Immunopathogenesis and immunotherapy of multiple sclerosis

Hemmer, Bernhard; Nessler, Stefan; Zhou, Dun; Kieseier, Bernd C.; Hartung, Hans‐Peter

doi:10.1038/ncpneuro0154

Cited by 236 publications

(176 citation statements)

References 91 publications

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“…In turn, effector cells release proinflammatory cytokines leading to the activation of the microglia and other local immune cells. Subsequently, additional autoreactive and conventional T cells, macrophages, granulocytes and B cells are attracted to the CNS accompanied by antibody production and complement deposition (Hemmer et al, 2006). This leads to the destruction of the myelin sheet, oligodendrocyte damage and axonal loss (Bjartmar and Trapp, 2001).…”

Section: Multiple Sclerosis and Its Animal Model Experimental Autoimmmentioning

confidence: 99%

Glucocorticoids in the control of neuroinflammation

Tischner

Reichardt

2007

Molecular and Cellular Endocrinology

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Glucocorticoids are a class of steroid hormones that are endowed with profound antiinflammatory and immunosuppressive activities. Endogenous glucocorticoids are key players in the modulation of the immune system and establish an endocrine basis of many inflammatory diseases. In addition, synthetic glucocorticoids are amongst the most commonly prescribed drugs worldwide for the treatment of autoimmune disorders. In this review we summarize our present knowledge on the mechanisms by which glucocorticoids impact on multiple sclerosis (MS), a highly prevalent neuroinflammatory disease, and its animal model experimental autoimmune encephalomyelitis (EAE). In spite of the new methodologies that have become available during recent years, we are still far from a comprehensive picture of the mechanism by which glucocorticoids control neuroinflammation. Keywords: Glucocorticoids; Multiple Sclerosis; Experimental AutoimmuneEncephalomyelitis; Apoptosis; Blood-brain barrier Page 2 of 33A c c e p t e d M a n u s c r i p t -3 IntroductionGlucocorticoids (GCs) are a class of steroid hormones that are commonly used to treat acute and chronic inflammatory disorders (Tuckermann et al., 2005). They exert most of their functions by binding to the glucocorticoid receptor (GR), which controls gene expression and signalling cascades through genomic as we ll as non-genomic mechanisms. By this means, GCs modulate the survival, differentiation, migration and various effector functions of leukocytes and other cell types and thereby impact both, innate and adaptive immunity. W hilst GCs administered at pharmacological concentrations are considered purely immunosuppressive, fluctuations in the levels of endogenous GCs, e.g. during stress, result in more complex immunomodulatory effects (Elenkov and Chrousos, 1999).One major application of GCs is the treatment of neuroinflammatory disorders, in particular multiple sclerosis (MS), the most prevalent chronic autoimmune disease of the central nervous system (CNS) in the Western world (Noseworthy et al., 2000). MS is characterized by infiltrating autoreactive T-cells in the CNS that initiate aninflammatory cascade involving leukocytes and humoral components (Sospedra and Martin, 2005). This causes demyelination and axonal loss, which eventually leads to severe functional deficits. While GCs have no positive effect on the long-term prognosis of MS, optic neuritis and other acute relapses are widely treated with high doses of methylprednisolone (Milligan et al., 1987). Still, such a therapy may lead to severe complications or incomplete recovery. Furthermore, it is known that the course of MS is influenced by the level of endogenous GCs (Elenkov and Chrousos, 1999). Women in the third trimester of pregnancy and Cushing syndrome patients often experience remission of the disease. This is explained by a polarization of the immune system towards T H 2 dominated responses as a consequence of increased Page 3 of 33A c c e p t e d M a n u s c r i p t -4 cortisol synthesis. Thus, fluctuations in G...

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Section: Multiple Sclerosis and Its Animal Model Experimental Autoimmmentioning

confidence: 99%

Glucocorticoids in the control of neuroinflammation

Tischner

Reichardt

2007

Molecular and Cellular Endocrinology

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“…Although the brain is subject to immunosurveillance under normal physiological conditions (7), disease progression in MS and EAE is commonly associated with increased lymphocyte infiltration/extravasation (5). In recent years, experimental MS therapies directed at either inhibiting lymphocyte trafficking to the CNS or suppressing inflammation have had varying degrees of success in clinical trials (8). Because adenosine has been shown to regulate leukocyte migration across endothelial barriers (9,10) and the production of inflammatory cytokines (11), we asked whether CD73 (ecto-5Ј-nucleotidase), a cell surface enzyme that catalyzes the formation of extracellular adenosine, has a role in EAE disease progression.…”

