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      Neuroimmunopathogenesis of ts1 MoMuLV Viral Infection

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          Abstract

          Newborn mice infected with ts1, a mutant of the Moloney murine leukemia virus, develop neuroimmunodegeneration with death and damage of thymocytes, astrocytes, and motor neurons by 24–38 days. T cells, B cells, and astrocytes, but not neurons, are infected by the virus. Primary splenocytes and thymocytes isolated from age-matched infected or control mice, when incubated in serum-deficient media containing phytohemagglutinin-L, either homotypically aggregate and survive or swell, expose their inner membrane phospholipids, and then shrink as they fragment their nuclei and excrete DNA-containing hypoploid minicells. In our present studies, the rates of these apoptotic changes were greatly increased in the infected cells. This thymocyte death was ameliorated in vitro by addition of Th2 cytokines, but not by Th1 cytokines, or by redox agents. In contrast, death of splenocytes, which were already mitogenically activated in vivo by the virus, was prevented by Th1 and Th2 cytokines plus redox support. In vivo, this ts1-induced neuroimmunodegenerative syndrome could be completely prevented by the immunomodulator polyinosine-cytosine and partially prevented by cytokines or redox modifiers. Viral titer primarily in the brain was also diminished by polyinosine-cytosine therapy. These observations indicate that the cell death in T cells and neurons in these ts1-infected neonatal mice can be prevented in vitro and in vivo by appropriate upregulation of the immune system.

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          Most cited references 10

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          Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.

          Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
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            Atm-deficient mice: a paradigm of ataxia telangiectasia.

            A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. The majority of animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.
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              Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo

              In a number of experimental systems in which lymphocyte depletion was induced by apoptosis-inducing manipulations, no apoptotic morphology and ladder-type DNA fragmentation were detected among freshly isolated peripheral lymphocytes ex vivo. Here we report that one alteration that can be detected among splenocytes stimulated with lymphocyte-depleting doses of dexamethasone (DEX) in vivo is a reduced uptake of 3,3'dihexyloxacarbocyanine iodide (DiOC6[3]), a fluorochrome which incorporates into cells dependent upon their mitochondrial transmembrane potential (delta psi m). In contrast, ex vivo isolated splenocytes still lacked established signs of programmed cell death (PCD):DNA degradation into high or low molecular weight fragments, ultrastructural changes of chromatin arrangement and endoplasmatic reticulum, loss in viability, or accumulation of intracellular peroxides. Moreover, no changes in cell membrane potential could be detected. A reduced delta psi m has been observed in response to different agents inducing lymphoid cell depletion in vivo (superantigen and glucocorticoids [GC]), in mature T and B lymphocytes, as well as their precursors. DEX treatment in vivo, followed by cytofluorometric purification of viable delta psi mlow splenic T cells ex vivo, revealed that this fraction of cells is irreversibly committed to undergoing DNA fragmentation. Immediately after purification neither delta psi mlow, nor delta psi mhigh cells, exhibit detectable DNA fragmentation. However, after short-term culture (37 degrees C, 1 h) delta psi mlow cells show endonucleolysis, followed by cytolysis several hours later. Incubation of delta psi mlow cells in the presence of excess amount of the GC receptor antagonist RU38486 (which displaces DEX from the GC receptor), cytokines that inhibit DEX-induced cell death, or cycloheximide fails to prevent cytolysis. The antioxidant, N- acetylcysteine, as well as linomide, an agent that effectively inhibits DEX or superantigen-induced lymphocyte depletion in vivo, also stabilize the DiOC6(3) uptake. In contrast, the endonuclease inhibitor, aurintricarboxylic acid acts at later stages of apoptosis and only retards the transition from the viable delta psi mlow to the nonviable fraction. Altogether, these data suggest a sequence of PCD-associated events in which a reduction in delta psi m constitutes an obligate irreversible step of ongoing lymphocyte death, preceding other alterations of cellular physiology, and thus allowing for the ex vivo assessment of PCD.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                1998
                October 1998
                14 September 1998
                : 5
                : 5
                : 248-260
                Affiliations
                Science Park-Research Division, M.D. Anderson Cancer Center, University of Texas, Smithville, Tex., USA
                Article
                26345 Neuroimmunomodulation 1998;5:248–260
                10.1159/000026345
                9730693
                © 1998 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.

                Page count
                Figures: 6, Tables: 1, References: 50, Pages: 13
                Categories
                Original Paper

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