In measles virus (MV) infection in humans, meningitis and encephalitis are important complications. However, little is known of the pathogenesis of MV encephalitis, in particular about the role of the immune response. We have examined the role of cytotoxic T lymphocytes (CTL) in a mouse model of MV-induced encephalitis. We report here that the resistance of inbred strains of mice to MV-induced encephalitis correlated with the major histocompatibility complex (MHC) haplotype and that only resistant mouse strains mounted an effective CTL response to MV. Mice with low susceptibility to MV infection, such as the BALB/c strain (H-2d), generated CTL, whereas the highly susceptible strains, C3H (H-2k) and C57BL/6 (H-2b), revealed very poor CTL responses. MV-induced CTL were usually CD8+, and the generation of these cells was independent of the route of inoculation or the time postinfection. CD4+ T cells were generally only weakly lytic. The nucleocapsid protein was the major target antigen for CTL in BALB/c mice, although in some experiments the hemagglutinin was also recognized. CTL from C3H and C57BL/6 mice did not lyse MV-infected target cells. However, targets infected with vaccinia virus recombinants expressing the nucleocapsid protein or hemagglutinin were lysed, but levels of cytotoxicity were still low. Experiments using target cells transfected with single MHC class I genes suggested inefficient antigen presentation of MV proteins by the MHC molecules of the H-2k and H-2b haplotypes.
Abstract Reaction of 6‐chloropyrimidines with diethyl [(2‐aminoethoxy)methyl]phosphonate allows for a ready access to acyclic nucleoside phosphonates. A series of 5‐substituted pyrimidines bearing a phosphonate side chain at position 6 were synthesized and tested against herpes simplex viruses (HSV‐1 and HSV‐2) and human immunodeficiency virus (HIV‐1). Some compounds showed weak antiviral activity against HSV‐1.
Lewis rats immunized with recombinant vaccinia virus expressing the nucleocapsid (N) protein of measles virus were protected from encephalitis when subsequently challenged by intracerebral infection with neurotropic measles virus. Immunized rats revealed polyvalent antibodies to the N protein of measles virus in the absence of any neutralizing antibodies as well as an N protein-specific proliferative lymphocyte response. Depletion of CD8+ T lymphocytes did not abrogate the protective potential of the N protein-specific cell-mediated immune response in rats, while protection could be adoptively transferred with N protein-specific CD4+ T lymphocytes. These results indicate that a CD4+ cell-mediated immune response specific for the N protein of measles virus is sufficient to control measles virus infections of the central nervous system.
T cells are believed to play an important role in the pathogenesis of Lyme arthritis (LA), an inflammatory joint disease caused by the spirochete Borrelia burgdorferi (Bb). The presence or absence of certain Bb-specific CD4+ T helper cells has been associated with prognosis. Since recent observations suggested the activation of CD8+ T cells during infection with Bb, we searched for CD8+ cytotoxic T lymphocytes in patients with LA. CD8+ T cell lines were generated from peripheral blood and synovial fluid of five patients with LA. In addition, CD8+ T cells were expanded by Ag-specific stimulation in bulk cultures. A cytotoxicity assay was established using target cells infected with recombinant vaccinia viruses expressing the borrelial proteins outer surface protein (Osp) A, OspB, or flagellin. We found Bb-specific CTL lines derived from the peripheral blood of three patients with LA with specificity for flagellin, OspA, and OspB. All Bb-specific CTL lines were CD3+, CD8+, and TCRalphabeta, and cytotoxic activity was HLA class I restricted. Moreover, CD8+ T cells expanded by Ag-specific stimulation in vitro demonstrated Bb-specific and HLA class I-restricted lysis toward individual borrelial proteins. Interestingly, Bb-specific lytic activity was only detected in patient samples obtained after the disappearance of arthritis. We report the detection of Bb-specific cytotoxic CD8+ T cells in patients with LA. The induction of specific CD8+ T cells may play an important role in disease control and may have important bearings for the development of effective vaccines against Lyme borreliosis.
We investigated the effects of continuous cancer gene therapy including (antigen-presenting cell) (APC) engineering and local stimulation of the immune system.Lewis lung carcinomas and B16 melanomas, intradermally established on C57/Bl6 mice, were shot using a gene gun every 4th day with a combination of plasmids. The first therapy group received plasmids coding the genes for interleukin (IL)-12 and IL-2. The second therapy group was treated with plasmids coding for B7.1 interferon-gamma (IFN-gamma)/IL-12 alternated by a plasmid coding IL-2. Control were mice without any therapy or treatment with the empty plasmid.Gene therapy led to reduced tumor sizes in the therapy groups of both models (significant for the Lewis lung carcinoma). We found an enhanced survival and reduced tumor growth rate in the therapy groups; however, the effects were not significant. IL- 12/IL-2 therapy was more effective, compared to B7.1/IFN-gamma/IL-12 and IL-2. Cytokine gene transfer let to a significantly lower metastasis rate in Lewis lung carcinoma.Continuous particle-mediated gene transfer is easy to handle and shows good results. Gene therapy combining the genes coding for IL-12 and IL-2 was superior to additional IFN-gamma/B7.1. APC engineering does not appear to be sufficient in these poorly antigenic tumors.
In the presence of the glucocorticoid hormone dexamethasone, bovine papillomavirus-1 (BPV-1)-transformed C127 mouse fibroblasts assume a flattened morphology and reach a saturation density of only 50% of that attained without hormone. This phenotypic reversion of transformation is dependent on the continued presence of dexamethasone and occurs with concentrations as low as 1 nM. Dexamethasone also suppresses the growth of the parental C127 cells as well as that of cells transformed by polyoma middle-T. In contrast, the growth of C127 cells transformed by the oncogenes v-H-ras, v-mos, or v-fes is inhibited by low concentrations of dexamethasone (1 nM) and stimulated by higher concentrations (0.1-1 microM), possibly due to dexamethasone-induced transcription from the viral long terminal repeat promoters as is shown for v-H-ras. On the other hand, inhibition of BPV-transformed cell line growth by dexamethasone does not appear to be related to hormone effects on BPV-1 oncogene transcription. Indeed, in several cases, dexamethasone increases the steady state transcript levels of the BPV-1 oncogenes, E5 and E6-E7, while suppressing cellular proliferation. Dexamethasone also rapidly reduces the steady state levels of c-myc in the BPV-transformed cells but has less effect on c-myc expression in the ras-transformed cells. These results demonstrate that the growth-promoting actions of the papillomavirus transforming genes, but not those of several retroviral oncogenes, may be overcome by dexamethasone, which appears to act by down-regulation of c-myc expression.
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