Cytokine induction in vitro in mouse brain endothelial cells and astrocytes by exposure to mouse hepatitis virus (MHV-4, JHM).
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Animals↗
Biomedical subjects
F D Lublin
Publications and source records attributed to F D Lublin.
T cell receptor V beta gene utilization in myelin basic protein specific clones from CXJ1 recombinant inbred mice.
CXJ1 mice are a recombinant inbred strain generated from experimental allergic encephalomyelitis (EAE) resistant BALB/c and EAE susceptible SJL/J progenitors. CXJ1 derive their major histocompatibility complex (MHC) class II and TCR genes from the BALB/c progenitor. However, their susceptibility to EAE is similar to SJL/J. Utilizing myelin basic protein (MBP)-specific CD4+ hybridoma clones and a MBP-specific T cell line (TCL) from CXJ1, we found the predominant T cell receptor (TCR) V beta chain expression to be V beta 8 and V beta 13. Our data support the concept of preferential, but not exclusive, TCR V beta usage in the MBP-specific response which is independent of MHC class II haplotype or immunodominant peptide.
Amino Acid Sequence↗
Effects of staphylococcal enterotoxin B on T cell receptor V beta utilization and clinical manifestations of experimental allergic encephalomyelitis.
Staphylococcal enterotoxin B (SEB) is a superantigen (SA) that up-regulates and then subsequently down-regulates and deletes T cells expressing V beta 8 T cell receptor (TcR) chains (Marrack and Kappler, 1990; Johnson et al., 1991). We have investigated the effect of SEB on experimental allergic encephalomyelitis (EAE) in PL/J mice, where the predominant encephalitogenic T cells are V beta 8+ (Acha Orbea et al., 1988; Zamvil et al., 1988). SEB did not enhance induction of EAE when administered prior to or after immunization for EAE. PL/J mice pretreated with SEB developed anergy and deletion of V beta 8 bearing cells and concomitant reduction in the incidence of EAE. Following SEB pretreatment, a redistribution in the TcR utilization of MBP-specific lymphocytes occurred. As a result, there was a low frequency of V beta 8 and expansion of other, normally less frequent, myelin basic protein (MBP)-specific clones. These observations indicate that systemic exposure to superantigen can influence organ-specific autoimmune diseases. We observed V beta-specific elimination, rather than activation, of autoimmune clones, a finding of potential therapeutic value. Modification of the TcR repertoire by systemic exposure to this SA indicates plasticity of immune reactivity and demonstrates a mechanism by which an environmental exposure (SEB) can influence a genetically determined, T cell mediated autoimmune disease.
Animals↗
Interleukin-6 induction in vitro in mouse brain endothelial cells and astrocytes by exposure to mouse hepatitis virus (MHV-4, JHM).
Interleukin-6 (IL-6) induction, as detected by bioassay and Northern analysis, was examined in vitro in endothelial cells or astrocytes derived from BALB/c (susceptible) or SJL (resistant) mice following exposure to mouse hepatitis virus (MHV-4) or UV inactivated MHV-4 (UV-MHV-4). In BALB/c endothelial cells, up to 16-fold more IL-6 (> 640 U/ml) was induced, compared to SJL cells which showed a minimal response (40 U/ml), relative to basal levels (< 20 U/ml). In contrast, both BALB/c and SJL astrocytes showed a substantial IL-6 response to MHV-4 and UV-MHV-4 exposure, although a strain difference persisted. Despite strain and cell specific differences in released IL-6, equivalent levels of IL-6 mRNA were induced in all cell types following exposure to MHV-4 or UV-MHV-4.
Animals↗
Interferon-gamma-inducible endothelial cell class II major histocompatibility complex expression correlates with strain- and site-specific susceptibility to experimental allergic encephalomyelitis.
