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Virus induced demyelination
114 TNF mediates oligodendrocyte damage in vivo Arthur M. Butt, Huw G. Jenkins
Division of Physiology, UMDS, St. Thomas's Hospital, Lambeth Palace Road, London SE1 7EH, UK The effect of intravitreally injected cytokines (TNFa, TNF/3, IL-1, IL-6, IFN--/) on glia in mouse optic nerves was determined, by using intracellular dye-injections to characterise their whole-cell morphology. Following intravitreal injection of TNFa or TNFI3, oligodendrocytes initially developed swellings along the length of their myelin segments, and internodal myelin segments became increasingly attenuated, until, in extreme examples, individual oligodendrocytes lost their full complement of myelin segments; oligodendrocyte changes were not observed with IL-1, IL-6 or IFN-7. Widespread astrocyte reactivity, characterised by astrogliosis and an upregulation of GFAP, was observed following intravitreal injection of TNFa, TNF/3, IL-1 or IL-6; IFN-7 alone had no effect. Similar glial changes have been seen during demyelination following inoculation with Semliki Forest virus. This study supports a role for TNF in T-cell mediated demyelination and for TNF, IL-1 and IL-6 in mediating astrogliosis and reactivity. Supported by The Wellcome Trust (A.M.B.) and the MS Society (H.G.J.)
TNFa induced demyelination in rat sciatic nerve Kenneth J. Smith a.b, E. Redford
a,
within the central nervous system (CNS), inhibits the development of experimental allergic encephalomyelitis (EAE) D. Baker a,b, D. Butler c, J.K. O'Neill a.b, J.L. Turk a, M. Feldmann c
Department of Clinical Ophthalmology, Institute of Ophthalmology, London, UK, b Department of Pathology, The Royal College of Surgeons of England, London, UK, c Sunley Division, The Kennedy Institute of Rheumatology, London, UK TNF has been implicated as an important pathogenic mediator in autoimmune disease and may provide a target for immunointervention. Repeated i.p. administrations of a TNF-specific mAb inhibited development of clinical disease, whilst therapy was maintained. Furthermore an ameliorating effect was evident when antibody was administered following the onset of clinical signs. Serum TNF levels were undetectable but TNF was observed within CNS lesions suggesting the CNS as the major location of TNF activity. Intracranial (i.c.) injection of TNF-specific mAb or human p55 and p75 TNF-receptor IgG fusion proteins were significantly more effective than systemic administration. Qualitatively, bivalent TNF-receptor fusion proteins exhibited similar immunomodulating potential as the mAb. Quantitatively the fusion proteins were at least 10-100 fold more active, which was reflected by their TNF neutralization capacity in vitro. TNF neutralization, especially within the CNS, can inhibit the development of EAE.
Susan M. Hall b
a Department of Neurology, b Division of Anatomy and Cell Biology, UMDS, Guy's Campus, London, SE1 9RT, UK Several observations suggest a role for T N Fa in demyelination, but direct evidence is lacking. We have examined rats (n = 34, male, Sprague-Dawley, 250-300 g) 1 and 7 days following intra-sciatic injection of human recombinant T N Fa (2 pA/fascicle, 270-13500 U/txl, Sigma and Bechem). At 1 day numerous inflammatory cells lay within and around injected fascicles, and adhered to the luminal surfaces of the endoneurial capillaries. No demyelination was evident at this time, but by 7 days up to 100 + axons had been demyelinated. The demyelinated axons were typically associated with debris-free Schwann cells. These changes were not present to any marked extent in control animals (n = 22) which received injections of saline.
Tumor necrosis factor (TNF) neutralization with specific antibodies and TNF-receptor fusion proteins,
Virus induced demyelination John K. Fazakerley, Heather Dyson, Pedro Simas
Department of Pathology, University of Cambridge, UK Study of experimental infections of the CNS of rodents has provided the basis for understanding virus interactions with CNS cells. Theiler's and Semliki Forest viruses infect CNS cells including neurons and oligodendrocytes. Both infections give rise to lesions of demyelination. Replication of Semliki Forest virus in mature CNS cells is restricted. The infection consists of small, scattered, perivascular loci which are cleared by the immune response. Subacute demyelination mediated by CD8 ÷ T cells is a consequence of this response. Demyelination in Theiler's virus is chronic, occurring sporadically months after infection. Different strains of mice are resistant or susceptible to development of this chronic disease which is associated with viral persistence in the CNS.
