Hypothesis: A role for tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis

Brosnan, Celia F.; Selmaj, Krzysztof; Raine, Cedric S.

doi:10.1016/0165-5728(88)90137-3

Cited by 196 publications

(75 citation statements)

References 21 publications

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“…with 2 ϫ 10 6 dTNFR-tsF (E) or tsF (F) day 7 p.i. (2). Although the single injection of dTNFR-tsF did not prevent onset of the relapse phase of EAE it could still ameliorate the severity of disease 5 wk later (p Ͻ 0.05) to a degree similar to that seen when dTNFR-tsF were administered during remission (day 28 p.i.)…”

Section: Discussionmentioning

confidence: 83%

“…TNF-␣ and TNF-␤ are pleiotropic cytokines produced by macrophages and activated T cells and are thought to be important proinflammatory mediators in many immunological disorders such as rheumatoid arthritis, septic shock, and MS (1,2). There is now strong evidence to support a role of TNF in the pathogenesis of EAE including cytotoxicity of oligodendrocytes (3), up-regulation of adhesion molecules on CNS endothelia (4), and the use of neutralizing TNF antagonists, notably specific anti-TNF Abs and TNFR-Ig fusion proteins (TNFRIg), particularly when injected into the CNS (5-7).…”

Section: E Xperimental Allergic Encephalomyelitis (Eae)mentioning

confidence: 99%

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Gene Therapy for Chronic Relapsing Experimental Allergic Encephalomyelitis Using Cells Expressing a Novel Soluble p75 Dimeric TNF Receptor

Croxford

Triantaphyllopoulos²,

Neve³

et al. 2000

The Journal of Immunology

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In a murine relapsing experimental allergic encephalomyelitis (EAE) model, gene therapy to block TNF was investigated with the use of a retroviral dimeric p75 TNF receptor (dTNFR) construct. To effectively produce these TNF inhibitors in vivo, a conditionally immortalized syngeneic fibroblast line was established, using a temperature-sensitive SV40 large T Ag-expressing retrovirus. These cells were subsequently infected with a retrovirus expressing soluble dTNFR. CNS-injected cells could be detected 3 mo after transplantation and were shown to produce the transgene product by immunocytochemistry and ELISA of tissue fluids. These levels of dTNFR protein were biologically active and could significantly ameliorate both acute and relapsing EAE. This cell-based gene-vector approach is ideal for delivering proteins to the CNS and has particular relevance to the control of inflammatory CNS disease.

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Section: Discussionmentioning

confidence: 83%

Section: E Xperimental Allergic Encephalomyelitis (Eae)mentioning

confidence: 99%

Gene Therapy for Chronic Relapsing Experimental Allergic Encephalomyelitis Using Cells Expressing a Novel Soluble p75 Dimeric TNF Receptor

Croxford

Triantaphyllopoulos²,

Neve³

et al. 2000

The Journal of Immunology

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“…Tumor necrosis factor-~ is a proinflammatory molecule that appears to play a role in the pathogenesis of AIDS and multiple sclerosis, both associated with chronic fatigue (Matsuyama et al, 1991, Brosnan et al, 1988. Lloyd et al, 1994 observed normal levels of serum TNF-7 in CFS and there was no further increase following exercise-induced fatigue.…”

Section: Tnf-~ Production In Cfsmentioning

confidence: 99%

Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome

Gupta

Aggarwal

See

et al. 1997

Journal of Psychiatric Research

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Summary--lt has been suggested that cytokines play a role in certain clinical manifestations of chronic fatigue syndrome (CFS). In this study adherent (monocytes) and non-adherent (lymphocytes) mononuclear cells were stimulated in the presence or absence of phytohemagglutinin (PHA) or lipopolysaccharide (LPS), respectively, and supernatants were assayed for IL-6, TNF-~, and IL-10 by ELISA. IL-6 was also measured at the mRNA level by polymerase chain reaction. The levels of spontaneously (unstimulated) produced TNF-.7 by non-adherent lymphocytes and spontaneously produced IL-6 by both adherent monocytes and non-adherent lymphocytes were significantly increased as compared to simultaneously studied matched controls. The abnormality of IL-6 was also observed at mRNA level. In contrast, spontaneously produced IL-10 by both adherent and non-adherent cells and by PHA-activated non-adherent cells were decreased. This preliminary study suggests that an aberrant production of cytokines in CFS may play a role in the pathogenesis and in some of the clinical manifestations of CFS. ,<) 1997 Elsevier Science Ltd.

