Facilitation of experimental allergic encephalomyelitis by irradiation and virus infection: role of inflammatory cells (original) (raw)
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Long-term effects of Semliki Forest virus infection in the mouse central nervous system
Neuropathology and Applied Neurobiology, 1997
Semliki Forest virus (SFV) infection of mice is used as a model to study pathogenic processes occurring in viral encephalitis and demyelinating disease. In this study, the long-term effects of infection by the avirulent M9 mutant of SFV on the central nervous system (CNS) of BALB/c and SJL mice were determined. The presence of infectious virus, viral RNA and cytokine mRNA in the brains of individual mice and the presence of lesions in the spinal cords of the same mice up to 360 days post-infection (d.p.i.) were analysed in order to detect any correlation between these parameters of pathogenesis. Infectious virus could not be detected beyond 7 d.p.i. for either mouse strain. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the presence of the E2 and nsP1 regions of the virus genome and mRNA for interferon-and tumour necrosis factor-. Viral RNA could be detected up to 90 d.p.i. for both mouse strains. Cytokine mRNA could be detected up to 28 d.p.i. for BALB/c mice but up to 360 d.p.i. for SJL mice. Inflammatory lesions, which were associated with cytokine mRNA expression, were not detected in BALB/c mice beyond 28 d.p.i. but were detected in two SJL mice at 90 d.p.i. It is concluded that M9-SFV infection induces long-term prolonged expression of pro-inflammatory cytokines in the CNS of the majority of SJL (but not BALB/c) mice which is not associated with persistence of the virus genome. M9-SFV infection of SJL mice may be a relevant model for the pathogenesis of multiple sclerosis in man.
Journal of Neuroimmunology, 1994
Cytokine production by T cells in the cerebrospinal fluid (CSF) and central nervous system (CNS) of SJL/J mice during myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE) was examined. Reverse transcriptase/ polymerase chain reaction (RT/PCR) was used to measure interleukin-2 (IL-2) and interferon-gamma (IFN-y) mRNA levels from perfused CNS tissue (brain and spinal cord) and from cells isolated from CSF. Animals were grouped according to EAE severity, ranging from asymptomatic (adjuvant only) to severe disease (paralysis or severe paresis). Cytokine signals, normalized to actin, were almost undetectable in control tissues, and only slightly elevated in whole CNS tissue from animals with mild EAE. Both cytokine messages were strongly upregulated in CNS tissues derived from severely affected animals, consistent with previous observations correlating disease progression with infiltration by memory/effector CD4 ÷ T cells, the major source of these cytokines. This cytokine upregulation was specific to the CNS, since other organs from the same animals did not express significant levels of IL-2 and IFN-y. CSF was obtained from the cisterna magna of unperfused mice and verified as such by absence of red blood cells (RBCs) and by immunoglobulin concentration orders of magnitude lower than in serum. Cytokine message was measured in RNA isolated from cells in CSF. Levels of IL-2 and IFN-y mRNA in CSF cells were significantly elevated in mild EAE and strongly upregulated in severe disease, correlating with those in total CNS tissue. These results confirm the CSF as representative of the immune status of the CNS and indicate a role for IL-2 and IFN-y in inflammatory CNS disease.
Cellular Immunology, 1997
follows infection or vaccination (4). EAE has also served for the testing of therapies for multiple sclerosis with FN18-CRM9 is an anti-rhesus anti-CD3 immunovariable predictive results (7). EAE is a far from perfect toxin that can transiently deplete T cells to 1% of model for multiple sclerosis. In part this is due to the initial values in both the blood and lymph node comvariability of the model in different genetic backpartments and can induce long-term tolerance to mismatched renal allografts. We have investigated grounds, observed in both inbred rodents and outbred the ability of this immunotoxin to interdict the nonhuman primates. In the latter case the disease course of an experimental rhesus T-cell-driven autoranges between monophasic and self-limiting, relapsimmune disease, experimental allergic encephaloing-remitting and monophasic hyperacute. However, myelitis (EAE) induced by myelin basic protein. Monmore than any other disease model, EAE has contribkeys showing CSF pleocytosis were then treated uted to current concepts of T-cell-mediated organ-spewith FN18-CRM9 alone or in combination with cracific immunity and has permitted a dissection of imnial irradiation (325 or 650 cGy). EAE in nontreated mune effector and suppresser mechanisms (7). control monkeys progressed rapidly. Paralysis oc-T lymphocytes play a central role in the induction curred 4-6 days after CSF pleocytosis. Paralysis was phase of EAE. This has been demonstrated by adoptive either delayed or never occurred in treated montransferring of MBP-reactive T cells to induce EAE in keys, and histopathology revealed few inflammatory naive syngeneic rodents and in unimmunized Callithrix plaques that were notable for their low or absent T