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Epidermal growth factor (EGF) represents the prototype of the group I EGF family. The pleiotropic effects of the EGF have attracted attention to the possibility that it could be implicated in autoimmune diseases, such as Multiple Sclerosis (MS). We show here that treatment with EGF, as a late prophylactic regime, improved the clinical and histological features of EAE, a preclinical model of MS. In silico analysis further corroborated these findings by demonstrating that EGF receptors are less expressed in CNS from patients with MS as compared to controls. Taken together these data provide clear-cut in vivo proof of concept for a beneficial role of exogenously administered EGF in MS, that may, therefore, represent a novel therapeutic approach., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions involved in the pathogenesis of autoimmune disorders, including Multiple Sclerosis (MS). We have first evaluated in silico the involvement of MIF, its homologue D-DT, and the receptors CD74, CD44, CXCR2 and CXCR4 in encephalitogenic T cells from a mouse model of MS, the Experimental Allergic Encephalomyelitis (EAE), as well as in circulating T helper cells from MS patients. We show an upregulation of the receptors involved in MIF signaling both in the animal model and in patients. Also, a significant increase in MIF receptors is found in the CNS lesions associated to MS. Finally, the specific inhibitor of MIF, ISO-1, improved both ex vivo and in vivo the features of EAE. Overall, our data indicate that there is a significant involvement of the MIF pathway in MS ethiopathogenesis and that interventions specifically blocking MIF receptors may represent useful therapeutic approaches in the clinical setting., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Guillain-Barré syndrome (GBS) is an immune-mediated acute disorder of the peripheral nervous system. Despite treatment, there is an associated mortality and severe disability in 9 to 17% of the cases. Decitabine (DAC) is a hypomethylating drug used in myelodisplastic syndrome, that has been shown to exert immunomodulatory effects. We have evaluated the effects of DAC in two rodent models of GBS, the Experimental Allergic Neuritis (EAN). Both prophylactic and therapeutic treatment with DAC ameliorated the clinical course of EAN, increasing the numbers of thymic regulatory T cells and reducing the production of proinflammmatory cytokines. Our data suggest the possible use of decitabine for the treatment of GBS., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an immunoinflammatory disease of the central nervous system that seems to be influenced by DNA methylation. We sought to explore the expression pattern of genes involved in the control of DNA methylation in Secondary Progressive (SP) MS patients' PBMCs. We have found that SP MS is characterized by a significant upregulation of two genes belonging to the MBD family genes, MBD2 and MBD4, and by a downregulation of TDG and TET3., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Transferrin (Tf) has a major role in T cell activation and proliferation. Here, we investigated whether Tf exerts immunomodulatory effects on T cells and in development of T-cell driven experimental autoimmune encephalomyelitis (EAE). While treatment of concanavalin A-stimulated splenocytes with apotransferrin (ApoTf) did not affect release of IL-1β, TNF, IFN-γ, IL-17, IL-4, and IL-10, it markedly and dose-dependently down-regulated synthesis of IL-2 in these cells. ApoTf also inhibited IL-2 generation in purified CD3+ T cells and the effect was accompanied with down-regulation of MAPK p44/42 and NFκB signaling. Despite impeded IL-2 release, proliferation of splenocytes was not inhibited by ApoTf. Importantly, ApoTf ameliorated EAE in mice and significantly reduced ex vivo IL-2 production in proteolipid protein-specific lymphocytes. Thus ApoTf may be a promising beneficial agent for multiple sclerosis., (© 2013.)

Multiple sclerosis (MS) is an immunoinflammatory disease that affects the central nervous system. Heme oxygenase-1 (HO-1) is one of the three isoforms of the heme oxygenase enzyme that catabolyzes the degradation of heme into biliverdin with the production of free iron and CO. We show in this study that HO-1 expression is reduced in PBMCs of MS patients and that during exacerbation of the disease there is a significant downregulation of this enzyme. We conclude that HO-1 may play a significant role in the maintenance of immune homeostasis which is disrupted in autoimmune disorders, such as MS., (Copyright © 2013 Elsevier B.V. All rights reserved.)

NO-hybridization of the HIV protease inhibitor Saquinavir generates a new chemical entity named Saq-NO, that retains the anti-viral activity and exerts lower toxicity. We show that Saq-NO inhibited the generation of various cytokines in ConA-stimulated unfractionated murine spleen cells and rat lymph nodes stimulated with ConA as well as in purified CD4(+) T cells in vitro and reduced the circulating levels of cytokines in mice challenged with anti-CD3 antibody. Furthermore, Saq-NO reduced IL-17 and IFN-γ production in myelin basic protein (MBP)-specific cells isolated from rats immunized with MBP. These findings translated well into the in vivo setting as Saq-NO ameliorated the course of the disease in two preclinical models of multiple sclerosis. Our results demonstrate that Saq-NO exerts immunomodulatory effects that warrant studies on its application in autoimmune diseases., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The aim of our investigation was to analyze the pattern of interleukin-1 (IL-1) family compounds: IL-1 beta, IL-1 receptor accessory protein (Acp), IL-1 receptor antagonist (IL-1Ra) and IL-1 receptor type II (IL-1RII) in the serum and cerebrospinal fluid (CSF) from 67 multiple sclerosis (MS) patients and 31 controls. We found significantly elevated CSF levels of IL-1 beta, IL-1Ra and Acp in MS patients compared to controls (p=0.001), while IL-1 beta and Acp were significantly elevated in MS sera (p=0.001). IL-1Ra and/or IL-1 RII increased in sera of all 10 investigated patients after the steroid treatment for relapse. Our findings suggest the important beneficial role of the induction of IL-1 RII and IL-1Ra in MS.

The immunosuppressive agent cyclophosphamide (CY) was tested in rat experimental allergic neuritis (EAN), a preclinical model of Guillain Barrè syndrome (GBS). CY prophylaxis (day 0 and 14 post-immunization [p.i.]) effectively prevents clinical and histological signs of EAN and also reduces the cytokine and the NF-kappaB p65 expression in the nervous tissue. When administered therapeutically (day 14th p.i.) to rats with established disease CY only affects the clinical symptoms. Both the prophylactic and therapeutic treatment with CY reduced ex vivo antigen-specific T cell proliferative responses. These results warrant studies with CY in those cases of GBS resistant to conventional therapies.

Macrophage migration inhibitory factor (MIF) is a proinflammatory type 1 cytokine that plays a pathogenic role in several inflammatory and autoimmune diseases. The role of this cytokine in peripheral nerve inflammatory disease has not been evaluated. Therefore, to evaluate the role of macrophage migration inhibitory factor (MIF) in Guillain-Barré syndrome (GBS) and experimental allergic neuritis (EAN), we determined MIF circulating levels in a series of patients with GBS and healthy subjects with ELISA and evaluated the effect of two specific inhibitors of MIF, a neutralizing monoclonal antibody or a chemical inhibitor ISO1 on the course of murine EAN. The data show increased MIF plasma levels in GBS patients as compared to healthy controls (p<0.0001) and a progressive increase of MIF circulating concentration with patient's disability (p<0.0001). Both anti-MIF mAb and ISO1 favorably influenced the course of EAN. Treated mice had a lower cumulative severity score (p=0.001) and reduced disease duration than the control mice (p<0.03). MIF may promote immune reaction in GBS. Therapeutic effects of both anti-MIF mAb and ISO1 in EAN suggest that MIF could be a promising therapeutic target in inflammatory demyelinating peripheral nerve disorders.