Alfavirusna kimerična cjepiva protiv alfavirusnih uzročnika encefalitisa

Encephalitic viruses in the Family Togaviridae, genus Alphavirus are zoonotic pathogens that are transmitted via hematophagous arthropods and have a widespread distribution in North, Central and South America and include Venezuelan equine encephalitis virus (VEEV), Western equine encephalitis virus (WEEV), Eastern equine encephalitis virus (EEEV). The deficit in specific antiviral drugs or vaccines for effective treatment or prevention of infection and disease in humans has prompted the development of recombinant live attenuated vaccines utilizing Sindbis virus (SIN), a relatively nonpathogenic alphavirus in humans, as a means for expression all of the structural proteins of the virulent alphaviruses. The safety and efficacy of these chimeric SIN/VEE viruses have been extensively evaluated in animal models, including immunodeficient mice. The epidemiological distribution of these viruses and the disease manifestations are reviewed briefly. Progress in the evaluation of the safety, immunogenicity and efficacy of the SIN/VEEV and SIN/EEEV candidate vaccines against VEEV and EEEV, respectively, as well as chimeric SIN/RVFV vaccine candidates and the potential for elucidation of the mechanism of efficacy employing mice with selective immunodeficiencies is discussed.Virusi encefalitisa iz porodice Togaviridae, roda Alphavirus su zoonozni uzročnicikoje prenose hematofagni člankonošci rasprostranjeni u Sjevernoj, Centralnoj i Južnoj Americi te uključuju virus venezuelskog konjskog encefalitisa (engl. Venezuelan equine encephalitis virus, VEEV), virus zapadnog konjskog encefalitisa (engl. Western equine encephalitis virus, WEEV) i virus istočnog konjskog encefalitisa (engl. Eastern equine encephalitis virus, EEEV). Manjak specifičnih antivirusnih lijekova ili cjepiva za učinkovito liječenje ili sprječavanje infekcija i bolesti u ljudi potaklo je razvoj rekombiniranih živih atenuiranih cjepiva koja sadrže Sindbis virus (SIN), relativno bezopasan alfavirus za ljude, kao ekspresijski vektor svih strukturalnih proteina virulentnih alfavirusa. Sigurnost i učinkovitost ovih kimeričnih SIN/VEE virusa opsežno je proučavana na životinjskim modelima, uključujući imunodeficijentne miševe. Epidemiološka rasprostranjenost ovih virusa i manifestacije bolesti ukratko su opisane. Raspravlja se o postignutom napretku u ocjenjivanju sigurnosti, imunogeničnosti i učinkovitosti SIN/VEEV i SIN/EEEV potencijalnih cjepiva protiv VEEV odnosno EEEV, kao i potencijalnih kimeričnih SIN/RVFV cjepiva te moguće razjašnjenje mehanizma djelotvornosti koristeći miševe selektivne imunodeficijentnosti

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ABSTRACT. Objective. Macrophage activation syndrome (MAS) is a well described, but purportedly uncommon manifestation of systemic juvenile idiopathic arthritis (SJIA). There is evidence to suggest that macrophage activation is integral to the pathogenesis of SJIA. Accordingly, many patients with SJIA may have evidence of mild MAS that is not appreciated clinically. We investigated the prevalence of occult MAS in children with SJIA by reviewing bone marrow aspirates (BMA). Methods. Patients diagnosed with SJIA who underwent bone marrow aspiration were identified retrospectively. Patients admitted with a diagnosis of fever of unknown origin and discharged with a diagnosis other than SJIA or malignancy, and who had a BMA, were identified as controls. The BMA were reviewed by a single hematopathologist for evidence of MAS, ranging from activated macrophages to frank hemophagocytic cells. Results. Eight of 15 (53%) patients with SJIA had BMA suggestive of MAS. Two of 15 patients (13%) were diagnosed clinically with MAS. Three patients (20%) were noted to have frank hemophagocytosis, only one of whom was diagnosed with MAS clinically. There were no statistically significant differences in the laboratory values for the patients with and without evidence of MAS on BMA. There was no evidence of increased macrophage activity or hemophagocytosis in any of the control BMA. Conclusion. Occult MAS appears to be common in patients with SJIA who undergo BMA. This suggests that macrophage activation may be integral to the pathogenesis of SJIA, with implications for treatment. (First Releas

