Elsevier

Clinical Immunology

Volume 117, Issue 1, October 2005, Pages 15-23
Clinical Immunology

Anti-TWEAK monoclonal antibodies reduce immune cell infiltration in the central nervous system and severity of experimental autoimmune encephalomyelitis

https://doi.org/10.1016/j.clim.2005.06.005Get rights and content

Abstract

TWEAK is a member of the TNF family, constitutively expressed in the central nervous system (CNS), with pro-inflammatory, proliferative or apoptotic effects depending upon cell types. Its receptor, Fn14, is expressed in CNS by endothelial cells, reactive astrocytes and neurons. We showed that TWEAK and Fn14 mRNA expression increased in spinal cord during experimental autoimmune encephalomyelitis (EAE). We investigated the role of TWEAK during EAE using neutralizing anti-TWEAK antibody in myelin oligodendrocyte glycoprotein (MOG) induced EAE in C57BL/6 mice. We observed a reduction of disease severity and leukocyte infiltration when mice were treated after the priming phase.

Introduction

Experimental autoimmune encephalomyelitis (EAE) is a Th1-mediated autoimmune disease of the central nervous system (CNS), which is a widely recognized model for multiple sclerosis (MS). In C57BL/6 mice, inoculation of the major immunodominant epitope of myelin oligodendrocyte glycoprotein (MOG 35–55) in complete Freund's adjuvant (CFA) results in a disease course characterized by an acute paralytic phase followed by a moderate remission and a chronic phase associated with demyelination [2]. Treatment of EAE has been investigated by several immunoregulatory approaches including blockade of costimulatory molecules involved in T cell activation or inhibition of members of the TNF receptor family and their ligands (Fas/FasL, TNF/TNFR, CD40/CD40L, TRAIL). These molecules are implicated in the pathogenesis of EAE. TNF-α, the most comprehensively studied molecule, regulates leukocyte movement during inflammation in CNS, mainly by influencing chemokine secretion [38], [43]. CD40–CD40L and Fas–FasL also play a crucial role in promoting inflammation and/or myelin destruction in the CNS during EAE [1], [5], [22], [35], [47]. TRAIL inhibits EAE and prevents activation of encephalitogenic T cells [19].

TWEAK is a new member of the TNF family. TWEAK mRNAs are ubiquitously expressed [8] and the expression is increased after injury including in CNS during EAE [12] and acute cerebral ischemia [37]. In vitro, TWEAK is known to induce apoptosis in some tumor cell lines [49]. It induces the expression of inflammatory mediators such as ICAM-1 and IL6 [15], [26], [41] on numerous cell types [7], [8], [9], [18], [24], [40], [50]. In neural cells, TWEAK induces astrocyte proliferation and neuronal cell death [12], [37]. Moreover, endothelial cells proliferate in response to TWEAK [27]. In vivo, TWEAK is characterized first as an angiogenic factor [13], [48]. Later, it was found that EAE severity is enhanced in transgenic mice overexpressing soluble TWEAK [12] and that neutralizing TWEAK reduces neurodegeneration [37], implicating possible roles of TWEAK in pathogenesis of CNS diseases.

TWEAK receptor is Fn14 [48]. This member of the TNF receptor superfamily mediates TWEAK-induced cell death, cytokines release and cell proliferation [4], [32], [48]. Fn14 mRNA expression is detected in many tissues in mouse including heart, ovary, lung and brain but not in spleen and liver [29]. Its expression is induced in nervous tissue during neurodegeneration [45] and cerebral ischemia [37], [46]. Moreover, Fn14 is shown to mediate also neurite outgrowth but independently of TWEAK [45].

In the present work, we report that, such as TWEAK, Fn14 expression increased in spinal cord during EAE. We further investigated the role of TWEAK during EAE using neutralizing anti-TWEAK antibodies in MOG-induced EAE in C57BL/6 mice. We observed a reduction of disease severity and of leukocyte CNS infiltration when mice were treated after the priming phase of disease induction.

Section snippets

Antibodies and reagents

Monoclonal antibody AB.G11 was generated in Armenian hamsters using immunization with soluble human TWEAK protein and standard hybridoma generation procedures as previously described [23]. The ability of AB.G11 to bind to human and murine TWEAK was demonstrated in an ELISA assay using recombinant soluble TWEAK. AB.G11 was shown to block TWEAK activity on the basis of its ability to inhibit soluble FLAG-tagged human TWEAK binding to HT29 cells in a FACS analysis. The hamster control

FN14 mRNAs are upregulated in spinal cord during acute phase of EAE

Previously, we showed using Northern blot that TWEAK mRNA increased in the spinal cord during the acute phase of EAE. We now analyzed the expression of TWEAK and Fn14 using real-time PCR in spinal cord and brain of three control and EAE mice, 48 h after disease onset (respective scores: 4, 2.5 and 3). As previously reported, statistically significant increase in TWEAK mRNA was observed (not shown). We also found that Fn14 mRNA expression was upregulated during EAE only in the spinal cord (Fig. 1

Discussion

Previously, we showed that EAE is exacerbated in transgenic mice overexpressing soluble TWEAK [12]. Mueller and colleagues reported also that overexpression of TWEAK induced by TWEAK DNA vaccination exacerbated the clinical course of EAE [30]. In this report, we have shown that blocking TWEAK activity by neutralizing anti-TWEAK antibodies results in a significant reduction of clinical severity and CNS inflammation during EAE. In our experiments, the treatment was effective when antibodies were

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