jacchus marmoset (1, 2, 4). Moreover, it has been shown cell content. While T cells repopulate in the periphrecently that T cell receptor transgenic mice specific for ery posttreatment, they do not return to the CNS in MBP develop spontaneous EAE at a very high incidence large numbers, suggesting that the newly repopu-(8). However, it is less clear what part T cells play in lated T cells have lost their previously acquired CNS homing capability. Anti-CD3 immunotoxin may be the ongoing disease, and what part is played by other useful in treating clinical T-cell-driven autoimmune activated cells that have the capacity to secrete chemodiseases such as rheumatoid arthritis and multiple kines such as monocytes, macrophages, and astrocytes sclerosis. (9-11) and the capacity to present CNS antigens. We have recently constructed an immunotoxin (IT) composed of an anti-rhesus monkey CD3 monoclonal
Cellular …, 1997
follows infection or vaccination (4). EAE has also served for the testing of therapies for multiple sclerosis with FN18-CRM9 is an anti-rhesus anti-CD3 immunovariable predictive results (7). EAE is a far from perfect toxin that can transiently deplete T cells to 1% of model for multiple sclerosis. In part this is due to the initial values in both the blood and lymph node comvariability of the model in different genetic backpartments and can induce long-term tolerance to mismatched renal allografts. We have investigated grounds, observed in both inbred rodents and outbred the ability of this immunotoxin to interdict the nonhuman primates. In the latter case the disease course of an experimental rhesus T-cell-driven autoranges between monophasic and self-limiting, relapsimmune disease, experimental allergic encephaloing-remitting and monophasic hyperacute. However, myelitis (EAE) induced by myelin basic protein. Monmore than any other disease model, EAE has contribkeys showing CSF pleocytosis were then treated uted to current concepts of T-cell-mediated organ-spewith FN18-CRM9 alone or in combination with cracific immunity and has permitted a dissection of imnial irradiation (325 or 650 cGy). EAE in nontreated mune effector and suppresser mechanisms (7). control monkeys progressed rapidly. Paralysis oc-T lymphocytes play a central role in the induction curred 4-6 days after CSF pleocytosis. Paralysis was phase of EAE. This has been demonstrated by adoptive either delayed or never occurred in treated montransferring of MBP-reactive T cells to induce EAE in keys, and histopathology revealed few inflammatory naive syngeneic rodents and in unimmunized Callithrix plaques that were notable for their low or absent T jacchus marmoset (1, 2, 4). Moreover, it has been shown cell content. While T cells repopulate in the periphrecently that T cell receptor transgenic mice specific for ery posttreatment, they do not return to the CNS in MBP develop spontaneous EAE at a very high incidence large numbers, suggesting that the newly repopu-(8). However, it is less clear what part T cells play in lated T cells have lost their previously acquired CNS homing capability. Anti-CD3 immunotoxin may be the ongoing disease, and what part is played by other useful in treating clinical T-cell-driven autoimmune activated cells that have the capacity to secrete chemodiseases such as rheumatoid arthritis and multiple kines such as monocytes, macrophages, and astrocytes sclerosis. (9-11) and the capacity to present CNS antigens. We have recently constructed an immunotoxin (IT) composed of an anti-rhesus monkey CD3 monoclonal
Journal of Neurovirology, 1997
Semliki Forest virus A7 (SFV-A7) is a neurotropic alphavirus that leads to an asymptomatic encephalitis in adult immunocompetent mice. We studied the expression of leukocyte and endothelial cell adhesion molecules in the spleen and in the central nervous system (CNS) during SFV-A7 infection. Kinetics of the expression of LFA-1a/CD11a, LFA-1b/CD18, Mac-1/CD11b, VLA-4/CD49d, ICAM-1/CD54 and L-selectin/CD62L was determined on splenic CD4 + and CD8 + T-cells and macrophages by¯ow cytometry. Time course of the expression of these antigens and VCAM-1/CD106 as well as viral antigens in the CNS was studied by immunoperoxidase staining. In the spleen, a sustained increase in LFA-1-expression and a temporary increase at day 7 in the expression of VLA-4, Mac-1 and ICAM-1 were detected on CD8 + T-cells. L-selectin was downregulated on CD4 + cells. Adhesion molecules on macrophages remained unchanged. In the CNS, expression of Mac-1 + , VLA-4 + and LFA-1 + cells increased in parallel with the kinetics of the expression of their ligands ICAM-1 and VCAM-1 on brain vessels. Upregulation of adhesion molecules peaked between days 5 ± 8 and was most prominent in the cerebellar and brain stem white matter where viral antigens were most abundant. We conclude that the adhesion molecules pro®le of splenic T cells is altered during SFV-A7 infection which may in¯uence their homing into the CNS. Macrophages are probably recruited non-speci®cally as a consequence of activation of the brain vascular endothelium in the in¯amed areas of the brain.
This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80 macrophages and Gr-1 neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R/ Kitw41/w41) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.