Division of Physiology, UMDS, St. Thomas's Hospital, Lambeth Palace Road, London SE1 7EH, UK The effect of intravitreally injected cytokines (TNFa, TNF/3, IL-1, IL-6, IFN--/) on glia in mouse optic nerves was determined, by using intracellular dye-injections to characterise their whole-cell morphology. Following intravitreal injection of TNFa or TNFI3, oligodendrocytes initially developed swellings along the length of their myelin segments, and internodal myelin segments became increasingly attenuated, until, in extreme examples, individual oligodendrocytes lost their full complement of myelin segments; oligodendrocyte changes were not observed with IL-1, IL-6 or IFN-7. Widespread astrocyte reactivity, characterised by astrogliosis and an upregulation of GFAP, was observed following intravitreal injection of TNFa, TNF/3, IL-1 or IL-6; IFN-7 alone had no effect. Similar glial changes have been seen during demyelination following inoculation with Semliki Forest virus. This study supports a role for TNF in T-cell mediated demyelination and for TNF, IL-1 and IL-6 in mediating astrogliosis and reactivity. Supported by The Wellcome Trust (A.M.B.) and the MS Society (H.G.J.)
TNFa induced demyelination in rat sciatic nerve Kenneth J. Smith a.b, E. Redford
a,
within the central nervous system (CNS), inhibits the development of experimental allergic encephalomyelitis (EAE) D. Baker a,b, D. Butler c, J.K. O'Neill a.b, J.L. Turk a, M. Feldmann c
Department of Clinical Ophthalmology, Institute of Ophthalmology, London, UK, b Department of Pathology, The Royal College of Surgeons of England, London, UK, c Sunley Division, The Kennedy Institute of Rheumatology, London, UK TNF has been implicated as an important pathogenic mediator in autoimmune disease and may provide a target for immunointervention. Repeated i.p. administrations of a TNF-specific mAb inhibited development of clinical disease, whilst therapy was maintained. Furthermore an ameliorating effect was evident when antibody was administered following the onset of clinical signs. Serum TNF levels were undetectable but TNF was observed within CNS lesions suggesting the CNS as the major location of TNF activity. Intracranial (i.c.) injection of TNF-specific mAb or human p55 and p75 TNF-receptor IgG fusion proteins were significantly more effective than systemic administration. Qualitatively, bivalent TNF-receptor fusion proteins exhibited similar immunomodulating potential as the mAb. Quantitatively the fusion proteins were at least 10-100 fold more active, which was reflected by their TNF neutralization capacity in vitro. TNF neutralization, especially within the CNS, can inhibit the development of EAE.
Susan M. Hall b
a Department of Neurology, b Division of Anatomy and Cell Biology, UMDS, Guy's Campus, London, SE1 9RT, UK Several observations suggest a role for T N Fa in demyelination, but direct evidence is lacking. We have examined rats (n = 34, male, Sprague-Dawley, 250-300 g) 1 and 7 days following intra-sciatic injection of human recombinant T N Fa (2 pA/fascicle, 270-13500 U/txl, Sigma and Bechem). At 1 day numerous inflammatory cells lay within and around injected fascicles, and adhered to the luminal surfaces of the endoneurial capillaries. No demyelination was evident at this time, but by 7 days up to 100 + axons had been demyelinated. The demyelinated axons were typically associated with debris-free Schwann cells. These changes were not present to any marked extent in control animals (n = 22) which received injections of saline.
Tumor necrosis factor (TNF) neutralization with specific antibodies and TNF-receptor fusion proteins,
Virus induced demyelination John K. Fazakerley, Heather Dyson, Pedro Simas
Department of Pathology, University of Cambridge, UK Study of experimental infections of the CNS of rodents has provided the basis for understanding virus interactions with CNS cells. Theiler's and Semliki Forest viruses infect CNS cells including neurons and oligodendrocytes. Both infections give rise to lesions of demyelination. Replication of Semliki Forest virus in mature CNS cells is restricted. The infection consists of small, scattered, perivascular loci which are cleared by the immune response. Subacute demyelination mediated by CD8 ÷ T cells is a consequence of this response. Demyelination in Theiler's virus is chronic, occurring sporadically months after infection. Different strains of mice are resistant or susceptible to development of this chronic disease which is associated with viral persistence in the CNS.