Cytokine secretion by human T cell clones is differentially regulated by eicosanoids.
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Alprostadil↗
Biomedical subjects
S Amor
Publications and source records attributed to S Amor.
Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif.
Myelin basic protein (MBP) and synthetic MBP peptides were screened for their ability to induce experimental allergic encephalomyelitis in Biozzi ABH (H-2Ag7) mice. In contrast to the failure of native MBP to induce experimental allergic encephalomyelitis, the use of overlapping MBP peptides revealed epitopes within MBP 12-26 and MBP 21-35, which induced mild disease. In comparison with disease induced by spinal cord homogenate or peptides of myelin oligodendrocyte glycoprotein (MOG) or proteolipid protein (PLP), the low incidence indicates that, at least in ABH mice, MBP is a minor encephalitogen. However, the data suggest the presence of a peptide core between MBP 21-26 (HARHGF), which contains similar elements to the previously defined encephalitogenic MOG 1-22 and PLP 56-70 peptides. The fine specificity of these epitopes was further investigated using frame-shifted peptides, which indicated cores between MOG 9-15 (GYPIRAL) and PLP 62-68 (NVIHAFQ). Based on these pathogenic peptides, a putative H-2Ag7 binding motif is suggested that contains a series of hydrophobic, basic, small, and large hydrophobic residues within a 6 to 7 amino acid core. The core and particular importance of these four residues in PLP 56-70 was confirmed in vitro using amino acid substitution studies. These findings support many of the predictions made by computer modeling of peptide:H-2Ag7 interactions. This may have relevance in the design of strategies in the treatment of experimental autoimmune diseases in animals that express this haplotype.
Amino Acid Sequence↗
Role of immune responses in protection and pathogenesis during Semliki Forest virus encephalitis.
The course of Semliki Forest virus (SFV) A7(74) infection in immunocompetent BALB/c, athymic nu/nu and severe combined immunodeficient (SCID) mice was compared. BALB/c mice remained healthy and exhibited transient viraemia and infectious virus in the brain from days 2 to 7. Antibodies were detectable by day 5. In comparison, SCID mice displayed a high incidence of paralysis and died: the average day of death was day 23. From infection until death, virus was present in blood and brain. No antibodies were detectable. Athymic mice were intermediate with a transient viraemia and a persistent (> 210 days) sub-clinical central nervous system (CNS) infection. These mice produced anti-viral IgM but not IgG. The pattern of infection in BALB/c or nu/nu mice could be recreated in infected SCID mice by transfer of immune serum from BALB/c or nu/nu mice with the important exception that although BALB/c immune serum could abolish infectivity titres in the CNS, scattered cells positive for viral RNA remained. Transfer of serum decreased mortality and delayed the onset of paralysis. Transfer to infected SCID mice of a non-neutralizing IgG anti-E2 monoclonal antibody did not affect the viraemia but could also reduce brain virus titres. Irrespective of specific immune responses, virus replication in CNS cells was restricted, was generally non-cytopathic and in the absence of specific immune responses could persist. From day 14 lesions of inflammatory, primary demyelination were observed throughout the CNS of BALB/c mice. In contrast, despite prolonged brain virus titres, no demyelinating lesions were observed in infected nu/nu or SCID mice. Lesions could be initiated in the latter by transfer of spleen cells but not antibody. In summary, the focal restricted infection in the CNS of adult mice infected with SFV A7(74) is independent of specific immune responses. IgM antibodies clear the viraemia. IgG antibodies including non-neutralizing antibodies reduce and clear infectious virus but cells positive for viral RNA remain. These may normally be cleared by T cell responses which are damaging and give rise to lesions of demyelination.
Alphavirus Infections↗
Morphology of oligodendrocytes during demyelination in optic nerves of mice infected with Semliki Forest virus.
Multiple sclerosis (MS) is a demyelinating disease which affects oligodendrocytes, the myelinating cells of the CNS. Demyelination is known to occur in the optic nerves of Balb/c mice infected with the avirulent A7(74) strain of Semliki Forest virus (SFV), and many of the changes are similar to those of patients with MS. The aim of the present study was to determine how demyelination proceeds in individual oligodendrocytes in SFV infection, to help in understanding the pathology of demyelination and remyelination in MS. The whole-cell morphology of individual oligodendrocyte units (defined as the oligodendrocyte, its processes and the internodal myelin segments of the axons it ensheaths) was characterized using intracellular dye injection in isolated intact optic nerves. In untreated control mice, oligodendrocytes had a relatively uniform morphology and each cell on average provided 20 or so nearby axons with single myelin sheaths with internodal lengths of approximately equal to 150 microns. In SFV infected mice, during the peak of demyelination at post-inoculation days 14-21, 55% of oligodendrocytes displayed a range of morphological abnormalities, which most likely represented sequential changes in oligodendrocytes during demyelination. Thus, at the earliest stage of demyelination oligodendrocytes developed swellings or vacuolations along their internodal myelin sheaths, which became gradually attenuated and were completely lost in extreme cases. The results show that whole oligodendrocyte units were affected during SFV-induced demyelination and this is the basis of the focal nature of lesions in this viral model of MS. Individual oligodendrocyte units which had lost their full complement of myelin sheaths had the appearance of immature oligodendrocytes, suggesting they had undergone dedifferentiation. We concluded that these cells may not be destroyed during demyelination and it is possible they are capable of remyelination which is a feature of SFV infection in mice and MS in humans.