Rhabdomyosarcoma and Wilms Tumors Contain a Subpopulation of Noggin Producing, Myogenic Cells Immunoreactive for Lens Beaded Filament Proteins

Myo/Nog cells are identified by their expression of the skeletal muscle specific transcription factor MyoD and the bone morphogenetic protein inhibitor noggin, and binding of the G8 monoclonal antibody. Their release of noggin is critical for morphogenesis and skeletal myogenesis. In the adult, Myo/Nog cells are present in normal tissues, wounds and skin tumors. Myo/Nog cells in the lens give rise to myofibroblasts that synthesize skeletal muscle proteins. The purpose of this study was to screen human lens tissue, rhabdomyosarcoma cell lines, and tissue sections from rhabdomyosarcoma, Wilms and tumors lacking features of skeletal muscle for co-localization of antibodies to Myo/Nog cell markers and the lens beaded filament proteins filensin and CP49. Immunofluorescence localization experiments revealed that Myo/Nog cells of the lens bind antibodies to beaded filament proteins. Co-localization of antibodies to G8, noggin, filensin and CP49 was observed in most RC13 and a subpopulation of RD human rhabdomyosarcoma cell lines. Western blotting with beaded filament antibodies revealed bands of similar molecular weights in RC13 and murine lens cells. Human alveolar, embryonal, pleomorphic and spindle cell rhabdomyosarcomas and Wilms tumors contained a subpopulation of cells immunoreactive for G8, noggin, MyoD and beaded filaments. G8 was also co-localized with filensin mRNA. Staining for beaded filament proteins was not detected in G8 positive cells in leiomyosarcomas, squamous and basal cell carcinomas, syringocarciomas and malignant melanomas. Lens beaded filament proteins were thought to be present only in the lens. Myo/Nog-like cells immunoreactive for beaded filaments may be diagnostic of tumors related to the skeletal muscle lineage

The Role of Stably Committed and Uncommitted Cells in Establishing Tissues of the Somite

Somites are blocks of embryonic mesoderm tissue that give rise to skeletal muscle, cartilage, and other connective tissues. The development of different tissues within the somite is influenced by adjacent structures, in particular, the neural tube and notochord. Results of experiments performed in vivo and in vitro suggest that somites contain populations of cells stably programmed to undergo either skeletal myogenesis or chondrogenesis and a population uncommitted to either pathway. The fate of the uncommitted cells would depend on a transfer of information from the committed cells. Communication between committed and uncommitted cells is regulated by cell and tissue interactions that either activate or inhibit this process

ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice

Cytokine storm syndromes, such as familial hemophagocytic lymphohistiocytosis (FHL), are lethal disorders caused by uncontrolled, systemic immune activation. In the murine model of FHL, in which perforin-deficient (Prf1(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV), disease is driven by overabundant interferon (IFN)γ-producing LCMV-specific CD8(+) T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However, this paradigm is insufficient to explain several fundamental aspects of FHL, namely, the inability of many pathogenic antigens to induce hyperinflammation, and the previously identified role of MyD88 in the disease. We now show a novel role for the MyD88-dependent interleukin-33 (IL-33) receptor, ST2, in FHL. Expression of IL-33 and ST2 is upregulated in LCMV-infected Prf1(-/-) mice. Blockade of ST2 markedly improves survival of LCMV-infected Prf1(-/-) mice and reduces the severity of multiple disease parameters, including serum levels of IFNγ. This decrease in IFNγ corresponds to a reduction in both the frequency of IFNγ(+) LCMV-specific CD8(+) and CD4(+) T cells and the magnitude of IFNγ expression in these cells. These findings demonstrate that disruption of ST2 signaling in the murine model of FHL reduces T cell-mediated production of IFNγ and suggest a revised paradigm in which danger signals such as IL-33 are crucial amplifiers of immune dysregulation in FHL. Furthermore, this study provides evidence to support blockade of ST2 as a novel therapeutic strategy for FHL