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multiple sclerosis and dendritic cells

Catharina C Gross, Diana Ahmetspahic, Tobias Ruck, Andreas Schulte-Mecklenbeck, Kathrin Schwarte, Silke Jörgens, Stefanie Scheu, Susanne Windhagen, Bettina Graefe, Nico Melzer, Luisa Klotz, Volker Arolt, Heinz Wiendl, Sven G Meuth, Judith Alferink
OBJECTIVE: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment. METHODS: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined...
December 2016: Neurology® Neuroimmunology & Neuroinflammation
Kristbjörg Bjarnadóttir, Mahdia Benkhoucha, Doron Merkler, Martin S Weber, Natalie L Payne, Claude C A Bernard, Nicolas Molnarfi, Patrice H Lalive
Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-β1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-β1 expression in B cells (B-TGF-β1(-/-)) were tested in EAE induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG)...
October 6, 2016: Scientific Reports
Michel Varrin-Doyer, Kara L Pekarek, Collin M Spencer, Claude C A Bernard, Raymond A Sobel, Bruce A C Cree, Ulf Schulze-Topphoff, Scott S Zamvil
OBJECTIVE: To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell-dependent MS model. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55-specific T cell receptor transgenic (2D2) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgH(MOG-ki) [Th]) mice...
October 2016: Neurology® Neuroimmunology & Neuroinflammation
Wai-Ping Lee, Barbara Willekens, Patrick Cras, Herman Goossens, Eva Martínez-Cáceres, Zwi N Berneman, Nathalie Cools
While emerging evidence indicates that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides prospect as disease-modifying therapy. Our observations reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment of monocyte-derived DC results in a semimature phenotype and anti-inflammatory cytokine profile as compared to conventional DC, in both healthy controls and MS patients. Importantly, 1,25(OH)2D3-treated DC induce T cell hyporesponsiveness, as demonstrated in an allogeneic mixed leukocyte reaction...
2016: Journal of Immunology Research
Lisa H Tostanoski, Yu-Chieh Chiu, James I Andorko, Ming Guo, Xiangbin Zeng, Peipei Zhang, Walter Royal Iii, Christopher M Jewell
Recent studies demonstrate that excess signaling through inflammatory pathways (e.g., toll-like receptors, TLRs) contributes to the pathogenesis of human autoimmune diseases, including lupus, diabetes, and multiple sclerosis (MS). We hypothesized that co-delivery of a regulatory ligand of TLR9, GpG oligonucleotide, along with myelin - the "self" molecule attacked in MS - might restrain the pro-inflammatory signaling typically present during myelin presentation, redirecting T cell differentiation away from inflammatory populations and towards tolerogenic phenotypes such as regulatory T cells...
August 31, 2016: ACS Nano
Pingxia Lu, Yingping Cao, Meihua Wang, Peizheng Zheng, Juan Hou, Chanhong Zhu, Jianda Hu
Multiple sclerosis (MS) is generally acknowledged to be an autoimmune disease, but its etiology remains unknown. The most intensively studied animal model of MS is experimental autoimmune encephalomyelitis (EAE). Dendritic cells (DCs), the professional antigen presenting cells (APCs), have gained increasing attention because they connect innate and adaptive immunity. The aim of this study was to determine the role of mature DCs in the pathogenesis of EAE. It was found that the number of mature DCs in the EAE spleen increased compared to the control group (p < 0...
2016: Central-European Journal of Immunology
Manoj K Mishra, V Wee Yong
Discussions of multiple sclerosis (MS) pathophysiology tend to focus on T cells and B cells of the adaptive immune response. The innate immune system is less commonly considered in this context, although dendritic cells, monocytes, macrophages and microglia - collectively referred to as myeloid cells - have prominent roles in MS pathogenesis. These populations of myeloid cells function as antigen-presenting cells and effector cells in neuroinflammation. Furthermore, a vicious cycle of interactions between T cells and myeloid cells exacerbates pathology...
September 2016: Nature Reviews. Neurology
Zaidoon Al-Jaderi, Azzam A Maghazachi
Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF), a related compound, has not been examined in greater details although it has the potential as a therapeutic drug for MS and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species...
