Vehicle Systems Panel deliberations

The Vehicle Systems Panel addressed materials and structures technology issues related to launch and space vehicle systems not directly associated with the propulsion or entry systems. The Vehicle Systems Panel was comprised of two subpanels - Expendable Launch Vehicles & Cryotanks (ELVC) and Reusable Vehicles (RV). Tom Bales, LaRC, and Tom Modlin, JSC, chaired the expendable and reusable vehicles subpanels, respectively, and co-chaired the Vehicle Systems Panel. The following four papers are discussed in this section: (1) Net Section components for Weldalite Cryogenic Tanks, by Don Bolstad; (2) Build-up Structures for Cryogenic Tanks and Dry Bay Structural Applications, by Barry Lisagor; (3) Composite Materials Program, by Robert Van Siclen; (4) Shuttle Technology (and M&S Lessons Learned), by Stan Greenberg

Vehicle systems

Perspectives of the subpanel on expendable launch vehicle structures and cryotanks are: (1) new materials which provide the primary weight savings effect on vehicle mass/size; (2) today's investment; (3) typically 10-20 years to mature and fully characterize new materials

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy.

Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease

Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

Submitted by Sandra Infurna ([email protected]) on 2017-02-21T11:07:45Z No. of bitstreams: 1 euzenir_sarno_etal_IOC_2016.pdf: 1438335 bytes, checksum: aa97b092804532f27f2c242364567135 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2017-02-21T11:30:39Z (GMT) No. of bitstreams: 1 euzenir_sarno_etal_IOC_2016.pdf: 1438335 bytes, checksum: aa97b092804532f27f2c242364567135 (MD5)Made available in DSpace on 2017-02-21T11:30:39Z (GMT). No. of bitstreams: 1 euzenir_sarno_etal_IOC_2016.pdf: 1438335 bytes, checksum: aa97b092804532f27f2c242364567135 (MD5) Previous issue date: 2016David Geffen School of Medicine at UCLA. Department of Molecular. Cell, and Developmental Biology. California, USA.David Geffen School of Medicine at UCLA. Division of Dermatology. California, USA.David Geffen School of Medicine at UCLA. Division of Dermatology. California, USA.David Geffen School of Medicine at UCLA. Division of Dermatology. California, USA.David Geffen School of Medicine at UCLA. Division of Dermatology. California, USA.David Geffen School of Medicine at UCLA. Department of Molecular. Cell, and Developmental Biology. California, USA.David Geffen School of Medicine at UCLA. Department of Molecular. Cell, and Developmental Biology. California, USA.University College London. Division of Infection and Immunity. London, United Kingdom.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.University of Southern California School of Medicine. Department of Dermatology. Los Angeles, CA, USA.University of Southern California School of Medicine. Department of Dermatology. Los Angeles, CA, USA.David Geffen School of Medicine at UCLA. Department of Molecular. Cell, and Developmental Biology. California, USA.University of Michigan School of Medicine. Department of Dermatology. Ann Arbor, Michigan, USA.Leiden University Medical Center. Department of Infectious Diseases. Leiden, Netherlands.Leiden University Medical Center. Department of Infectious Diseases. Leiden, Netherlands.Harvard School of Public Health. Boston, Massachusetts, USA.David Geffen School of Medicine at UCLA. Department of Molecular. Cell, and Developmental Biology. California, USA.David Geffen School of Medicine at UCLA. Division of Dermatology. California, USA / UCLA. Department of Microbiology, Immunology and Molecular Genetics. Los Angeles, California, USATranscriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease

T-Cell Regulation in Lepromatous Leprosy

Regulatory T (T(reg)) cells are known for their role in maintaining self-tolerance and balancing immune reactions in autoimmune diseases and chronic infections. However, regulatory mechanisms can also lead to prolonged survival of pathogens in chronic infections like leprosy and tuberculosis (TB). Despite high humoral responses against Mycobacterium leprae (M. leprae), lepromatous leprosy (LL) patients have the characteristic inability to generate T helper 1 (Th1) responses against the bacterium. In this study, we investigated the unresponsiveness to M. leprae in peripheral blood mononuclear cells (PBMC) of LL patients by analysis of IFN-γ responses to M. leprae before and after depletion of CD25(+) cells, by cell subsets analysis of PBMC and by immunohistochemistry of patients' skin lesions. Depletion of CD25(+) cells from total PBMC identified two groups of LL patients: 7/18 (38.8%) gained in vitro responsiveness towards M. leprae after depletion of CD25(+) cells, which was reversed to M. leprae-specific T-cell unresponsiveness by addition of autologous CD25(+) cells. In contrast, 11/18 (61.1%) remained anergic in the absence of CD25(+) T-cells. For both groups mitogen-induced IFN-γ was, however, not affected by depletion of CD25(+) cells. In M. leprae responding healthy controls, treated lepromatous leprosy (LL) and borderline tuberculoid leprosy (BT) patients, depletion of CD25(+) cells only slightly increased the IFN-γ response. Furthermore, cell subset analysis showed significantly higher (p = 0.02) numbers of FoxP3(+) CD8(+)CD25(+) T-cells in LL compared to BT patients, whereas confocal microscopy of skin biopsies revealed increased numbers of CD68(+)CD163(+) as well as FoxP3(+) cells in lesions of LL compared to tuberculoid and borderline tuberculoid leprosy (TT/BT) lesions. Thus, these data show that CD25(+) T(reg) cells play a role in M. leprae-Th1 unresponsiveness in LL

CD8⁺ Regulatory T Cells, and Not CD4⁺ T Cells, Dominate Suppressive Phenotype and Function after <i>In Vitro</i> Live <i>Mycobacterium bovis-</i>BCG Activation of Human Cells

<div><p><i>Mycobacterium bovis</i> bacillus Calmette-Guérin (<i>M. bovis</i> BCG), the only currently available vaccine against tuberculosis, has been reported to induce regulatory T cells in humans. The activity of regulatory T cells may not only dampen immunogenicity and protective efficacy of tuberculosis-vaccines, but also hamper diagnosis of infection of tuberculosis, when using immune (e.g. IFNγ-release) assays. Still, in settings of infectious diseases and vaccination, most studies have focused on CD4⁺ regulatory T cells, and not CD8⁺ regulatory T-cells. Here, we present a comparative analysis of the suppressive phenotype and function of CD4⁺ versus CD8⁺ T cells after <i>in vitro</i> live BCG activation of human cells. Moreover, as BCG is administered as a (partly) live vaccine, we also compared the ability of live versus heatkilled BCG in activating CD4⁺ and CD8⁺ regulatory T cell responses. BCG-activated CD8⁺ T cells consistently expressed higher levels of regulatory T cell markers, and after live BCG activation, density and (co-)expression of markers were significantly higher, compared to CD4⁺ T cells. Furthermore, selection on CD25-expression after live BCG activation enriched for CD8⁺ T cells, and selection on co-expression of markers further increased CD8⁺ enrichment. Ultimately, only T cells activated by live BCG were functionally suppressive and this suppressive activity resided predominantly in the CD8⁺ T cell compartment. These data highlight the important contribution of live BCG-activated CD8⁺ Treg cells to immune regulation and emphasize their possible negative impact on immunity and protection against tuberculosis, following BCG vaccination.</p></div

Longitudinal immune profiles in type 1 leprosy reactions in Bangladesh, Brazil, Ethiopia and Nepal

Immunogenetics and cellular immunology of bacterial infectious disease