Mannan-MOG35-55 Reverses Experimental Autoimmune Encephalomyelitis, Inducing a Peripheral Type 2 Myeloid Response, Reducing CNS Inflammation, and Preserving Axons in Spinal Cord Lesions.

CNS autoantigens conjugated to oxidized mannan (OM) induce antigen-specific T cell tolerance and protect mice against autoimmune encephalomyelitis (EAE). To investigate whether OM-peptides treat EAE initiated by human MHC class II molecules, we administered OM-conjugated murine myelin oligodendrocyte glycoprotein peptide 35-55 (OM-MOG) to humanized HLA-DR2b transgenic mice (DR2b.Ab°), which are susceptible to MOG-EAE.

A Cyclic Altered Peptide Analogue Based on Myelin Basic Protein 87-99 Provides Lasting Prophylactic and Therapeutic Protection Against Acute Experimental Autoimmune Encephalomyelitis.

In this report, amide-linked cyclic peptide analogues of the 87-99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP-induced EAE in Lewis rats. The Lys and Pro of MBP are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS.

Bioinformatically Informed Design of Synthetic Mammalian Promoters.

Synthetic promoters have been developed in a number of different organisms and are capable of mediating specific and enhanced levels of gene expression. Typically, cis-regulatory regions from a few genes are randomly combined to generate a synthetic promoter library, and the sequences with the highest activity are selected for in target cell lines. Here we describe a novel approach that can be employed in the construction of synthetic promoters .

Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis.

Antigen presenting cells (APC) are critical for regulating immune responses. We tested mannan-peptide conjugates for targeting myelin peptides to APC to induce T cell tolerance and resistance to experimental autoimmune encephalomyelitis (EAE). Myelin peptides conjugated to mannan in oxidized (OM) or reduced (RM) forms protected mice against EAE in prophylactic and therapeutic protocols, with OM-conjugated peptides giving best results.

Rational design and synthesis of altered peptide ligands based on human myelin oligodendrocyte glycoprotein 35-55 epitope: inhibition of chronic experimental autoimmune encephalomyelitis in mice.

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG), plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents.

Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-kappaB.

Tumour necrosis factor mediates chronic inflammatory pathologies including those affecting the central nervous system, but non-selective tumour necrosis factor inhibitors exacerbate multiple sclerosis. In addition, TNF receptor SF1A, which encodes one of the tumour necrosis factor receptors, has recently been identified as a multiple sclerosis susceptibility locus in genome-wide association studies in large patient cohorts. These clinical data have emphasized the need for a better understanding of the beneficial effects of tumour necrosis factor during central nervous system inflammation.

Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer's disease and stroke for identifying commonly regulated and disease-specific gene changes.

The brain responds to injury and infection by activating innate defense and tissue repair mechanisms. Working upon the hypothesis that the brain defense response involves common genes and pathways across diverse pathologies, we analysed global gene expression in brain from mouse models representing three major central nervous system disorders, cerebral stroke, multiple sclerosis and Alzheimer's disease compared to normal brain using DNA microarray expression profiling. A comparison of dysregulated genes across disease models revealed common genes and pathways including key components of estrogen and TGF-beta signaling pathways that have been associated with neuroprotection as well as a neurodegeneration mediator, TRPM7.

TNFRI is a positive T-cell costimulatory molecule important for the timing of cytokine responses.

Tumor necrosis factor (TNF)- and TNF receptor I (TNFRI)-deficient mice are resistant to initiation and show delayed resolution of disease in paradigms of autoimmune disease, but the contribution of TNF/TNFRI signaling to T-cell activation and effector responses has not been determined. In this study, we investigated the role of TNFRI in T-cell receptor (TCR)-mediated T-cell activation in vitro and in vivo using CD3(+)-enriched primary T cells and mice deficient in TNFRI. Following TCR engagement, TNFRI knockout (KO) T cells showed significantly delayed proliferation, cell division, upregulation of interleukin 2 (IL-2) and IL-2 receptor alpha chain (CD25) mRNA and cell-surface expression of CD25 compared with wild-type (WT) cells.

Neuronal I kappa B kinase beta protects mice from autoimmune encephalomyelitis by mediating neuroprotective and immunosuppressive effects in the central nervous system.

Some aspects of CNS-directed autoimmunity in multiple sclerosis are modeled in mice by immunization with myelin Ags where tissue damage is driven by myelin-reactive Th1 and Th17 effector lymphocytes. Whether the CNS plays an active role in controlling such autoimmune diseases is unknown. We used mice in which IkappaB kinase beta was deleted from Ca(2+)/calmodulin-dependent kinase IIalpha-expressing neurons (nIKKbetaKO) to investigate the contribution of neuronal NF-kappaB to the development of myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis.

TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury.

CNS neurons use robust cytoprotective mechanisms to ensure survival and functioning under conditions of injury. These involve pathways induced by endogenous neuroprotective cytokines such as erythropoietin (EPO). Recently, in contrast to its well known deleterious roles, TNF has also been shown to exhibit neuroprotective properties.

Cellular FLIP long isoform transgenic mice overcome inherent Th2-biased immune responses to efficiently resolve Leishmania major infection.

c-FLIP(L) expression in T cells is required for mounting effective T cell responses and can also be critical for effector T cell differentiation, as has recently been shown by a number of in vivo studies in conditional knockout and transgenic mouse systems. Available data supports therefore a novel immunomodulatory role of this anti-apoptotic protein besides its traditionally proposed function in homeostatic maintenance of T cell populations. In this study, the responses to infection with Leishmania major of mice over-expressing FLIP(L) specifically in the T cell compartment (TgFLIP(L)) are assessed.

Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: a role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation.

Modification of arginine residues by citrullination is catalyzed by peptidylarginine deiminases (PADs), of which five are known, generating irreversible protein structural modifications. We have shown previously that enhanced citrullination of myelin basic protein contributed to destabilization of the myelin membrane in the CNS of multiple sclerosis (MS) patients. We now report increased citrullination of nucleosomal histones by PAD4 in normal-appearing white matter (NAWM) of MS patients and in animal models of demyelination.

Cellular FLIP (long isoform) overexpression in T cells drives Th2 effector responses and promotes immunoregulation in experimental autoimmune encephalomyelitis.

Cellular FLIP (c-FLIP) is an endogenous inhibitor of death receptor-induced apoptosis through the caspase 8 pathway. It is an NF-kappaB-inducible protein thought to promote the survival of T cells upon activation, and its down-regulation has been implicated in activation-induced cell death. We have generated transgenic mice overexpressing human c-FLIP long form (c-FLIP(L)) specifically in T cells using the CD2 promoter (TgFLIP(L)).

Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis.

In multiple sclerosis, in which brain tissue becomes permeable to blood proteins, extravascular fibrin deposition correlates with sites of inflammatory demyelination and axonal damage. To examine the role of fibrin in neuroinflammatory demyelination, we depleted fibrin in two tumor necrosis factor transgenic mouse models of multiple sclerosis, transgenic lines TgK21 and Tg6074. In a genetic analysis, we crossed TgK21 mice into a fibrin-deficient background.