2016: Frontiers in Immunology
Roham Parsa, Harald Lund, Ivana Tosevski, Xing-Mei Zhang, Ursula Malipiero, Jan Beckervordersandforth, Doron Merkler, Marco Prinz, Alexandra Gyllenberg, Tojo James, Andreas Warnecke, Jan Hillert, Lars Alfredsson, Ingrid Kockum, Tomas Olsson, Adriano Fontana, Tobias Suter, Robert A Harris
Intracerebral levels of Transforming Growth Factor beta (TGFβ) rise rapidly during the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of Multiple Sclerosis (MS). We addressed the role of TGFβ responsiveness in EAE by targeting the TGFβ receptor in myeloid cells, determining that Tgfbr2 was specifically targeted in monocyte-derived dendritic cells (moDCs) but not in CNS resident microglia by using bone-marrow chimeric mice. TGFβ responsiveness in moDCs was necessary for the remission phase since LysM(Cre) Tgfbr2(fl/fl) mice developed a chronic form of EAE characterized by severe demyelination and extensive infiltration of activated moDCs in the CNS...
November 2016: Glia
Yuanming Xu, Fang Zhao, Quan Qiu, Kun Chen, Juncheng Wei, Qingfei Kong, Beixue Gao, Johanna Melo-Cardenas, Bin Zhang, Jinping Zhang, Jianxun Song, Donna D Zhang, Jianing Zhang, Yunping Fan, Huabin Li, Deyu Fang
Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis...
2016: Nature Communications
M M Odinak, G N Bisaga, V S Chirskii, M V Pashchenkov, I A Baldueva, V M Moiseenko, T L Nekhaeva, N M Kalinina, N I Davydova, N V Bychkova, A V Pozdnyakov
For the first time we carried out a clinical assessment of the safety, tolerability and clinical efficacy course of repeated administration of experimental modified autologous vaccine interleykin (IL-10) dendritic cells in two patients with secondary-progressive multiple sclerosis patient and one with relapsing-remitting multiple sclerosis. In the course of treatment, we carried out clinical and immunological monitoring. It was found out that intradermal dose of 3 x 10⁶ cells applied to spinal area 6-12. times did not cause any serious side effects...
April 2016: Voenno-medit︠s︡inskiĭ Zhurnal
Ahmad Reza Dorosty-Motlagh, Niyaz Mohammadzadeh Honarvar, Mohsen Sedighiyan, Mina Abdolahi
Vitamin A, considered to be an essential nutrient, has important actions in immunological responses and the central nervous system (CNS). Neuroimmunological functions of vitamin A are mediated through its active metabolite, retinoic acid (RA). In the CNS, RA contributes to regeneration and plasticity, while also playing a key role in enhancing tolerance and reducing inflammatory responses by regulating T cell, B cell and dendritic cell populations. However, evidence has indicated lower plasma levels of vitamin A in patients with multiple sclerosis (MS)...
September 2016: Journal of Molecular Neuroscience: MN
Lisa H Tostanoski, Emily A Gosselin, Christopher M Jewell
Autoimmune diseases occur when cells of the adaptive immune system incorrectly recognize and attack "self" tissues. Importantly, the proliferation and differentiation of these cells is triggered and controlled by interactions with antigen presenting cells (APCs), such as dendritic cells. Thus, modulating the signals transduced by APCs (e.g., cytokines, costimulatory surface proteins) has emerged as a promising strategy to promote tolerance for diseases such as multiple sclerosis, type 1 diabetes, and lupus...
May 2016: Discovery Medicine
Sushrut Jangi, Roopali Gandhi, Laura M Cox, Ning Li, Felipe von Glehn, Raymond Yan, Bonny Patel, Maria Antonietta Mazzola, Shirong Liu, Bonnie L Glanz, Sandra Cook, Stephanie Tankou, Fiona Stuart, Kirsy Melo, Parham Nejad, Kathleen Smith, Begüm D Topçuolu, James Holden, Pia Kivisäkk, Tanuja Chitnis, Philip L De Jager, Francisco J Quintana, Georg K Gerber, Lynn Bry, Howard L Weiner
The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders. Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43). Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes...
