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  • 1
    ISSN: 1432-0533
    Keywords: Blood-brain barrier ; Lymphocytic choriomeningitis ; Mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ultrastructure and the blood-brain-barrier (BBB) permeability were studied in mice suffering from lymphocytic choriomeningitis (LCM). Brains and meninges from mice suffering from LCM virus-induced lymphocytic choriomeningitis were studied by investigating the BBB function and by electron and light microscopy. The cellular exudate in the leptomeninges was located in the subarachnoid space, in arachnoidea and pia, and it was dominated by proliferated pial cells and mononuclear cells, most of which were lymphocytes, while there were only a few neutrophil granulocytes. Many intravascular lymphocytes were seen adhering to as well as penetrating the vessel walls. Many of these lymphocytes were morphologically compatible with T cells. Lymphocytes and larger mononuclear cells were also accumulated in the choroid plexus, and lymphocytes were present in the ventricular system with a tendency to adhere to ependymal epithelial cells. Inspection of the ultrathin sections incubated for horseradish peroxidase (HRP)-activity revealed that the overwhelming part of the peroxidase activity was localized in the extracellular space of the meningeal vessel walls and especially in the abundant intercellular fluid which, like the inflammatory cells, was found in the subarachnoid space in arachnoidea and in pia. In the neuropil, only very small quantities of reaction product were seen intercellularly in the most superficial layers of the cortex. The tight junctions were always intact, but the possibility of a non-demonstrable opening is discussed. Evaluation of the BBB permeability for 2-amino[1-14C]isobutyric acid (AIB) was made by quantitative autoradiography, and it was demonstrated convincingly that AIB concentrations in the subpial and perichoroidal tissues were markedly increased in diseased animals as compared to the controls. Our results seem to contradict previous theories on the cause of death resulting from the LCM disease. The findings presented here do not speak in favor of a pronounced brain edema, just as results obtained by us and others do not speak for the possibility of the death being caused by convulsive seizures with subsequent brain anoxia. However, our observations are compatible with the hypothesis that cytotoxic T cells may interact in vivo with virus-infected targets, which are essential for the regulation of the composition of the cerebrospinal fluid. On the other hand, the dysfunction of the BBB demonstrated adds a new element to the pathologic mechanism in a model for the study of virus-induced meningitis.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Medical microbiology and immunology 175 (1986), S. 121-124 
    ISSN: 1432-1831
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-1831
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 24 (1986), S. 0 
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: When the virus dose is increased from 102 (low dose) to 104 LD50 (high dose) a fatal lymphocytic choriomeningitis virus (LCMV) infection is changed into a subclinical one, and a selective virus-specific delayed-type hypersensitivity (DTH) unresponsiveness is induced, while the cytotoxic T-cell response remains essentially unchanged. When low-dose spleen effectors were transferred intravenously into intracerebrally infected high-dose mice, fatal LCM disease occurred, which means that infected central nervous system target structures in these animals are sensitive to virus-specific T cells. When low-dose cells were transferred to intravenously infected high-dose mice, these animals regained their TD function (the effect of T cells mediating DTH). Since this indicates that the survival of intracerebrally infected high-dose mice is intimately linked with the absence of virus-specific DTH reactivity, a search for T suppressor (Ts) activity in these animals was performed by transferring high-dose spleen cells to lethally (intracerebrally) infected low-dose recipients. In this way we obtained an afferent suppression, which was not H-2 restricted, but was abrogated when the spleen cells were pretreated with neutralizing anti-LCMV serum, indicating a suppressive effect of virus transferred with the infected cells. When tolerance induction was attempted with virus alone, a potentially fatal immune reaction could be altered to unresponsiveness (i.e. survival) as late as 4 days after an otherwise lethal infection with LCMV. The results indicate that the maturation of the virus-specific TD response is sensitive to large amounts of virus antigen. We conclude that this impairment and the resulting DTH unresponsiveness is due to a clonal deletion or anergy rather than to the effect of Ts cells, and that the TD effector function is critical to the development of fatal LCM disease.