Immunosuppressive treatment in multiple sclerosis

Weiner, Howard L.

doi:10.1016/j.jns.2004.04.013

Cited by 29 publications

(15 citation statements)

References 79 publications

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“…Yes (licensed, widely used (Teitelbaum et al, 1971;1973;1974;2004;Keith et al, 1979;Lisak et al, 1983;Aharoni et al, 1993;1997;Johnson et al, 1995;Gran et al, 2000;Gilgun-Sherki et al, 2003;Illes et al, 2004;Stern et al, 2004;Giuliani et al, 2005a,b;Jee et al, 2007;Begum-Haque et al, 2008;Stern et al, 2008;Kala et al, 2010) Altered peptide ligands Chen et al, 1994;Whitacre et al, 1996) Blockade of second signal CTLA4-Ig; non-depleting antiCD3 No (trials unsuccessful or inconclusive) (Croxford et al, 1998a;Tran et al, 2001) DNA therapy cDNA 'vaccination' e.g. MBP, PLP Yes (promising) (Waisman et al, 1996;Lobell et al, 1998;Selmaj et al, 2000) Pathogenic (e.g.…”

Section: Glatiramer Acetatementioning

confidence: 99%

“…A substantial number of other studies have shown treatment success with concordant results in EAE and MS, using a variety of compounds. Some of these agents, like the immunosuppressants azathioprine (Hauser et al, 1983;Massacesi et al, 2005;Casetta et al, 2007;Elkhalifa and Weiner, 2010), mitoxantrone (Hartung et al, 2002;Weiner, 2004;Martinelli Boneschi et al, 2005) are licenced or wellestablished therapies for specific groups of patients with MS. Others, like laquinimod or fingolimod, have reached late phase clinical trials or are awaiting licencing decisions (please see Table 1 for examples). Table 5 lists some approaches with some degrees of evidence of success in MS with proof of concept/mechanisms supported by concordant success in EAE.…”

Section: Adhesion Molecule Blockadementioning

confidence: 99%

“…As discussed above, GA a random copolymer of tyrosine, glutamate, alanine and lysine in ratios resembling myelin basic protein. (Abreu, 1982;Jacobs et al, 1982;Hertz and Deghenghi, 1985;Abreu et al, 1986;Paty and Li, 1993; Brod and Burns, 1994;Ruuls et al, 1996;Yu et al, 1996; Croxford et al, 1998b;van der Meide et al, 1998;Luca et al, 1999;Yasuda et al, 1999;Wender et al, 2001;Schaefer et al, 2006;Jaini et al, 2006;Martin-Saavedra et al, 2007) Other drugs et al, 1971;1973;1974;2004; Keith et al, 1979;Lisak et al, 1983; Aharoni et al, 1993;1997;Johnson et al, 1995;Gran et al, 2000; Gilgun-Sherki et al, 2003;Illes et al, 2004;Stern et al, 2004; Giuliani et al, 2005a,b of the immunogenicity of proteins. GA was developed initially as a putative encephalitogen; however, it showed ...…”

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confidence: 99%

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Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Constantinescu

Farooqi

O’Brien

et al. 2011

British J Pharmacology

1,218

989

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Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter-regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell-mediated organ-specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro-and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune-mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions. LINKED ARTICLESThis article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10. 1111/bph.2011.164.issue-4 Abbreviations ADEM, acute disseminated encephalomyelitis; ADNP, activity dependent neuroprotective protein; AHR, aryl hydrocarbon receptor; APC, antigen-presenting cells; APL, altered peptide ligand; AT, adoptive transfer; C1 and CB2 receptors, cannabinoid receptors 1 and 2; CIS, clinically isolated syndrome; CNS, central nervous system; DA, dark agouti; DMT, disease-modifying treatment; EAE, experimental autoimmune (allergic) encephalomyelitis; EAN, experimental autoimmune (allergic) neuritis; EBV, Epstein-Barr virus; GA, glatiramer acetate; IFN, interferon; IL, interleukin; IL-1RA, interleukin 1 receptor antagonist; JCV, John Cunningham virus; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NABT, normal appearing brain tissue; NAWM, normal appearing white matter; NMO, neuromyelitis optica; NK1 receptor, neurokinin 1 receptor; PGE, prostaglandin E; PLP, proteolipid protein; PP, primary progressive; PR, progressive relapsing; ROR, retinoid orphan receptor; RR, relapsing-remitting; SP, secondary progressive; TCR, T-cell receptor; TGF, transforming growth...

