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      Tumor Necrosis Factor and Motoneuronal Degeneration: An Open Problem

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      Neuroimmunomodulation

      S. Karger AG

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          Abstract

          Tumor necrosis factor (TNF) has been implicated in the pathogenesis of various central nervous system diseases with an inflammatory component. Elevated TNF levels were observed in animal models of motor neuron disease (MND), and activation of the TNF system has been reported in patients with amyotrophic lateral sclerosis (ALS). The easy availability of scientific reports to the layman through the web, often based only on the abstracts, has prompted many patients to ask whether anti-TNF therapy might be beneficial in ALS. This review discusses the possible role of TNF in motoneuronal degeneration. Although TNF is mostly regarded as neurotoxic cytokine, there are reports of a neuroprotective and neurotrophic action. Studies with animal models of ALS are not sufficient to show whether TNF has a pathogenic or a protective role in MND though anti-TNF antibodies have shown protective effects in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). On the other hand, while TNF-deficient mice are protected from EAE, anti-TNF antibodies worsen the disease in MS patients, suggesting caution in extrapolating preliminary basic studies to the patient.

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          Most cited references 12

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          Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy.

          Autoimmunity to antigens of the central nervous system is usually considered detrimental. T cells specific to a central nervous system self antigen, such as myelin basic protein, can indeed induce experimental autoimmune encephalomyelitis, but such T cells may nevertheless appear in the blood of healthy individuals. We show here that autoimmune T cells specific to myelin basic protein can protect injured central nervous system neurons from secondary degeneration. After a partial crush injury of the optic nerve, rats injected with activated anti-myelin basic protein T cells retained approximately 300% more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other antigens. Electrophysiological analysis confirmed this finding and suggested that the neuroprotection could result from a transient reduction in energy requirements owing to a transient reduction in nerve activity. These findings indicate that T-cell autoimmunity in the central nervous system, under certain circumstances, can exert a beneficial effect by protecting injured neurons from the spread of damage.
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            Tumor necrosis factor receptor and Fas signaling mechanisms.

            Four members of the tumor necrosis factor (TNF) ligand family, TNF-alpha, LT-alpha, LT-beta, and LIGHT, interact with four receptors of the TNF/nerve growth factor family, the p55 TNF receptor (CD120a), the p75 TNF receptor (CD120b), the lymphotoxin beta receptor (LT beta R), and herpes virus entry mediator (HVEM) to control a wide range of innate and adaptive immune response functions. Of these, the most thoroughly studied are cell death induction and regulation of the inflammatory process. Fas/Apo1 (CD95), a receptor of the TNF receptor family activated by a distinct ligand, induces death in cells through mechanisms shared with CD120a. The last four years have seen a proliferation in knowledge of the proteins participating in the signaling by the TNF system and CD95. The downstream signaling molecules identified so far--caspases, phospholipases, the three known mitogen activated protein (MAP) kinase pathways, and the NF-kappa B activation cascade--mediate the effects of other inducers as well. However, the molecules that initiate these signaling events, including the death domain- and TNF receptor associated factor (TRAF) domain-containing adapter proteins and the signaling enzymes associated with them, are largely unique to the TNF/nerve growth factor receptor family.
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              An identified neuron mediates the unconditioned stimulus in associative olfactory learning in honeybees.

               Adam Hammer (1993)
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2001
                February 2002
                15 February 2002
                : 9
                : 4
                : 178-182
                Affiliations
                ‘Mario Negri’ Institute for Pharmacological Research, Milan, Italy
                Article
                49024 Neuroimmunomodulation 2001;9:178–182
                10.1159/000049024
                11847479
                © 2002 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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                References: 51, Pages: 5
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