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Provided that intracerebral inoculation is applied, an increase in the virus dose from 102to 104 LD50 of lymphocytic choriomeningitis virus (LCMV) leads to strikingly reduced mortality. To analyse the background for this autointerferencc, we measured several virologic and immunologic variables in mice infected with these doses of virus. In the high-dose mice we found generally higher organ virus titres and serum interferon titres than in the low-dose mice. Since we could demonstrate that virus-specific T-cell cytotoxicity in spleen, peripheral blood, and meningeal exudate was similar after intracerebral infection with large and small virus doses, and since the LCMV infection in the brain qualitatively and quantitatively was independent of the size of virus inoculum, the explanation for the survival of the high-dose animals is obviously not lack of possibilities for interaction between cytotoxic T cells and infected sensitive targets in the central nervous system. On the other hand, high doses of virus caused a clear suppression of the LCMV-specific delayed-type hypersensitivity(DTH). In addition, when splenocytes from high-dose animals were transferred either intravenously or locally into the footpad of newly virus-challenged mice. DTH was markedly suppressed as compared with the response after transfer of spleen cells from low-dose mice. We therefore conclude that autointerferencc in the LCMV infection is due to a selective suppression of Td function. Large amounts of persistent virus late after infection with high doses of virus suggest a central role for Td function also in virus clearance. Finally, our results indicate the existence of two subsets of K, D region-restricted T cells, one mediating cytotoxicity and the other mediating DTH. This possibility is discussed.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 25 (1987), S. 0 
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The pathogenicity of lymphocytic choriomeningitis virus (LCMV) inoculated intracercbrally (i.e.) varies with virus sirain and dose as well as with the mouse strain used as host. Recently, results have indicated that susceptibility to lethal disease correlates directly with the ability of the host to produce early and high vinis-spccific Tc activity However, in the present studies we demonstrate that even though this holds true in many mouse/virus combinations, it does not apply in others Thus, in C3H mice infected with (moderately) high doses of Traub strain LCMV, early and high Tc activity was found despite a mortality rate of only 10–20%. Similarly. in C3H mice inoculated with the aggressive and docile suhstrains of UBC strain LCMV, which differ markedly in their pathogenicity for this mouse strain, similar kinetics of Tc induction were observed. Finally. in DBA/2 mice which do not die following infection with the otherwise lethal aggressive substrain. Tc induction could he found to be as efficient as m BALB/c mice, all of which die from acute LCM disease when infected with this virus isolate. The results indicate, therefore, that early and high Tc activiiy does not constitute a sufficient prerequisite for lethal disease. and that different Tc response profiles may he associated with low mortaility following i.e. inoculation with LCMV.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 40 (1994), S. 0 
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Adult C57BL/6 mice infected with LP-BM5 murine leukaemia virus represent a model of murine AIDS (MAIDS). In this study we have analysed the capacity of CD4+ T cells from infected mice to produce IL-3 following stimulation with ConA for 24–72 h. In contrast to the position with IL-2, the production of which is markedly impaired during LP-BM5 infection, similar levels of IL-3 were measured in culture supernatants of splenocytes from infected and uninfected mice harvested at 24 h of stimulation. Forty eight and 72 h of ConA stimulation led to increasing levels of IL-3 being measured in cultures from uninfected mice, whilst in cultures from infected animals, IL-3 levels remained stagnant. Similar results were obtained 4, 8 and 13 weeks post-infection. In view of the fact that parallel experiments revealed markedly impaired proliferative responses to ConA during MAIDS, we conclude that IL-3 production is basically intact at the cellular level in T cells during MAIDS; but when in a situation requiring clonal expansion of the activated T cells, IL-3 production will be inhibited owing to the impaired capacity for proliferation.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 24 (1986), S. 0 