Animals↗
Prevention of experimental autoimmune encephalomyelitis in Lewis rats by a novel fungal source of gamma-linolenic acid.
The effects of oral administration of linoleic- and gamma-linolenic-acid-rich oils on the clinical and histopathological manifestations of experimental autoimmune encephalomyelitis (EAE) were investigated in Lewis rats 7 d post-inoculation. gamma-Linolenic-acid-rich fungal (Mucor javanicus) oil at 500 mg/kg body weight abrogated clinical and histological signs of EAE although at doses of 200 and 1000 mg/kg body weight it was only effective in delaying the onset of clinical disease. Linoleic-acid-rich safflower-seed (Carthamus tinctorius) oil at 500, 750 and 1000 mg/kg body weight decreased the severity of clinical EAE disease in a dose-dependent manner. The effects in healthy animals of orally administered gamma-linolenic-acid-rich fungal oil (500 mg/kg body weight) and linoleic-acid-rich safflower-seed oil (1000 mg/kg body weight) on splenic lymphocyte proliferative responses to the T-cell mitogen concanavalin-A (Con A), membrane fatty acid composition and lymphocyte sub-sets were also studied. Both treatments enhanced the T-cell proliferative response to Con A. There was no significant effect on the proportion of splenic CD8+ or CD4+ lymphocytes. Compositional studies on splenic phosphoglyceride fatty acids of oil-treated animals suggest the above responses were associated with increases in spleen dihomo-gamma-linolenic and arachidonic acids.
Administration, Oral↗
Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice.
A recombinant protein corresponding to the Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) and synthetic 15-mer peptides of the whole MOG molecule with eight amino acid overlaps were screened for their ability to induce experimental allergic encephalomyelitis (EAE) in Biozzi AB/H (H-2dq1) and SJL (H-2S) mice. Clinical and histologic evidence of EAE developed after sensitization with the recombinant MOG protein in both AB/H and SJL mice. In AB/H mice at least three MOG epitopes within residues 1-22, 43-57, and 134-148 induced clinical and histologic EAE, whereas only the sequence 92-106 was encephalitogenic in SJL mice. Histologically, the inflammatory response in the central nervous system consisted of perivascular accumulations of CD5+ T cells and F4/80+ macrophage/microglia cells equally distributed in the brain and spinal cord. The subpial/meningeal infiltration, characteristic of mouse EAE induced with spinal cord homogenate, was only observed in cases of severe clinical disease in SJL mice in which the cellular infiltrates predominated in the spinal cord. In spite of the presence of histologic lesions in AB/H mice immunized with MOG, clinical disease either rapidly resolved or was clinically silent. In contrast to immunization of SJL mice with recombinant MOG, sensitization to MOG 92-106 induced severe clinical paralysis. After recovery these animals relapsed and exhibited demyelinated lesions. This study is the first to describe encephalitogenic epitopes of MOG that induce both clinical and histologic signs of EAE in mice. These and previous findings implicating MOG as a target Ag for Ab-mediated attack in EAE suggest that such autoreactivity to MOG may be significant in the development of human demyelinating diseases such as multiple sclerosis.
Amino Acid Sequence↗
Experimental encephalomyelitis modulates inositol and taurine in the spinal cord of Biozzi mice.
In this high resolution magnetic resonance spectroscopic study of experimental allergic encephalomyelitis (EAE) and Semliki Forest virus (SFV) infection of the Biozzi AB/H mouse, marked increases in the initially low levels of N-trimethyl compounds in the spinal cord were observed during probable demyelinating episodes. There was also a pronounced and reproducible modulation of the levels of taurine and myo-inositol during acute and again during chronic relapsing EAE. The ratio of N-acetyl-aspartate to creatine in the spinal cord of mice infected with the mutant M9 strain of SFV decreased to approximately 70% of that seen in normal mice.
Alphavirus Infections↗
Identification of a major encephalitogenic epitope of proteolipid protein (residues 56-70) for the induction of experimental allergic encephalomyelitis in Biozzi AB/H and nonobese diabetic mice.
