseley, I. F.; MacManus, David; Donoghue, Stephen; Miller, David H.

doi:10.1212/wnl.53.3.466

Cited by 292 publications

(163 citation statements)

References 13 publications

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“…g/ml, 90 min pretreatment) blocks Jurkat T cell binding to fibronectin by 56±9% (n=2, data not shown) and that Jurkat cells have high expression of § 4 protein (Western analysis, not shown). Clinical trials have determined that Antegren ® , a monoclonal antibody specific for the § 4 integrin, significantly reduces the number of new brain lesions [21,22]. It is speculated that Antegren ® interferes in § 4 g 1 or § 4 g 7 interactions with the immunoglobulin superfamily member VCAM-1.…”

Section: Discussionmentioning

confidence: 99%

“…2) and others have shown that Rac-1 regulates T cell actin polymerization [13], we hypothesized that the Rac-1/CYFIP2 pathway regulates fibronectin-mediated binding. We chose to study fibronectin, as this protein interacts physically with § 4 and g 1 family integrin proteins [20], and recent clinical trials have shown that Antegren ® (an antibody to § 4 protein) reduced new brain lesions in MS patients as determined by MRI [21,22]. In Jurkat cells, wortmannin dose-dependently reduced Rac-1 activity ( Fig.…”

Section: Rac-1 Activity or An Increase In Cyfip2 Protein Levels Enhanmentioning

confidence: 99%

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CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

et al. 2004

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DNA microarray profiling of CD4 + and CD8 + cells from non-treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4 + cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral-mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin-mediated adhesion. Secondly, CYFIP2 knock-down experiments using antisense oligodeoxynucleotides reduced fibronectin-mediated binding in Jurkat and CD4 + cells. Thirdly, inhibition of Rac-1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin-mediated adhesion in Jurkat and CD4 + cells. Finally, inhibition of Rac-1 or reduction of CYFIP2 protein decreased fibronectin-mediated adhesion in CD4 + cells from MS patients to levels similar to controls. These studies suggest that overabundance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.

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Section: Discussionmentioning

confidence: 99%

Section: Rac-1 Activity or An Increase In Cyfip2 Protein Levels Enhanmentioning

confidence: 99%

CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

et al. 2004

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“…The results imply that therapeutic interventions targeted at interactions between T cells and ECMP (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) will be only partially effective in collagenous tissues if they do not block the costimulatory effects of type I collagen. This possibility is supported by the reports that VLA-4-blocking peptide and mAb are unable to inhibit cutaneous contact hypersensitivity, delayed-type hypersensitivity, or adjuvant arthritis in rodents by more than 35-60% (14,15,20,25).…”

Section: Discussionmentioning

confidence: 99%

“…This has led to multiple reports of the development and testing of potentially therapeutic VLA-4 Abs and peptide ligands, both in vitro and in animal models of inflammatory and autoimmune diseases, and transplantation (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Early human studies with VLA-4 targeting agents are also in progress, for example in patients with multiple sclerosis (26,27).…”

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confidence: 99%

Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

Rao

Hales

Camp

2000

The Journal of Immunology

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Purified, resting peripheral blood T lymphocytes were previously reported to undergo β1 integrin-dependent activation when cultured with anti-CD3 mAb coimmobilized with fibronectin, but not type I collagen. However, the extravascular T cells that encounter immobilized extracellular matrix proteins and are involved in disease pathogenesis have different properties from resting peripheral blood cells. In this study, we confirm that resting CD4+ and CD8+ T cells from peripheral blood are costimulated by immobilized fibronectin, but not type I collagen. In contrast, Ag- or mitogen-stimulated CD4+ and CD8+ T cell lines, used as models of the effector cells involved in disease, are more potently costimulated by type I collagen than fibronectin. The collagen-induced effects are similar in assays with serum-free medium and in more physiological assays in which anti-CD3 mAb is replaced by a threshold concentration of Ag and irradiated autologous PBMC as APC. The responses are β1 integrin dependent and mediated largely by very late Ag (VLA) 1 and 2, as shown by their up-regulation on the T cell lines as compared with freshly purified resting PBL, and by the effects of blocking mAb. Reversed phase HPLC located the major costimulatory sequence(s) in the α1 chain of type I collagen, the structure of which was confirmed by amino acid sequencing. The results demonstrate the potential importance of type I collagen, an abundant extracellular matrix protein, in enhancing the activation of extravascular effector T cells in inflammatory disease, and point to a new immunotherapeutic target.

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“…Some reports have suggested that an increased level of MS disease activity (radiological disease or relapse) may occur following natalizumab cessation, even after switching to other therapies, including GA and fingolimod [13,19,28]; however, in some cases this was attributed to an initial high level of disease activity and/or few doses of natalizumab prior to interruption [11,16,18,29]. Importantly, these studies did not use monthly MRI scans to monitor subclinical disease activity.…”

Section: Timing Of Gd? Lesion Appearancementioning

confidence: 99%

Radiologic MS disease activity during natalizumab treatment interruption: findings from RESTORE

et al. 2014

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The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumabtreated patients with no gadolinium-enhancing (Gd?) lesions at screening (n = 175) were randomized 1:1:2 to continue natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd? lesions during natalizumab treatment interruption were evaluated. The numbers of Gd? lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd? lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd? lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had [5 Gd? lesions on C1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd? lesions prenatalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd? lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological Drs. Ticho and Duda are former employees of Biogen Idec Inc. and were at the company during study conduct.

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The effect of anti-α4 integrin antibody on brain lesion activity in MS

Abstract: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Cited by 292 publications

References 13 publications

CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

Radiologic MS disease activity during natalizumab treatment interruption: findings from RESTORE

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The effect of anti-α4 integrin antibody on brain lesion activity in MS

Abstract: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Cited by 292 publications

References 13 publications

CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion

CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion

Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

Radiologic MS disease activity during natalizumab treatment interruption: findings from RESTORE

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Product

Resources

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CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion