Article

Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells

Department of Neuroimmunology, Max Planck Institute of Neurobiology, D-82152 Martinsried, Germany.
Journal of Experimental Medicine (Impact Factor: 13.91). 07/2009; 206(6):1303-16. DOI: 10.1084/jem.20090299
Source: PubMed

ABSTRACT We describe new T cell receptor (TCR) transgenic mice (relapsing-remitting [RR] mice) carrying a TCR specific for myelin oligodendrocyte glycoprotein (MOG) peptide 92-106 in the context of I-A(s). Backcrossed to the SJL/J background, most RR mice spontaneously develop RR experimental autoimmune encephalomyelitis (EAE) with episodes often altering between different central nervous system tissues like the cerebellum, optic nerve, and spinal cord. Development of spontaneous EAE depends on the presence of an intact B cell compartment and on the expression of MOG autoantigen. There is no spontaneous EAE development in B cell-depleted mice or in transgenic mice lacking MOG. Transgenic T cells seem to expand MOG autoreactive B cells from the endogenous repertoire. The expanded autoreactive B cells produce autoantibodies binding to a conformational epitope on the native MOG protein while ignoring the T cell target peptide. The secreted autoantibodies are pathogenic, enhancing demyelinating EAE episodes. RR mice constitute the first spontaneous animal model for the most common form of multiple sclerosis (MS), RR MS.

3 Bookmarks
 · 
196 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic monoclonal antibodies (mAbs) are a relatively novel class of drugs that has substantially advanced immunotherapy for patients with multiple sclerosis. The advantage of these agents is that they bind specifically and exclusively to predetermined proteins or cells. Natalizumab was the first mAb in neurology to obtain approval. It is also considered one of the most potent options for annualized relapse rate reduction among available therapeutic options. Alemtuzumab is currently also approved in several countries. Several mAbs have been tested in clinical studies in multiple sclerosis. Here, we review the history of drug development of therapeutic mAbs and their classification. Furthermore, we outline the putative mechanisms of action, clinical evidence and safety of approved mAbs and those in different stages of clinical development in multiple sclerosis and neuromyelitis optica.
    Expert Review of Clinical Immunology 12/2014; 11(1):1-16. DOI:10.1586/1744666X.2015.992881 · 3.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli, sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.015 · 7.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Relapse-remitting multiple sclerosis is a chronic disease of the CNS that affects 350,000 individuals in the U.S, reducing the quality of life and often resulting in paralysis. Most current therapies do not target the underlying pathophysiology of multiple sclerosis (MS). This study examined the therapeutic efficacy of an endogenous peptide (opioid growth factor, OGF) known to inhibit cell replication in a receptor-mediated manner, utilizing a mouse model of relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE). RR-EAE was induced by immunization of SJL/J mice with proteolipid protein. Two days following establishment of clinical disease, treatment with OGF (10mg/kg) or saline was initiated and mice were observed on a daily basis. OGF treated mice had markedly reduced clinical signs of disease over the course of 40 days. OGF treatment increased the incidence and lengthened the time of remissions relative to saline-treated mice with RR-EAE. OGF therapy also reduced relapses, and facilitated extended periods of mild disease. Neuropathological examination of lumbar spinal cord after 40 days of treatment revealed decreased numbers of Iba-1 and CD3+ reactive cells, suggesting that OGF inhibited proliferation of microglia/macrophages and T lymphocytes, as well as decreasing the number of proliferating activated astrocytes (Ki67 and GFAP dual labeled sections). Peptide treatment for 40 days diminished levels of demyelination in comparison to saline-treated mice with RR-EAE. These data are the first to demonstrate that exposure to OGF initiated at the time of established disease can reverse the course of RR-EAE and reduce neuropathological deficits. Copyright © 2015. Published by Elsevier Inc.
    Brain Research Bulletin 01/2015; 112. DOI:10.1016/j.brainresbull.2015.01.009 · 2.97 Impact Factor

Full-text (4 Sources)

Download
4 Downloads
Available from
Feb 11, 2015