2016: Nature Communications
Pan Su, Sheng Chen, Yu Han Zheng, Hai Yan Zhou, Cheng Hua Yan, Fang Yu, Ya Guang Zhang, Lan He, Yuan Zhang, Yanming Wang, Lei Wu, Xiaoai Wu, Bingke Yu, Li Yan Ma, Zhiru Yang, Jianhua Wang, Guixian Zhao, Jinfang Zhu, Zhi-Ying Wu, Bing Sun
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model for human MS. Although Th17 cells are important for disease induction, Th2 cells are inhibitory in this process. In this article, we report the effect of a Th2 cell product, extracellular matrix protein 1 (ECM1), on the differentiation of Th17 cells and the development of EAE. Our results demonstrated that ECM1 administration from day 1 to day 7 following the EAE induction could ameliorate the Th17 cell responses and EAE development in vivo...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
María José Mansilla, Raian Contreras-Cardone, Juan Navarro-Barriuso, Nathalie Cools, Zwi Berneman, Cristina Ramo-Tello, Eva María Martínez-Cáceres
BACKGROUND: Tolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). In a previous study, we demonstrated that the administration of antigen-specific vitamin D3 (vitD3) tolDC in mice showing clinical signs of experimental autoimmune encephalomyelitis (EAE; the animal model of MS) resulted in abrogation of disease progression. With the purpose to translate this beneficial therapy to the clinics, we have investigated the effectivity of vitD3-frozen antigen-specific tolDC pulsed with myelin oligodendrocyte glycoprotein 40-55 peptide (f-tolDC-MOG) since it would reduce the cost, functional variability and number of leukapheresis to perform to the patients...
2016: Journal of Neuroinflammation
Kerstin Göbel, Susann Pankratz, Chloi-Magdalini Asaridou, Alexander M Herrmann, Stefan Bittner, Monika Merker, Tobias Ruck, Sarah Glumm, Friederike Langhauser, Peter Kraft, Thorsten F Krug, Johanna Breuer, Martin Herold, Catharina C Gross, Denise Beckmann, Adelheid Korb-Pap, Michael K Schuhmann, Stefanie Kuerten, Ioannis Mitroulis, Clemens Ruppert, Marc W Nolte, Con Panousis, Luisa Klotz, Beate Kehrel, Thomas Korn, Harald F Langer, Thomas Pap, Bernhard Nieswandt, Heinz Wiendl, Triantafyllos Chavakis, Christoph Kleinschnitz, Sven G Meuth
Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein-kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells...
2016: Nature Communications
Christian Kleist, Elisabeth Mohr, Sadanand Gaikwad, Laura Dittmar, Stefanie Kuerten, Michael Platten, Walter Mier, Michael Schmitt, Gerhard Opelz, Peter Terness
BACKGROUND: Dendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease. METHODS: We replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone(®)), a drug approved for the treatment of MS...
2016: Journal of Translational Medicine
Tiffany Satoorian, Bo Li, Xiaolei Tang, Jidong Xiao, Weirong Xing, Weixing Shi, Kin-Hing William Lau, David J Baylink, Xuezhong Qin
Multiple sclerosis (MS) is an incurable central nervous system autoimmune disease. Understanding MS pathogenesis is essential for the development of new MS therapies. In the present study, we identified a novel microRNA (miR) that regulates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Expression of miR223 was up-regulated specifically in spinal cords and lymphoid organs but not in other examined tissues. A global miR223 knockout (miR223(-/-) ) in mice led to a significant delay in EAE onset, reduction in spinal cord lesion, and lessening of neurological symptoms...
August 2016: Immunology
Jan Thöne, Ralf A Linker
Laquinimod (ABR-215062) is a new orally available carboxamide derivative, which is currently developed for relapsing remitting (RR) and chronic progressive (CP) forms of multiple sclerosis (MS; RRMS or CPMS) as well as neurodegenerative diseases. Its mechanism of action may comprise immunomodulatory effects on T-cells, monocytes, and dendritic cells as well as neuroprotective effects with prominent actions on astrocytes. Laquinimod was tested in Phase II and III clinical trials in RRMS at different dosages ranging from 0...
2016: Drug Design, Development and Therapy
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