The interaction between encephalitogenic lymphocytes and the cerebral microvascular lining is considered to be an important initial step in the recruitment of immune cells into the central nervous system (CNS) under pathological conditions such as multiple sclerosis (MS) and its investigative analog, experimental allergic encephalomyelitis (EAE). This study was conducted in order to examine whether differences in microvascular endothelial cell expression of several molecules involved in lymphovascular interactions correlate with the strain and organ-specific development of EAE. Cerebral and epididymal microvascular endothelial cells (EC) were isolated from SJL and B10.S mice, which, despite MHC-compatibility (H-2S), differ in their ability to develop EAE. The subcultured cells were then analyzed by flow cytometry for their ability to express class I MHC, class II MHC and ICAM-1 molecules in response to treatment with murine recombinant interferon-gamma (IFN-gamma). Over a range of doses and times, cerebral EC cultures derived from EAE-susceptible SJL mice expressed two-fold higher levels and higher cell surface densities of class II molecules than cerebral EC cultures derived from EAE-resistant B10.S mice, whereas class I and ICAM-1 molecules were comparably upregulated on both SJL and B10.S cerebral EC. In contrast, both SJL and B10.S epididymal EC cultures expressed lower but comparable levels of class II molecules in response to IFN-gamma. Class I and ICAM-1 molecules, however, were upregulated to at least the same degree as that observed on cerebral EC derived from both strains.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up.
A pilot study was undertaken to test the safety and establish the side effect profile of recombinant human interferon-beta 1b (Betaseron, Berlex Laboratories, Richmond, CA), in patients with relapsing-remitting multiple sclerosis (RRMS). During the initial dose finding period (24 weeks), five groups of 6 patients each were treated by subcutaneous injection three times each week with either 0.8, 4, 8, or 16 million units (mU) of Betaseron or placebo (WHO Standard). Although some side effects were noted in all groups, a dose-related trend in reduction of exacerbation frequency and side-effect profile was noted. Patients given 16 mU had no exacerbations during the initial dosing period, but associated side effects led to dose reduction or dropout. An 8 mU dose was selected for further study after 24 weeks, and continuous dosing at 8 mU in 15 patients has now exceeded 6 years. Side effects abated over time. Neutralizing antibody developed in most patients, but titers were variable, fluctuated independently of clinical course, and tended to fall with prolonged treatment. A dose-dependent rise in neopterin levels was observed during the initial dosing period. This pilot study has demonstrated responsiveness to Betaseron, shown a stable safety profile over time, and established guidelines for a dosing regimen to evaluate and optimize further the efficacy of Betaseron in RRMS.
Adolescent↗
Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis.
Interferon-gamma (IFN-gamma) is a cytokine with multiple activities on a variety of cells. Under various circumstances, IFN-gamma can exhibit either pro-inflammatory or inhibitory actions. Treatment of SJL/J mice with a monoclonal antibody (Mab) to IFN-gamma during the afferent limb of the immune response to myelin protein produced an enhancement of acute experimental allergic encephalomyelitis (EAE), with increased morbidity, mortality and earlier onset of disease. Systemic administration of IFN-gamma did not improve or worsen clinical outcome, but delayed disease onset. Passive transfer of immune lymph node cells co-activated with MBP and anti-IFN-gamma Mab resulted in more sever disease than that induced by MBP stimulated cells or MBP and IFN-gamma co-stimulated cells. However, in vitro proliferation of an MBP specific T cell line was not influenced by IFN-gamma nor anti-IFN-gamma treatment. Mab to IFN-gamma inhibited suppressor function, in a non-specific assay. These in vivo and in vitro results suggest that systemic IFN-gamma serves as a physiological regulator of a suppressor mechanism in EAE. The abrogation of this regulatory mechanism by anti-IFN-gamma administration contributes to a more severe form of experimental allergic encephalomyelitis.
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Immunopathogenic mechanisms in experimental allergic encephalomyelitis.