PLOS One, 2011
An enriched environment has previously been described as enhancing natural killer cell activity of recognizing and killing virally infected cells. However, the effects of environmental enrichment on behavioral changes in relation to virus clearance and the neuropathology of encephalitis have not been studied in detail. We tested the hypothesis that environmental enrichment leads to less CNS neuroinvasion and/or more rapid viral clearance in association with T cells without neuronal damage. Stereology-based estimates of activated microglia perineuronal nets and neurons in CA3 were correlated with behavioral changes in the Piry rhabdovirus model of encephalitis in the albino Swiss mouse. Two-month-old female mice maintained in impoverished (IE) or enriched environments (EE) for 3 months were behaviorally tested. After the tests, an equal volume of Piry virus (IEPy, EEPy)-infected or normal brain homogenates were nasally instilled. Eight days postinstillation (dpi), when behavioral changes became apparent, brains were fixed and processed to detect viral antigens, activated microglia, perineuronal nets, and T lymphocytes by immuno-or histochemical reactions. At 20 or 40 dpi, the remaining animals were behaviorally tested and processed for the same markers. In IEPy mice, burrowing activity decreased and recovered earlier (8-10 dpi) than open field (20-40 dpi) but remained unaltered in the EEPy group. EEPy mice presented higher T-cell infiltration, less CNS cell infection by the virus and/or faster virus clearance, less microgliosis, and less damage to the extracellular matrix than IEPy. In both EEPy and IEPy animals, CA3 neuronal number remained unaltered. The results suggest that an enriched environment promotes a more effective immune response to clear CNS virus and not at the cost of CNS damage.
Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) resulting in cognitive and motor impairment. Experimental autoimmune encephalomyelitis (EAE) is a useful animal model of MS, because it is also characterized by lesion formation in the CNS, motor impairment and is also driven by autoimmune and inflammatory reactions. One of the EAE models is induced with a peptide derived from the myelin oligodendrocyte protein (MOG) 35-55 in mice. The EAE mice develop a progressive disease course. This course is divided into three phases: the preclinical phase (day 0 -9), the disease onset (day 10 -11) and the acute phase (day 12 -14). MS and EAE are induced by autoreactive T cells that infiltrate the CNS. These T cells secrete chemokines and cytokines which lead to the recruitment of further immune cells. Therefore, the immune cell distribution in the spinal cord during the three disease phases was investigated. To highlight the time point of the disease at which the activation/proliferation/accumulation of T cells, B cells and monocytes starts, the immune cell distribution in lymph nodes, spleen and blood was also assessed. Furthermore, the levels of several cytokines TNFα, IFNγ) in the three disease phases were determined, to gain insight into the inflammatory processes of the disease. In conclusion, the data provide an overview of the functional profile of immune cells during EAE pathology.
Barthelmes et al. - 2016 - Induction of Experimental Autoimmune Encephalomyelitis in Mice.pdf
Multiple sclerosis is presumed to be an inflammatory autoimmune disease, which is characterized by lesion formation in the central nervous system (CNS) resulting in cognitive and motor impairment. Experimental autoimmune encephalomyelitis (EAE) is a useful animal model of MS, because it is also characterized by lesion formation in the CNS, motor impairment and is also driven by autoimmune and inflammatory reactions. One of the EAE models is induced with a peptide derived from the myelin oligodendrocyte protein (MOG) 35-55 in mice. The EAE mice develop a progressive disease course. This course is divided into three phases: the preclinical phase (day 0 -9), the disease onset (day 10 -11) and the acute phase (day 12 -14). MS and EAE are induced by autoreactive T cells that infiltrate the CNS. These T cells secrete chemokines and cytokines which lead to the recruitment of further immune cells. Therefore, the immune cell distribution in the spinal cord during the three disease phases was investigated. To highlight the time point of the disease at which the activation/proliferation/accumulation of T cells, B cells and monocytes starts, the immune cell distribution in lymph nodes, spleen and blood was also assessed. Furthermore, the levels of several cytokines TNFα, IFNγ) in the three disease phases were determined, to gain insight into the inflammatory processes of the disease. In conclusion, the data provide an overview of the functional profile of immune cells during EAE pathology.
Acceleration of experimental allergic encephalomyelitis in hamsters with antecedent virus infection
Clinical immunology and immunopathology, 1981
As previously reported, random bred hamsters, sensitized with neuroantigen and immunologic adjuvants, seldom exhibit clinical or histopathologic manifestations of experimental allergic encephalomyelitis (EAE) before 40-250 days (mean 95 t 6 days) postsensitization. Wheh hamsters were infected intracerebrally with hamster brain subacute sclerosing panencephalitis virus (HBS) prior to sensitization, 34% of the animals developed EAE acutely. Extending these studies which focus on the role of persistent virus infection of the CNS in rendering hamsters more susceptible to EAE, it is now apparent as described here that a major effect of virus in the central nervous system is to significantly reduce the latent period between sensitization and onset of paralysis. Intraperitoneal infection with HBS virus, on the other hand, does not accelerate the onset of EAE suggesting that altered patterns of EAE in HBS-infected hamsters are due to virus-induced changes in the target tissue.