Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

Theien, Bradley E.; Vanderlugt, Carol L.; Eagar, Todd N.; Nickerson‐Nutter, Cheryl; Nazareno, Remederios; Kuchroo, Vijay K.; Miller, Stephen D.

doi:10.1172/jci11717

Cited by 109 publications

(110 citation statements)

References 40 publications

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“…The widely held view that CNS immune surveillance is principally mediated by interactions between ␣ 4 ␤ 1 -integrin bearing lymphocytes and VCAM-expressing endothelium is supported by several observations in preclinical models of experimental autoimmune encephalomyelitis; [22][23][24][25] and the clinical efficacy demonstrated by natalizumab in MS patients. 26 However, the introduction of immunosuppressive agents for inflammation that directly or indirectly impair leukocyte trafficking (such as a natalizumab, efalizumab, and rituximab), have also been associated with rare instances of fatal progressive multifocal leukoencephalopathy, 4 -6,26 suggesting that substantial impairment of normal CNS immune trafficking is undesirable, given the high proportion of individuals with latent JC virus infection.…”

Section: Discussionmentioning

confidence: 97%

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

Allavena

Andrews

et al. 2010

The American Journal of Pathology

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The mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) appear to play roles in the recruitment of leukocytes to specialized endothelium lining the gastrointestinal tract. The purpose of this study was to clarify the role of MAdCAM and VCAM in the central nervous system by comparing protein expression in patients with multiple sclerosis (MS) and control subjects by immunohistochemistry. Specific antibodies to human VCAM and MAdCAM were used to confirm expression in control and MS nervous system specimens by immunohistochemistry. VCAM immunoreactivity was detected in endothelial cells, perivascular tissue, and in some cases, leukocytes within the meninges, gray, and white matter, of both controls and MS patients. VCAM immunoreactivity was maximal in a patient with acute active plaques, but of lower intensity and reduced distribution in controls and those with chronic active or inactive MS plaques. In contrast, MAdCAM immunoreactivity could not be detected in brain tissue from unaffected or MS patients. Taken together, these data support a role of VCAM, but not MAdCAM in the development of MS. (Am J Pathol 2010,

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Section: Discussionmentioning

confidence: 97%

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

Allavena

Andrews

et al. 2010

The American Journal of Pathology

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“…Similarly, VCAM-1 and VLA-4, its ligand expressed on T cells, have been linked to the ability of neuroantigen-reactive T cells to migrate to the CNS and cause EAE (31). However, in contrast to these results, application of anti-VLA-4 Abs prevented or ameliorated EAE only if it was initiated before the onset of disease (37). Moreover, treatment with anti-VLA-4 Abs during acute disease exacerbated EAE and enhanced the accumulation of T cells in the CNS, which produced higher levels of IFN-␥ and IL-2.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System

Denkinger

Kort

et al. 2003

The Journal of Immunology

102

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Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T cell activation. However, its role in the pathogenesis of T cell-mediated autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), has remained unresolved. In this study, we report that anti-MIF Ab treatment of SJL mice with acute EAE improved the disease severity and accelerated the recovery. Furthermore, the anti-MIF treatment impaired the homing of neuroantigen-reactive pathogenic T cells to the CNS in a VCAM-1-dependent fashion. Interestingly, MIF blockade also decreased the clonal size of the neuroantigen-specific Th1 cells and increased their activation threshold. Taken together, the results demonstrate an important role for MIF in the pathogenesis of EAE/multiple sclerosis and suggest that MIF blockade may be a promising new strategy for the treatment of multiple sclerosis.

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“…Since OX-40 is an important costimulatory molecule with prosurvival activity for CD4 + T cells, and signaling through this molecule breaks peripheral T cell tolerance (11,21), our data suggest that leptin may affect expression of key molecules on T lymphocytes involved in the mechanisms of immune tolerance. Surprisingly, we also observed that leptin neutralization induced increased expression of VLA-4, the α4β1 integrin shown to play an integral part in the homing and migration of cells that induce EAE (13). However, experimental evidence has shown that administration of anti-VLA-4 ameliorated EAE only if it was initiated before disease onset, whereas treatment during acute disease exacerbated EAE and enhanced the accumulation of T cells in the CNS (13).…”

Section: Discussionmentioning

confidence: 64%

Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis

Rosa

Procaccini

Cava

et al. 2006

Journal of Clinical Investigation

122

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Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP 139-151 -induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP 139-151 -specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 + T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27 Kip-1 ) in autoreactive CD4 + T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.

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Discordant effects of anti–VLA-4 treatment before and after onset of relapsing experimental autoimmune encephalomyelitis

Cited by 109 publications

References 40 publications

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

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

In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System

Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis

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