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“…In chronic MS, IFN-y-producing cells, CD4+ T cells and MHC class Il-positive endothelial cells and astrocytes were consistently found at the lesion edge and also into the adjacent normal white matter (Traugott, 1987;Traugott & Lebon, 1988), In contrast, astrocytes from control CNS are MHC class-II negative and rarely express MHC class I antigen (Wong et al, 1984), This suggests that after the CD4+ T cells induce altered MHC antigen expression, via production of IFN-y and TNF (Wong et al, 1984;Fierz et al, 1985;Massa et al, 1987), the possibility of local antigen presentation within the CNS is ascertained (Pober et al, 1983;Traugott, Scheinberg & Raine, 1985), Moreover, T lymphocytes can also affect demyelination directly (Lyman et al, 1986), possibly via TNF, by causing damage to the myelin sheath (Brosnan, Selmaj & Raine, 1988), In addition, macrophages can be attracted to and activated at the site of inflammation under the influence ofT cell lymphokines, e.g. IFN-y (Mogensen & Virelizier, 1987;Stout & Bottomly, 1989).…”

Section: Discussionmentioning

confidence: 99%

Relative increase of inflammatory CD4+ T cells in the cerebrospinal fluid of multiple sclerosis patients and control individuals

Rotteveel

Kuenen

Kokkelink

et al. 1990

Clinical and Experimental Immunology

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SUMMARYOf three patients with multiple sclerosis (MS) and two non-MS individuals a large number of CD4+ T cell clones was obtained from the cerebrospinal fluid and peripheral blood by direct limiting dilution. The CD4+ T cell clones from cerebrospinal fluid and peripheral blood lymphocytes were compared for their cytotoxic activity and lymphokine production. Cytotoxic capacity of cloned T cells was analysed with the use of anti-CD3 antibodies and target cells bearing Fc receptors for murine IgG. Recently, we demonstrated the existence of two different subsets of human CD4+ T cell clones by phenotypic and functional criteria. One type of CD4+ T cell with anti-CD3 mediated cytotoxic activity, in analogy with murine studies, is the inflammatory or THI subtype, the main producer of interleukin (IL-2), interferon-gamma (IFN-y) and tumour necrosis factor (TNF)-a, -)S, whereas the other type of CD4+ T cell clone lacked anti-CD3 mediated cytotoxicity and produced minimal amounts of IL-2 concomitant with reduced levels of IFN-y and TNF-a, -fi. The present study demonstrates that among three MS patients, relatively more inflammatory CD4+ T cell clones with cytotoxic activity and IFN-y and TNF-a, -fi production were derived from the cerebrospinal fluid as compared with peripheral blood lymphocytes. Also among control individuals more inflammatory CD4+ T cell clones could be obtained from the cerebrospinal fluid as from the peripheral blood. The enrichment of inflammatory CD4+ T cells, therefore, appears to be physiological rather than associated with the disease.

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Hypothesis: A role for tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis

Cited by 196 publications

References 21 publications

Gene Therapy for Chronic Relapsing Experimental Allergic Encephalomyelitis Using Cells Expressing a Novel Soluble p75 Dimeric TNF Receptor

Gene Therapy for Chronic Relapsing Experimental Allergic Encephalomyelitis Using Cells Expressing a Novel Soluble p75 Dimeric TNF Receptor

Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome

Relative increase of inflammatory CD4+ T cells in the cerebrospinal fluid of multiple sclerosis patients and control individuals

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