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    You are here : Home » MS Research News » New Discoveries » Dendritic Cells

    Dendritic Cells

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    Discovery of immune cells that protect against MS offers hope for new treatment

    Dendritic CellsIn multiple sclerosis, the immune system attacks nerves in the brain and spinal cord, causing movement problems, muscle weakness and loss of vision. Immune cells called dendritic cells, which were previously thought to contribute to the onset and development of multiple sclerosis, actually protect against the disease in a mouse model, according to a study published by Cell Press in the August issue of the journal Immunity. These new insights change our fundamental understanding of the origins of multiple sclerosis and could lead to the development of more effective treatments for the disease.

    "By transfusing dendritic cells into the blood, it may be possible to reduce autoimmunity," says senior study author Ari Waisman of University Medical Center of Johannes Gutenberg University Mainz. "Beyond multiple sclerosis, I can easily imagine that this approach could be applied to other autoimmune diseases, such as inflammatory bowel disease and psoriasis."

    In an animal model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE), immune cells called T cells trigger the disease after being activated by other immune cells called antigen-presenting cells (APCs). Dendritic cells are APCs capable of activating T cells, but it was not known whether dendritic cells are the APCs that induce EAE.

    In the new study, Waisman and his team used genetic methods to deplete dendritic cells in mice. Unexpectedly, these mice were still susceptible to EAE and developed worse autoimmune responses and disease clinical scores, suggesting that dendritic cells are not required to induce EAE and other APCs stimulate T cells to trigger the disease. The researchers also found that dendritic cells reduce the responsiveness of T cells and lower susceptibility to EAE by increasing the expression of PD-1 receptors on T cells.

    "Removing dendritic cells tips the balance toward T cell-mediated autoimmunity," says study author Nir Yogev of University Medical Center of Johannes Gutenberg University Mainz. "Our findings suggest that dendritic cells keep immunity under check, so transferring dendritic cells to patients with multiple sclerosis could cure defects in T cells and serve as an effective intervention for the disease."

    Source: Science Codex (17/08/12)

    Breakthrough in the development of possible therapy for MS

    Dendtritic CellsMultiple sclerosis and psoriasis are two of the most common autoimmune diseases. Most surprisingly, almost any therapy effective in one of the two diseases causes rather harm in the other, even though similar modes of inflammation underlie both diseases.

    A research group of the Tübingen University Hospital studied a small, body-derived molecule called di-methyl fumarate (DMF), that is the first molecule improving both diseases psoriasis and multiple sclerosis. They found that this body-derived molecule strongly influences natures most potent immune stimulators, the dendritic cells that have recently been awarded by the Nobel Prize to Ralph Steinman.

    Normally, dendritic cells should recognise danger caused by bacteria or viruses, alarm the immune system and raise protective responses.

    Unfortunately, when fooled, dendritic cells induce by error immunity against the bodys own cells and start to destroy them.

    The Tübingen team has now shown, that small molecules like DMF re-educate the dendritic cells and turn them into a cell that protects from tissue destruction, the so-called type 2 dendritic cells. Using complex series of experiments, they uncover the mechanisms underlying this re-education of the dendritic cells. This establishes general rules for the development of new, most likely safe drugs that will significantly improve the life of patients with severe autoimmune diseases, namely psoriasis or multiple sclerosis.

    The University of Tübingen holds a patent on this principle.

    Published in the Journal of Experimental Medicine 2011, October online
    Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.

    Ghoreschi K, Brück J, Kellerer C, Deng C, Peng H, Rothfuss O, Hussain RZ, Gocke AR, Respa A, Glocova I, Valtcheva N, Alexander E, Feil S, Feil R, Schulze-Osthoff K, Rupec RA, Lovett-Racke AE, Dringen R, Racke MK, Röcken M.

    Source: J Exp Med. 2011 Oct 10. [Epub ahead of print] PMID:21987655 DOI 10.1084/jem.20100977 (19/10/11)

    Dendritic cells ensure immune tolerance

    Dendritic cells

    One of the most important tasks of the immune system is to identify what is foreign and what is self. If this distinction fails, then the body's own structures will be attacked, the result of which could be an autoimmune disease such as diabetes mellitus type 1 or multiple sclerosis. The only way to protect against these afflictions is to destroy all immune factors that turn against the body's own tissue - in other words: immune tolerance.

    A team working with LMU researcher Dr. David Vöhringer has now investigated exactly what role dendritic cells play in this process. There has long been suspicion that these cells, which are important for the body's defenses, are also essential for the establishment and maintenance of immune tolerance. "We investigated mice that lacked this cell type from birth," reports Vöhringer. "It turned out that immune cells that attack the body's own tissue survive in these animals, and thereby trigger an autoimmune response. It follows that dendritic cells play a major part in protecting against autoimmune disease."

    T cells are a type of white blood cell that are key actors in the body's immune defenses. Each T cell has a receptor on its surface for recognizing just one single antigen. Antigens are molecular structures, mostly fragments of proteins. T cells do not dock onto free antigens, however: they rely on other cells which can present antigens to them. It is the dendritic cells that are primarily responsible for this job. They present the T cells with various antigens, and if an antigen matches a receptor, then that T cell will trigger an immune response from the body.

    This is how the body defends itself against pathogens and other intruders. But behind this tactic lies an element of danger to the organism: what happens if the antigen is not foreign, but originates from the body's own tissue instead? A wrongly induced immune response can lead to a severe autoimmune disease that, if left untreated, could lead to destruction of organs or even death. So-called autoreactive T cells, which recognize the body's own structures, must be eradicated or pacified to avoid that they can cause harm. A T cell screening process therefore takes place in the thymus, the bilobular organ in the upper thorax, to distinguish the good from the bad of these dangerous lone mavericks. Each individual T cell is tested, and the autoreactive ones destroyed.