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: An increase in the virus dose from 102 LD50 (low dose) to 104 LD50 (high dose) of lymphocytic choriomeningitis virus (LCMV) results in markedly delayed virus clearance, in spite of a potent cytotoxic T-cell (Tc) response. However, virus-specific delayed-type hypersensitivity (DTH) reactivity is markedly depressed in high-dose mice, suggesting an association between DTH and virus clearance. When virus-primed memory cells are transferred, DTH reactivity as well as virus-clearing capacity is restored in high-dose mice, indicating that the virus is not present in a changed or concealed form. The role of T-cells mediating DTH (TD cells) in virus clearance was also studied by adoptive transfer to naive recipients. Here the high-dose primed cells did mediate virus clearance, although no DTH reaction was detectable 24–72 h after transfer. However, when footpad swelling was measured 96 h or more after transfer a DTH response emerged, indicating that TD priming had taken place in high-dose animals. Pre-irradiation of high-dose primed cells markedly inhibited the antiviral activity as well as DTH, suggesting that upon transfer to naive recipients TD precursors from high-dose mice would proliferate into effector cells capable of mediating both functions. Treatment with anti-Lyt 2+C’ abrogated the capacity to induce virus-specific DTH, thus confirming that the cells involved are not helper T (TH) cells. We conclude that the DTH unresponsiveness in high-dose mice reflects a defective differentiation of TD precursor into effector cells which is reversible upon transfer to a less antigen loaded environment. Furthermore, it is suggested that TD function is crucial to the process of virus clearance.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Scandinavian journal of immunology 40 (1994), S. 0 
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Parameters of the virus-specific T-cell response were analysed in order to dissect the contribution of CD4+ and CDS+ T cells to cell-mediated immunity to lymphocytic choriomeningitis virus. In MHC class II deficient mice, initial T-cell responsiveness was not impaired, but virus clearance was delayed, and virus-specific Td activity declined more rapidly. Furthermore, class I restricted Tc memory appeared to be impaired in these mice. To directly evaluate the role of CD4+ cells in virus clearance and T-cell mediated inflammation, MHC class I deficient mice were also studied. No virus-specific delayed-type hypersensitivity reaction was detected following infection of the footpad, and only a few mice died from intracerebral challenge. However analysis of markers of T-cell activation as well as direct evaluation of CSF infiammation unveiled a low degree of T-cell activation and a chronic cellular exudate. This low-grade response was associated with some degree of virus control as organ titres were lower in these animals than in matched T-cell deficient nu/nu mice or class I deficient mice treated with anti-CD4 monoclonal antibody. This confirms that CD4+ cells are not needed to induce a virus-specific CD8+ T-cell response, but our findings strongly suggest that CD4+ T cells are critical for maintaining full antiviral immunity. Furthermore, CD4+ T cells per se have a low potential for mediating virus-specific infiammation that is associated with a low degree of virus control.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Flow cytometric analysis of splenocytes from mice infected with lymphocytic Choriomeningitis virus revealed marked and long-standing up-regulation of LFA-1 expression on CD8+, but not on CD4+ T cells. Appearance of CD8+ T cells with a changed expression of adhesion molecules reflected polyclonal activation and expansion which was demonstrated not to depend on CD4+ T cells or their products. Cell sorting experiments defined virus-specific CTL to be included in this population (LFA-1hiMEL-14lo), but since about 80% of splenic CD8+ T cells have a changed phenotype, extensive bystander activation must take place; this is indicated also by the finding that CD8+LFA-lhi cells transiently express several markers of cellular activation, e. g. transferrin receptor, IL-2Rα and β. Analysis of cells from the cerebrospinal fluid of mice infected intracerebrally showed that virtually all T cells present belonged to the CD8LFA-lhi subset and, correspondingly, the ligand ICAM-1 was found to be up-regulated on endothelial cells in the inflamed meninges. Preincubation of LCMV-primed donor splenocytes with anti-LFA-1 markedly inhibited the transfer of virus-specific delayed-type hypersensitivity to naive recipients. Together, these findings indicate that up-regulation of LFA-1 expression is a critical factor involved in directing activated CD8+ T cells to sites of viral infection.
    Type of Medium: Electronic Resource
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