A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Miller, David H.; Khan, Omar; Sheremata, William A.; Blumhardt, L D; Rice, George P.; Libonati, Michele; Willmer-Hulme, A. J.; Dalton, Catherine M.; Miszkiel, Katherine; O’Connor, Paul

doi:10.1056/nejmoa020696

Cited by 1,151 publications

(726 citation statements)

References 24 publications

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“…This finding may be useful for the treatment of autoimmune hepatitis, a feared complication occurring in 10-20% of APS I patients, using the VLA-4 therapy blocking VCAM-1 interaction [54,55]. Taken together, our results demonstrate that Aire plays a role in peripheral DC in maintaining self tolerance by regulating the antigenic response of T cells.…”

Section: Discussionsupporting

confidence: 52%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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Patients with autoimmune polyendocrine syndrome type I (APS I)suffer from endocrine and non-endocrine disorders due to mutations in the autoimmune regulator gene (AIRE). Mouse Aire is expressed both in thymic medullary epithelial cells and in peripheral antigen-presenting cells, suggesting a role in both central and peripheral tolerance. We here report that Aire -/-dendritic cells (DC) activate naive T cells more efficiently than do Aire +/+ DC. Expression array analyses of Aire -/-DC revealed differential regulation of 68 transcripts, among which, the vascular cell adhesion molecule-1 (VCAM-1) transcript was up-regulated in Aire -/-DC. Concurrently, the expression of the VCAM-1 protein was up-regulated on both Aire -/-DC and monocytes from APS I patients. Blocking the interaction of VCAM-1 prevented enhanced Aire -/-DC stimulation of T cell hybridomas. We determined an increased number of DC in spleen and lymph nodes and of monocytes in the blood from Aire -/-mice, and an increased number of blood monocytes in APS I patients. Our findings imply a role for Aire in peripheral DC regulation of T cell activation, and suggest that Aire participates in peripheral tolerance.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35240_s.pdf IntroductionInactivation of the autoimmune regulator gene (AIRE) [1][2][3] causes autoimmunity in patients with autoimmune polyendocrine syndrome type I (APS I, APECED, OMIM 240300) and in a gene targeted mouse model [4,5]. APS I is a rare monogenic autosomal recessive disease without HLA association [6,7], which is prevalent in isolated populations [8][9][10]. APS I patients develop a progressive loss of tolerance against self antigens and suffer from multiorgan failures due to the immunological destruction of adrenals, parathyroid glands and b cells of the islets of Langerhans [11]. Many of the APS I organ-specific autoantigens have been identified and characterized [12,13]. In addition, as a sign of immune dysfunction, these patients have difficulties clearing Candida albicans infections in mucosal membranes [14]. Functional studies of AIRE suggest a role as a transcription factor and in vitro transactivating studies support this notion [15][16][17][18]. Moreover, the PHD1 domain of AIRE has been suggested to have an E3 ubiquitin ligase activity in cell-free assays [19], findings in variance with a recent report [20]. Aire is highly expressed in a subset of the medullary thymic epithelial cells (mTEC) as well as in DC in the spleen and lymph nodes [21][22][23][24], indicating a potential role in immunological tolerance.To characterize the function of Aire, we previously engineered an Aire-deficient mouse targeting the most common APS I mutation [4]. Aire-deficient mice develop multiple organ-specific autoantibodies and lymphocytic infiltrates, thus mimicking some of the features of human APS I [4]. Subsequently, the role of Aire in negative selection was demonstrated [5]. These findings were further supported using TCR transgenic mic...

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Section: Discussionsupporting

confidence: 52%

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

et al. 2006

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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%

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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“…The occurrence of PML during natalizumab treatment in patients with MS is a highly relevant and problematic issue for several reasons: (1) Natalizumab is a highly effective therapy that can greatly diminish the frequency of clinical relapses, and the accumulation of lesions in the brain on neuroimaging38, 39, 40; (2) the substantial risk of PML very likely reduces the number of patients and clinical providers who prescribe this highly effective agent; (3) there is currently no biological or biochemical marker that allows the identification of PML at‐risk individuals with sufficient precision; (4) risk‐stratification algorithms have not reduced the incidence of PML under natalizumab 41, 42, 43…”

Section: Discussionmentioning

confidence: 99%

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Hussain

Cravens

Doelger

et al. 2018

Ann Clin Transl Neurol

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ObjectiveNatalizumab blocks α4‐integrin‐mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors. We hypothesized that TLR3 agonism reestablishes CNS immune competence in the setting of α4‐integrin deficiency.MethodWe generated the conditional knock out mouse strain Mx1.Cre+ α4‐integrinfl/fl, in which the α4‐integrin gene is ablated upon treatment with the TLR3 agonist poly I:C. Adoptive transfer of purified lymphocytes from poly I:C‐treated Mx1.Cre+ α4‐integrinfl/fl donors into naive recipients recapitulates immunosuppression under natalizumab. Active experimental autoimmune encephalomyelitis (EAE) in Mx1.Cre+ α4‐integrinfl/fl mice treated with poly I:C represents immune‐reconstitution.ResultsAdoptive transfer of T cells from poly I:C treated Mx1.Cre+ α4‐integrinfl/fl mice causes minimal EAE. The in vitro migratory capability of CD45+ splenocytes from these mice is reduced. In contrast, actively‐induced EAE after poly I:C treatment results in full disease susceptibility of Mx1.Cre+ α4‐integrinfl/fl mice, and the number and composition of CNS leukocytes is similar to controls. Extravasation of Evans Blue indicates a compromised blood‐brain barrier. Poly I:C treatment results in a 2‐fold increase in IFN β transcription in the spinal cord.InterpretationOur data suggest that TLR3 agonism in the setting of relative α4‐integrin deficiency can reestablish CNS immune surveillance in an experimental model. This pathway may present a feasible treatment strategy to treat and prevent PML under natalizumab therapy and should be considered for further experimental evaluation in a controlled setting.

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A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Abstract: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Cited by 1,151 publications

References 24 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

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

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

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A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Abstract: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Cited by 1,151 publications

References 24 publications

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

Increased antigen presenting cell‐mediated T cell activation in mice and patients without the autoimmune regulator

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

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

Contact Info

Product

Resources

About

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