Experimental allergic encephalomyelitis, a cell-mediated autoimmune disease, continues to provide interesting data on the mechanisms subserving organ-specific autoimmunity. The elements of the trimolecular complex have been further defined and the conserved molecular basis of the interaction between the T-cell receptor and the major histocompatibility complex class II-peptide antigen complex is better understood. This model also provides new insights into the cellular interactions within the brain during the course of the autoimmune inflammatory response.
Animals↗
The sensitivity of the Mini-Mental State Exam in the white matter dementia of multiple sclerosis.
Fifty-six patients diagnosed with definite multiple sclerosis (MS) according to Poser criteria were administered the Mini-Mental State Examination (MMSE) and a comprehensive battery of neuropsychological tests. Extent of cerebral lesion involvement was determined by quantitative magnetic resonance imaging (MRI) ratings. The MMSE correlated with overall levels of physical disability, but did not correlate with total lesion area on MRI. Sensitivity of the MMSE to the subcortical dementia of MS was low (28%) when performance on the neuropsychological testing battery was used as the criterion. Impairment on tests of memory, speed of information processing, abstract reasoning, naming/verbal fluency, as well as visuoperceptual organization, were correlated highly with total lesion area on MRI. The low sensitivity of the MMSE to cognitive impairment in MS is discussed in terms of its item composition and the characteristic pattern of deficits found in MS.
Adult↗
Autoimmune inflammation of astrocyte transplants.
Astrocytes have been shown to be capable of serving as antigen-presenting cells and as targets for encephalitogenic cytotoxic T lymphocytes. The role of astrocytes in central nervous system (CNS) autoimmune inflammation is unclear. To study this further, we transplanted astrocyte aggregates into the anterior eye chamber of the mouse. The astrocytic nature of these transplants was confirmed by immunohistochemical detection of glial fibrillary acidic protein and the inability to detect oligodendrocyte or microglial markers. When mice bearing transplants were induced to develop experimental allergic encephalomyelitis by either passive or active protocols, the astrocyte transplants developed a perivascular inflammatory response similar to that seen in the host CNS during the course of the encephalomyelitis. The data suggest that astrocytes could serve as targets for the autoimmune attack of experimental allergic encephalomyelitis and support the possibility that the pathogenesis of this disease may involve an autoimmune reaction against a site other than the myelin sheath.
Animals↗
Distribution of the blood-brain barrier in heterotopic brain transplants and its relationship to the lesions of EAE.
The blood-brain barrier (BBB) is recognized as a barrier to the trafficking of molecules and cellular elements into the central nervous system (CNS). Horseradish peroxidase (HRP) exclusion is used as a measure of BBB integrity. The BBB is altered and becomes permeable during the course of experimental allergic encephalomyelitis (EAE). Heterotopic brain transplantation into the anterior eye chamber is a technique for studying genetic influences and the role of individual cell types on the development of EAE. Prior to EAE induction, HRP is excluded from the central portion of the transplant, demonstrating an intact BBB. In contrast, HRP localization is found at the periphery of the transplant, suggesting an incomplete barrier. However, EAE lesions typically occur within the more central regions of the transplant, where the BBB is intact, and not at peripherally located "leaky" areas. This suggests that endothelial cells at intact BBB sites may direct trafficking of lymphocytes (gating) into the CNS during the development of EAE, rather than the passive entry of lymphocytes into the CNS through a leaky BBB.
Animals↗
Susceptibility to experimental allergic encephalomyelitis in animal models of autoimmunity.
Experimental allergic encephalomyelitis (EAE) continues to serve as a useful model of organ-specific autoimmunity and as a model for the human demyelinating disease, multiple sclerosis. Current studies focus on the role of the various cellular components involved in mediating disease, the nature and molecular characterization of the immune process, and the target site within the central nervous system (CNS). The results of these studies are providing new therapeutic rationales.
Animals↗
Lower extremity motor evoked potentials in multiple sclerosis.