Native proteolipid (PLP) and synthetic 15- or 16-mer peptides of the whole PLP molecule, with eight amino acid overlaps, were screened for their ability to induce experimental allergic encephalomyelitis in Biozzi AB/H (H-2dq1) mice. Clinical and histological evidence of experimental allergic encephalomyelitis developed after sensitization with native PLP and with the PLP sequence 56-70 (DYEYLINVIHAFQYV) but not with the other synthetic PLP peptides used. Nonobese diabetic mice that share similar MHC determinants (H-2Anod) with Biozzi AB/H mice, could be induced to develop experimental allergic encephalomyelitis after sensitization with either mouse spinal cord homogenate or the PLP 56-70 peptide. Although the PLP 56-70 overlaps with the encephalitogenic epitope of PLP (residues 43-64) in PL/J (H-2u) mice the Biozzi AB/H mice did not exhibit disease with either PLP 43-64 peptide or the nonapeptide PLP 56-64 that overlaps both the Biozzi AB/H and PL/J encephalitogenic peptides. The identification of a novel major encephalitogenic epitope of PLP for Biozzi AB/H mice, increases the repertoire of encephalitogenic epitopes of PLP and supports a role for PLP as a target Ag in autoimmune demyelinating diseases.
Amino Acid Sequence↗
Replication of the A7(74) strain of Semliki Forest virus is restricted in neurons.
In neonatal mice the A7(74) and L10 strains of Semliki Forest virus (SFV) are virulent. In 3- to 4-week-old mice the L10 strain is virulent, the A7(74) strain is avirulent. Following intraperitoneal inoculation of 3- to 4-week-old mice both strains produce a transient plasma viremia. This is cleared by IgM antibodies. IgG antibodies of all subclasses are produced. The distribution of viral RNA in the brain as determined by autoradiographic analysis of in situ hybridizations shows that in all cases virus is first apparent as small foci of infected cells around cerebral capillaries. In both neonatal and 3- to 4-week-old mice infected with L10 or neonatal mice infected with A7(74), infection spreads rapidly from the original foci to infect large areas throughout the brain. Both neurons and glial cells are infected resulting in pycnosis and death of the animals. In the brains of 3- to 4-week-old mice infected with A7(74) virus there is little spread from the original perivascular foci. Again neurons and oligodendrocytes are infected but cellular destruction is minimal. The same pattern of A7(74) infection is observed in 3- to 4-week-old athymic nu/nu mice and mice with severe combined immunodeficiency, indicating that failure to spread is not related to specific immune responses. Furthermore, in nu/nu and SCID mice the small restricted foci of A7(74) infection persist. Comparison of the replication of these two viruses by electronmicroscopy shows that although A7(74) virus replicates completely in the neurons of neonatal mice, the virus is unable to bud from the neurons of 3- to 4-week-old mice and aggregates of viral RNA and capsid accumulate. We conclude that there is an age-related restriction of A7(74) replication in mouse neurons and that this restriction is not associated with the maturity of virus-specific immune responses but probably reflects age-related changes in neurons.
Animals↗
Inhibition of chronic relapsing experimental allergic encephalomyelitis in the mouse by the alkyl-lysophospholipid ET-18-OCH3.
The effect of the anti-tumour agent alkyl-lysophospholipid (ALP) ET-18-OCH3 on the development of chronic relapsing experimental allergic encephalomyelitis (CREAE) in the mouse was investigated. Experimental allergic encephalomyelitis developed in the majority (greater than 96%) of mice immunized with autologous spinal cord homogenate in Freund's complete adjuvant. Alkyl-lysophospholipid, in doses of 25 mg/kg/day or 50 mg/kg/day, inhibited the onset of clinical signs of acute phase CREAE when orally administered starting on the day of disease induction. Similarly if treatment with 50 mg/kg/day was delayed until day 9 post-inoculation the incidence of disease and severity of clinical signs were also significantly reduced (P less than 0.02) as compared with vehicle fed animals. However, when treatment began on day 12, just prior to the onset of clinical disease, although the incidence of disease was not significantly altered the severity of disease was significantly (P less than 0.002) reduced compared with vehicle treated animals. These data suggest that although the major effect of ALP is on the inhibition of the generation of the autoimmune response there appeared to be some therapeutic benefit at a later stage of acute disease. Therefore, this study was extended to the treatment of post-acute phase remission animals. It was found that the oral administration of 50 mg/kg/day marginally reduced and that 75 mg/kg/day significantly (P less than 0.05) reduced the incidence of relapsing disease compared with vehicle treated controls. This suggests that ET-18-OCH3 may have some potential in the treatment of ongoing autoimmune disease of the central nervous system.