    The remaining T cells are checked a second time in the peripheral lymphatic organs of the body. This constant quality control goes on mostly in the lymph nodes and the spleen. As has been known for a while now, dendritic cells can induce peripheral tolerance although it remained unclear whether they are essential for this process. Dendritic cells migrate continuously out of tissues and organs into the lymph nodes, bringing tissue material with them and present it to T cells. Any T cell that reacts to the body's own proteins is then deactivated or killed off.

    Most recent findings have shown that dendritic cells are essential to generate and maintain immunological tolerance. "Our work on mice has proven that without dendritic cells, even the first, central screening of autoreactive T cells in the thymus runs only at reduced efficiency," reports Vöhringer. "In these animals, the thymus releases T cells that react to the body's own material. These are then activated in the peripheral organs - and trigger autoimmunity."

    In light of the crucial role these cells play, it is a logical question as to how autoimmunity can be triggered at all without dendritic cells. After all, it is the dendritic cells that undertake certain critical tasks during an immune response. "Among other things, they are specialized in presenting antigens to T cells, which is what makes an immune response at all possible in the first place," says Vöhringer. "So we are left with the question as to what type of cell activates the autoreactive T cells if the supposedly most important antigen-presenting cells - the dendritic cells - are missing. We already have a few candidates for this, and are studying their function more closely now."

    Full bibliographic information: "Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity",
    Caspar Ohnmacht, Andrea Pullner, Susan B.S. King, Ingo Drexler, Stefanie Meier, Thomas Brocker, and David Voehringer,
    Journal of Experimental Medicine, 16 March 2009
    DOI: 10.1084/jem.20082394

    Source: News-Medical.Net © 2009 News-Medical.Net (17/03/09)

    Macrophages In The Spleen Regulate The Immune Response And Immune Tolerance
    Autoimmune diseases such as multiple sclerosis and arthritis result from the body’s immune system attacking it’s own tissues or ‘self antigens’. Therefore, researchers have long desired to understand how a state of immune tolerance (the inability to mount an immune response against an antigen) may be forcibly induced as a therapeutic approach to treating autoimmune disease.

    In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Masato Tanaka and colleagues from RIKEN Research Center for Allergy and Immunology in Japan investigated the contribution of cells in the spleen known as macrophages to the establishment of immunological tolerance.

    The authors generated transgenic mice in which macrophages in an area known as the marginal zone in the spleen were transiently deleted by the administration of diphtheria toxin (DT). In healthy mice, injected, dying cells are normally selectively engulfed and destroyed by immune cells known as dendritic cells, and as such the presence of cell-associated antigens does not trigger an immune response.

    By contrast, in DT-treated mice that lacked macrophages in the marginal zone of the spleen, the ingestion and destruction of the dying cells by dendritic cells was irregular and the mice became susceptible to the development of a multiple sclerosis-like autoimmune response.

    This is the first study demonstrating that macrophages in the marginal zone of the spleen regulate not only efficient clearance of dying cells, but also the selective engulfment of dying cells by dendritic cells, and that functional failure of these macrophages impairs the induction of tolerance to cell-associated antigens.

    Source: Journal of Clinical Investigation. (30/07/07)

    Dendritic cells in multiple sclerosis display increased interleukin production
    According to recent research from the United States, interleukin-23 (IL-23) is increased in dendritic cells (DCs) in multiple sclerosis (MS) and down-regulation of IL-23 by antisense oligos increases DC IL-10 production.

    "IL-23 is a heterodimeric cytokine comprising a p19 subunit associated with the IL-12/23p40 subunit. Like IL-12, IL-23 is expressed predominantly by activated DCs and phagocytic cells, and both cytokines induce IFN-gamma secretion by T cells.

    "The induction of experimental autoimmune encephalitis, the animal model of MS, occurs in mice lacking IL-12, but not in mice with targeted disruption of IL-23 or both IL-12 and IL-A. Thus, IL-23 expression in DCs may play an important role in the pathogenesis of human autoimmune diseases such as MS," wrote A. Vaknin-Dembinsky and colleagues, Brigham & Women's Hospital.

    "We quantified the expression of IL-23 in monocyte-derived DCs in MS patients and healthy donors and found that DCs from MS patients secrete elevated amounts of IL-23 and express increased levels of IL-23p19 mRNA. Consistent with this abnormality, we found increased IL-17 production by T cells from MS patients.

    "We then transfected monocyte-derived DCs from healthy donors with antisense oligonucleotides specific for the IL-23p19 and IL-12p35 genes and found potent suppression of gene expression and blockade of bioactive IL-23 and IL-12 production without affecting cellular viability or DCs maturation," reported the authors.

    "Inhibition of IL-23 and IL-12 was associated with increased IL-10 and decreased TNF-alpha production. Furthermore, transfected DCs were poor allostimulators in the MLR," the scientists wrote.

    They concluded, "Our results demonstrate that an abnormal Th1 bias in DCs from MS patients related to IL-23 exists, and that antisense oligonucleotides specific to IL-23 can be used for immune modulation by targeting DC gene expression."

    Vaknin-Dembinsky and colleagues published their study in the Journal of Immunology (IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol, 2006;176(12):7768-7774).

    This article was prepared by Gene Therapy Weekly editors from staff and other reports. Copyright 2006, Gene Therapy Weekly via NewsRx.com. (03/08/06)

    © Multiple Sclerosis Resource Centre

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