Transcranial magnetic stimulation was performed on 25 patients with definite multiple sclerosis. Motor evoked potentials were recorded from the anterior tibial muscle. Central motor conduction time was calculated using the equation (F + M-1)/2 by stimulation of the common peroneal nerve. Motor evoked potentials were capable of detecting subclinical pyramidal tract lesions in multiple sclerosis. In patients with multiple sclerosis, the incidence of abnormality of motor and somatosensory evoked potentials was similar. Central motor conduction time was correlated with overall and pyramidal tract subscores on the Kurtzke Disability Status Scale and the Scripps Neurological Rating Scale. Central motor conduction time abnormalities correlated best with the presence of a Babinski's sign but also correlated significantly with weakness and hyperreflexia.
Adult↗
Mouse hepatitis virus (MHV-4, JHM) blocks gamma-interferon-induced major histocompatibility complex class II antigen expression on murine cerebral endothelial cells.
The regulation of gamma-interferon-induced major histocompatibility complex (MHC) class II antigen expression on mouse cerebral endothelial cells by the neurotropic mouse hepatitis virus (MHV-4, JHM) was studied in vitro. The results presented demonstrate that MHV-4 can selectively block gamma-interferon-induced class II antigen expression on cerebral endothelial cells. The blocking effect of class II expression occurs in a strain-dependent manner, and is limited to virus-susceptible mouse strains. Virus replication is not required to obtain the blocking effect since UV-inactivated MHV-4 produces the same result. MHV-4 blocking of gamma-interferon-induced class II antigen expression is observed at both the cell surface (flow cytometry) and transcriptional level (Northern analysis).
Animals↗
Regulation of MHC class I and II antigens on cerebral endothelial cells and astrocytes following MHV-4 infection.
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Animals↗
Antibodies to GM1 and GD1b in patients with motor neuron disease without plasma cell dyscrasia.
Fifty-nine percent of 49 patients with motor neuron disease and 25% of 91 control subjects had IgM antibodies to ganglioside GM1 but usually not to GD1b at titers less than 1:80. This suggests that antibodies to GM1 may be part of the normal human antibody repertoire. However, given the higher incidence of antibodies to GM1 in patients with motor neuron disease, there may be specific epitopes important in antiganglioside antibodies associated with motor neuron disease.
Autoantibodies↗
Differential modulation of MHC class I antigen expression on mouse brain endothelial cells by MHV-4 infection.
Virus-induced modulation of mouse cerebral endothelial cell class I and class II antigens by the neurotropic coronavirus, MHV-4 (JHM), was examined by flow cytometry. In susceptible BALB/c, H-2Kd was downregulated, while H-2Dd was upregulated following infection by MHV-4. In contrast, H-2K and H-2D antigens were both upregulated in either MHV-4-susceptible B10.S and (BALB/c x SJL) F1, or MHV-4-resistant SJL-derived cerebral endothelial cells following infection with this virus. Class II antigen expression was unchanged following MHV-4 infection. Virus-induced MHC class I modulation is genetically regulated, and may influence virus clearance by class I-dependent CTL.
Animals↗
Down-regulation of interferon-gamma-induced class II expression on human glioma cells by recombinant interferon-beta: effects of dosage treatment schedule.
We have examined the influence of human recombinant interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) on class II antigen expression on cultured glioblastoma multiforme cells by flow cytometry. Class II molecules were not constitutively expressed on these cells, nor induced by IFN-beta. IFN-gamma increased class II expression in a dose-dependent fashion. We demonstrate that IFN-beta is either antagonistic or synergistic with IFN-gamma in class II induction depending upon dose and schedule of administration. Both interferons at 100 IU/ml reduce class II expression by 18%, compared to IFN-gamma alone. Pretreatment with IFN-beta for 72 h, followed by both interferons yielded a 90% reduction. In contrast, lower concentrations (10 IU/ml) of both interferons were synergistic.
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