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confidence: 99%

CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis

Mills

Thompson

Mueller

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

183

197

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CD73 is a cell surface enzyme of the purine catabolic pathway that catalyzes the breakdown of AMP to adenosine. Because of the strong immunosuppressive and antiinflammatory properties of adenosine, we predicted that cd73 ؊/؊ mice would develop severe experimental autoimmune encephalomyelitis (EAE), an animal model for the central nervous system (CNS) inflammatory disease, multiple sclerosis. Surprisingly, cd73 ؊/؊ mice were resistant to EAE. However, CD4 T cells from cd73 ؊/؊ mice secreted more proinflammatory cytokines than wild-type (WT) mice and were able to induce EAE when transferred into naïve cd73 ؉/؉ T cell-deficient recipients. Therefore, the protection from EAE observed in cd73 ؊/؊ mice was not caused by a deficiency in T cell responsiveness. Immunohistochemistry showed that cd73 ؊/؊ mice had fewer infiltrating lymphocytes in their CNS compared with WT mice. Importantly, susceptibility to EAE could be induced in cd73 ؊/؊ mice after the transfer of WT CD73 ؉ CD4 ؉ T cells, suggesting that CD73 must be expressed either on T cells or in the CNS for disease induction. In the search for the source of CD73 in the CNS that might facilitate lymphocyte migration, immunohistochemistry revealed a lack of CD73 expression on brain endothelial cells and high expression in the choroid plexus epithelium which regulates lymphocyte immunosurveillance between the blood and cerebrospinal fluid. Because blockade of adenosine receptor signaling with the A 2a adenosine receptor-specific antagonist SCH58261 protected WT mice from EAE induction, we conclude that CD73 expression and adenosine receptor signaling are required for the efficient entry of lymphocytes into the CNS during EAE development.adenosine ͉ multiple sclerosis ͉ inflammation ͉ choroid plexus

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“…Although the precise etiology of MS is unknown, key features of its pathogenesis and clinical evolution are emerging. [1][2][3] Among various immune cellular effectors that have been implicated, pathogenic T cells loom large as pivotal drivers of the disease. As a consequence, various therapeutic paths are converging on T effectors as targets, with complementary goals of blocking their activation and re-activation, eliminating them from the larger T-cell reservoir, and interfering with their transit to sites of pathogenesis within the CNS.…”

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confidence: 99%

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

Razmara

Hilliard

Ziarani

et al. 2009

The American Journal of Pathology

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Hallmarks of the pathogenesis of autoimmune encephalomyelitis include perivascular infiltration of inflammatory cells into the central nervous system, multifocal demyelination in the brain and spinal cord, and focal neuronal degeneration. Optimal treatment of this complex disease will ultimately call for agents that target the spectrum of underlying pathogenic processes. In the present study, Fn14-TRAIL is introduced as a unique immunotherapeutic fusion protein that is designed to exchange and redirect intercellular signals within inflammatory cell networks, and, in so doing, to impact multiple pathogenic events and yield a net anti-inflammatory effect. In this soluble protein product, a Fn14 receptor component (capable of blocking the pro-inflammatory TWEAK ligand) is fused to a TRAIL ligand (capable of inhibiting activated, pathogenic T cells). Sustained Fn14-TRAIL expression was obtained in vivo using a transposon-based eukaryotic expression vector. Fn14-TRAIL expression effectively prevented chronic, nonremitting, paralytic disease in myelin oligodendrocyte glycoprotein-challenged C57BL/6 mice. Disease suppression in this model was reflected by decreases in the clinical score, disease incidence, nervous tissue inflammation, and Th1, Th2, and Th17 cytokine responses. Significantly, the therapeutic efficacy of Fn14-TRAIL could not be recapitulated simply by administering its component parts (Fn14 and TRAIL) as soluble agents, either alone or in combination. Its functional pleiotropism was manifest in its additional ability to attenuate the enhanced permeability of the blood-brain barrier that typically accompanies autoimmune encephalomyelitis. (Am J Pathol

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Immunopathogenesis and immunotherapy of multiple sclerosis

Cited by 236 publications

References 91 publications

Glucocorticoids in the control of neuroinflammation

Glucocorticoids in the control of neuroinflammation

CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis

Fn14-TRAIL, a Chimeric Intercellular Signal Exchanger, Attenuates Experimental Autoimmune Encephalomyelitis

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