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Section: Glatiramer Acetatementioning

confidence: 99%

Section: Adhesion Molecule Blockadementioning

confidence: 99%

mentioning

confidence: 99%

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Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Constantinescu

Farooqi

O’Brien

et al. 2011

British J Pharmacology

1,218

989

View full text Add to dashboard Cite

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“…Myelin-reactive Th1 cells that secrete IFN-g-and IL-17-producing (Th17) cells are pathogenic, whereas Th2 cells that produce IL-4, IL-5, or IL-10, are nonpathogenic and can protect from disease (2)(3)(4)(5)(6)(7)(8). Therapies for multiple sclerosis downregulate T cell proinflammatory cytokines or deviate the response toward a Th2 phenotype (9). Thus, a greater understanding of the signals that control phenotypic differentiation of T cells into subsets that produce particular cytokines is an important goal in the development of new therapies for multiple sclerosis.…”

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confidence: 99%

IL-10 Mediates Resistance to Adoptive Transfer Experimental Autoimmune Encephalomyelitis in MyD88−/− Mice

Cohen

Nussbaum³

2009

The Journal of Immunology

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MyD88 is an adaptor molecule that functions in the innate signaling induced by proinflammatory adjuvants that interact with TLRs. Mice lacking MyD88, for example, resist active experimental autoimmune encephalomyelitis (EAE) induced by immunization with an encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide in CFA. We reasoned that MyD88−/− mice, nevertheless, should be susceptible to EAE mediated by adoptive transfer of activated encephalitogenic T cell lines, which do not require adjuvant signaling for their effector functions. We now report, however, that mice lacking MyD88 also resist adoptive EAE mediated by an anti-MOG T cell line that is strongly encephalitogenic in wild-type (WT) mice. The transferred anti-MOG T cells proliferated, secreted INF-γ, and migrated to the CNS in the MyD88−/− mice, as they did in WT mice, but inflammatory infiltrates did not progress and clinical EAE did not develop. The resistance of the MyD88−/− mice to adoptive EAE mediated by the otherwise encephalitogenic T cells was found to result from the secretion of IL-10 by recipient T cells of two different specificities: those specific for MOG and those responding to the T cell clone itself—both anticlonotypic and antiergotypic T regulators were detected. IL-10–producing anti-MOG T cells isolated from immunized MyD88−/− mice suppressed the induction of active EAE in WT recipients. Moreover, the absence of IL-10 production in MyD88/IL-10 double-knockout mice rendered the mice susceptible to adoptive transfer of EAE. Thus, MyD88 signaling appears to be a key factor in determining the cytokine phenotype of T cells involved in autoimmune inflammation and regulation.

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“…MS is a demyelinating disease with a chronic inflammation of the central nervous system (Weiner, 2004a). Dendritic cells are professional APC that initiate the immune response by activating naive T cells.…”

Section: -Discussionmentioning

confidence: 99%

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

Vaknin‐Dembinsky¹,

Murugaiyan²,

Hafler³

et al. 2008

Journal of Neuroimmunology

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). In MS, myeloid dendritic cells (mDCs) secrete elevated amounts of IL-23, a potent pro-inflammatory cytokine, compared to healthy donors. Here, we examined the role of CD46, a complement binding factor, in mDCs by analyzing cytokine and chemokine production in healthy donors and patients with MS. There were striking differences between these groups with increased IL-23p19, CCL2 and CCL5 production, but decreased CCL2 levels in patients. This demonstrates major differences of DC activation upon CD46 activation, with a potential role in the pathogenesis of MS. KeywordsMultiple sclerosis; human dendritic cells; chemokines; IL-23; CD46 1-IntroductionMultiple sclerosis is a chronic inflammatory demyelinating disease of the CNS (Hafler et al., 2005;Weiner, 2004b) in which both the release of inflammatory mediators and chemotaxis are important (Adorini, 2004;Elhofy et al., 2002). DCs are professional antigen-presenting cells (APC) which secrete cytokines and chemokines upon maturation and play a key role in the induction of immune responses by activating naïve T cells. We previously demonstrated that mDCs from patients with MS secrete elevated amounts of IL-23 compared to healthy controls (Vaknin-Dembinsky et al., 2006). IL-23 is a proinflammatory cytokine that consists of a specific p19 subunit associated with the shared IL-12p40 subunit (also called IL-12 beta1 subunit which associates with IL-12p35 to form IL-12 (p70)) (Frucht, 2002;Oppmann et al., 2000;Trinchieri et al., 2003). IL-23 promotes the expansion of a specific subset of T cells secreting IL-17, a potent inflammatory cytokine (Bettelli et al., 2007) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Comabella et al., 1998;Soldan et al., 2004). Therefore, production of both IL-12 and IL-23 are dysregulated in patients with MS (Gran et al., 2004). NIH Public AccessThe engagement of CD46 at the surface of APC has been shown to modulate the production of IL-12 (p70) and/or p40 subunit, either increasing or decreasing their expression depending on the cell type and stimulus used (Karp et al., 1996;Kurita-Taniguchi et al., 2000;Schnorr et al., 1997;Smith et al., 2003). CD46 is a widely expressed transmembrane protein initially identified as a complement regulatory protein (Seya et al., 1986). It has then been described as a 'magnet for pathogens ' (Cattaneo, 2004), acting as a receptor for several virus and bacteria. More recently, it was identified as a co-stimulatory molecule for T cell activation (Astier et al., 2000;Ma...

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Immunosuppressive treatment in multiple sclerosis

Cited by 29 publications

References 79 publications

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

IL-10 Mediates Resistance to Adoptive Transfer Experimental Autoimmune Encephalomyelitis in MyD88−/− Mice

Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis

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