Animals↗
CNS pathogenesis following a dual viral infection with Semliki Forest (alphavirus) and Langat (flavivirus).
Mice inoculated intraperitoneally with the alphavirus Semliki Forest were protected against a subsequent challenge with the flavivirus Langat. The protection was seen as a reduction in the Langat virus titres, mortality index and percentage deaths. The severity of the brain pathology was greater in the simultaneously infected mice, or when the time interval between administration of the viruses was 7 days, compared to that seen following a single infection of either Semliki Forest or Langat virus. When the time interval was greater than 14 days the severity of the histopathological lesions were reduced. Two factors were considered to be of possible importance in the protection afforded by the original alphavirus. Either persistence of the alphavirus interfering with the challenge flavivirus or cross-reactive immunity arising from a common host cell membrane derived glycolipid component present in both viral envelopes. This latter phenomenon could be important as anti-glycolipid activity present at 14 days after the first virus increased significantly after challenge with the second virus.
Animals↗
Persistence of encephalitogenic arboviruses in brain cell culture. Brief report.
Virus recovery from brain cultures of mice infected with either Semliki Forest and/or Langat depended on the time interval between inoculation of either virus. Mixed infections may alter the course of a disease.
Animals↗
The effect of cycloleucine on SFV A7(74) infection in mice.
Cycloleucine (CL), a non-metabolizable amino acid analogue, was found to reduce thymus and spleen weights in Semliki Forest virus (SFV) strain A7(74) infected and control mice. The maximum effects were seen when three daily doses of CL were given to mice 24 h after an SFV A7(74) infection. In these mice thymus atrophy led to abolition of thymus dependent immune responses and changes in the pathological features of the viral infection--the most striking feature being prevention of demyelination. In addition virus titres in the brains of CL treated infected mice were increased and prolonged. These results show that demyelination following an SFV A7(74) infection is not a result of direct virus action, but of a T-cell mediated mechanism.
Amino Acids↗
Use of N-acetylethyleneimine [AEI] for the inactivation of Semliki Forest virus in vitro.
N-Acetylethyleneimine (AEI) was used to inactivate the avirulent Togavirus Semliki Forest virus (A774 strain) grown in chick embryo, Vero, and brain cell cultures. The purity of the virus preparation affected the kinetics of inactivation. The rate of inactivation increased with a rise in temperature from 5 to 40 degrees C and in concentration of AEI from 0.025 to 0.1%. The resultant vaccine was inoculated into adult mice to test its antigenicity and into suckling mice to test for the presence of infective virus. Semliki Forest virus-specific IgG was produced equal to that of mice given live virus, and mice were protected against the lethal SFV L10 strain. No suckling mice died, and the brains of the adult mice showed no pathology.
Animals↗
Reconstitution of Semliki forest virus infected mice, induces immune mediated pathological changes in the CNS.
Reconstitution of Semliki forest virus infected nude mice with spleen cells from their immunocompetent nu/+ litter mates resulted in an abolition of the otherwise persistent brain virus, production of anti-SFV IgG, and development of normally absent brain pathology. The brain pathological changes, including demyelination, seem to be mediated by T cells, and are maximum 14 days after sensitization of the reconstituting spleen cells. Sensitization of the spleen cells 7 days before transfer to the nude mice results in pathological changes advanced by about 8 days, compared to reconstitution with unsensitized cells. The involvement of T cells in the virus-induced pathology is discussed.
Animals↗
Transient virus infection and multiple sclerosis.
Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS in which autoimmunity to myelin plays a role in pathogenesis. The epidemiology of MS indicates that it may be triggered by a virus infection before the age of adolescence, but attempts to associate a specific virus with MS have produced equivocal results. Many studies of the aetiology of MS have postulated that a persistent virus infection is involved, but transient virus infection may provide a plausible alternative mechanism that could explain many of the inconsistencies in MS research. The most studied animal model of MS is chronic relapsing experimental autoimmune encephalomyelitis (CREAE), which is induced in susceptible animals following injection of myelin components. While CREAE cannot provide information on the initiating factor for MS, it may mimic disease processes occurring after an initial trigger that may involve transient virus infection. The disease process may comprise separate triggering and relapse phases. The triggering phase may involve sensitisation to myelin antigens as a result of damage to oligodendrocytes or molecular mimicry. The relapse phase could be similar to CREAE, or alternatively relapses may be induced by further transient virus infections which may not involve infection of the CNS, but which may involve the recrudescence of anti-myelin autoimmunity. Although current vaccines have a high degree of biosafety, it is suggested that the measles-mumps-rubella vaccine in particular could be modified to obviate any possibility of triggering anti-myelin autoimmunity.
Animals↗