CD134 plays a crucial role in the pathogenesis of EAE and is upregulated in the CNS of patients with multiple sclerosis

Carboni, Susanna; Aboul‐Enein, Fahmy; Waltzinger, Caroline; Killeen, Nigel; Lassmann, Hans; Peña-Rossi, C

doi:10.1016/j.jneuroim.2003.07.001

Cited by 56 publications

(47 citation statements)

References 49 publications

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“…This widely used model mimics early and inflammatory stages of SSc. Blocking OX40L exerted antifibrotic effects in this model by decreasing the infiltration of T cells into lesional skin, as is consistent with previous reports in other preclinical models of autoimmune disorders (3,(19)(20)(21)(22). Our data support the notion that OX40L regulates the cytokine balance toward a proinflammatory and profibrotic profile, because lower levels of TNF-α and IL-6 were detected in ox40l −/− mice.…”

Section: Discussionsupporting

confidence: 92%

OX40L blockade protects against inflammation-driven fibrosis

Elhaï

Avouac

Hoffmann-Vold

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

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Section: Discussionsupporting

confidence: 92%

OX40L blockade protects against inflammation-driven fibrosis

Elhaï

Avouac

Hoffmann-Vold

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…il6 Ϫ/Ϫ mice develop milder EAE, even though IL-21 can substitute IL-6 in Th17 induction. 35 Tnfrsf4 Ϫ/Ϫ mice also show attenuated EAE, 36 and administration of an OX40/OX40L-blocking antibody has been shown to ameliorate EAE symptoms. 37 However, they have never been studied together or in the context of MC-Treg interactions.…”

Section: Discussionmentioning

confidence: 99%

Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Piconese

Gri

Tripodo

et al. 2009

Blood

193

177

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IntroductionTraditionally associated with the allergic response, mast cells (MCs) are now viewed as important players in a variety of immune processes, such as pathogen clearance, graft acceptance, tumor immunity, and many inflammatory and autoimmune diseases, where they exhibit either pro-or anti-inflammatory potential depending on the context. 1 Interactions of MCs with T cells have a functional role in some T cell-mediated pathologies, such as neutrophilic airway inflammation, 2,3 and autoimmune disease of the central nervous system (CNS). 4 MC-deficient mouse models show reduced development of both allergic and neutrophilic airway hyperreactivity (AHR). 2,3 MCderived tumor necrosis factor-␣ (TNF-␣) is required for T helper cell (Th17) development in the lung on ovalbumin (OVA) challenge of OTII transgenic mice, 3 a neutrophilic AHR model strictly dependent on interleukin-17 (IL-17). 5 In multiple sclerosis, MCs colocalize with demyelinating plaques in inflamed brain, and many MC-associated markers have been detected in the affected tissue. 6 The MC-deficient strain Kit W/W-v shows decreased incidence and severity of experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis. 7 MCs could be directly activated during EAE by either the specific myelin peptides or locally released agonists, including complement, cytokines, and neuropeptides, but also indirectly stimulated via Fc⑀RI by specific IgE elicited on activation of Th2 response. 1,8 In the CNS, the local release of inflammatory cytokines, proteases, oxygen radicals, and chemokines by MCs directly contributes to myelin degradation, disruption of the blood-brain barrier, and recruitment and activation of other immune cells as T lymphocytes and granulocytes in the brain parenchyma, thus exacerbating the effector phase of autoimmune response. 4 MCs are also thought to be involved in initiating EAE, through the interaction with dendritic cells and T cells in secondary lymphoid organs. 9 IL-17-secreting Th17 are considered one of the major pathogenic immune components in both EAE 10 and neutrophilic AHR. 3 Th17 cells differentiate from uncommitted precursors on antigenic activation and costimulation in the concomitant presence of a suppressive and a pro-inflammatory signal delivered by transforming growth factor-␤ (TGF-␤) and IL-6 and/or IL-21, respectively. Once primed in lymph nodes, pathogenic Th17 cells reach the inflamed tissue where they recruit granulocytes and intensify inflammation. 11 Regulatory T cells (Tregs) are one of the most relevant sources of TGF-␤ both in vitro and in vivo. This CD4 ϩ T lymphocyte subset, characterized by the constitutive expression of several costimulatory molecules and the transcription factor Foxp3, is endowed with immune-suppressive properties necessary to induce and maintain tolerance. 12 Recent findings support the notion of Treg plasticity in vivo because inflammatory stimuli can counteract Treg suppression and even promote differentiation into pathogenic Th17 cells. 13 MCs may directly or...

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“…It has been shown that the costimulatory molecules CD28 and ICOS participate in the induction of Th17 differentiation. 44,45 Although OX40 has been implicated in Th17-mediated diseases such as EAE and multiple sclerosis, 29,30,46,47 little is known about OX40 during the differentiation of Th17 cells. In the current study, we have shown that the activation of Th17 cells is influenced by the expression and subsequent ligation of OX40.…”

Section: Discussionmentioning

confidence: 99%

Activation of OX40 Augments Th17 Cytokine Expression and Antigen-Specific Uveitis

Zhang

Zhong

Hinrichs

et al. 2010

The American Journal of Pathology

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Uveitis is a major and common cause of visual disability.Recent studies have shown that Th17 cells are implicated in the pathogenesis of this serious intraocular disorder. Activated T cells express an inducible costimulatory molecule called OX40, and OX40 in turn promotes the activation and proliferation of these lymphocytes. Nevertheless, it is unclear whether OX40 plays a vital role in enhancing the effector function of Th17 cells as well as the severity of uveitis. In this study, we demonstrated an increase of OX40 transcription in ovalbumin-induced uveitis, whereas anti-OX40L antibody substantially inhibited the antigen-specific ocular inflammation. Next , results from flow cytometry showed that activated Th17 cells expressed OX40, and OX40-activating antibody significantly augmented the production of Th17 cytokines in vitro. To validate the impact of OX40 in vivo, we stimulated ovalbumin-specific T cells with the OX40-activating antibody. Compared to donor cells without OX40 activation, adoptive transfer of OX40-stimulated lymphocytes elicited more severe ocular inflammation. Furthermore, an interleukin-17-neutralizing antibody attenuated OX40-mediated uveitis. In conclusion, our findings suggest that activation of OX40 augments Th17 cell function and thereby contributes to ocular inflammation. This study thus enhances our knowledge of costimulatory molecule-mediated immunopathological mechanisms of uveitis and suggests a future therapeutic strategy to treat uveitis by the targeting of OX40. (Am J

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CD134 plays a crucial role in the pathogenesis of EAE and is upregulated in the CNS of patients with multiple sclerosis

Cited by 56 publications

References 49 publications

OX40L blockade protects against inflammation-driven fibrosis

OX40L blockade protects against inflammation-driven fibrosis

Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation

Activation of OX40 Augments Th17 Cytokine Expression and Antigen-Specific Uveitis

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