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  • 1
    Online Resource
    Online Resource
    Genetic immunization in the lung induces potent local and systemic immune responses
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 51 ( 2010-12-21), p. 22213-22218
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 51 ( 2010-12-21), p. 22213-22218
    Abstract: Successful vaccination against respiratory infections requires elicitation of high levels of potent and durable humoral and cellular responses in the lower airways. To accomplish this goal, we used a fine aerosol that targets the entire lung surface through normal respiration to deliver replication-incompetent recombinant adenoviral vectors expressing gene products from several infectious pathogens. We show that this regimen induced remarkably high and stable lung T-cell responses in nonhuman primates and that it also generated systemic and respiratory tract humoral responses of both IgA and IgG isotypes. Moreover, strong immunogenicity was achieved even in animals with preexisting antiadenoviral immunity, overcoming a critical hurdle to the use of these vectors in humans, who commonly are immune to adenoviruses. The immunogenicity profile elicited with this regimen, which is distinct from either intramuscular or intranasal delivery, has highly desirable properties for protection against respiratory pathogens. We show that it can be used repeatedly to generate mucosal humoral, CD4, and CD8 T-cell responses and as such may be applicable to other mucosally transmitted pathogens such as HIV. Indeed, in a lethal challenge model, we show that aerosolized recombinant adenoviral immunization completely protects ferrets against H5N1 highly pathogenic avian influenza virus. Thus, genetic immunization in the lung offers a powerful platform approach to generating protective immune responses against respiratory pathogens.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1015536108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 2
    Online Resource
    Online Resource
    Profound functional and signaling changes in viable inflammatory neutrophils homing to cystic fibrosis airways
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 11 ( 2008-03-18), p. 4335-4339
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 11 ( 2008-03-18), p. 4335-4339
    Abstract: Blood neutrophils recruited to cystic fibrosis (CF) airways are believed to be rapidly killed by resident bacteria and to passively release elastase and other toxic by-products that promote disease progression. By single-cell analysis, we demonstrate that profound functional and signaling changes readily occur within viable neutrophils recruited to CF airways, compared with their blood counterparts. Airway neutrophils have undergone conventional activation, as shown by decreased intracellular glutathione, increased lipid raft assembly, surface mobilization of CD11b+ and CD66b+ granules, and increased levels of the cytoskeleton-associated phospho-Syk kinase. Unexpectedly, they also mobilize to the surface CD63+ elastase-rich granules, usually confined intracellularly, and lose surface expression of CD16 and CD14, both key receptors in phagocytosis. Furthermore, they express CD80, major histocompatibility complex type II, and the prostaglandin D2 receptor CD294, all normally associated with other lineages, which reflects functional reprogramming. This notion is reinforced by their decreased total phosphotyrosine levels, mirroring a postactivated stage, and increased levels of the phospho-S6 ribosomal protein, a key anabolic switch. Thus, we identified a subset of neutrophils within CF airways with a viable but dysfunctional phenotype. This subset provides a possible therapeutic target and indicates a need to revisit current paradigms of CF airway disease.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0712386105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 3
    Online Resource
    Online Resource
    Two physically, functionally, and developmentally distinct peritoneal macrophage subsets
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 6 ( 2010-02-09), p. 2568-2573
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 6 ( 2010-02-09), p. 2568-2573
    Abstract: The peritoneal cavity (PerC) is a unique compartment within which a variety of immune cells reside, and from which macrophages (MØ) are commonly drawn for functional studies. Here we define two MØ subsets that coexist in PerC in adult mice. One, provisionally called the large peritoneal MØ (LPM), contains approximately 90% of the PerC MØ in unstimulated animals but disappears rapidly from PerC following lipopolysaccharide (LPS) or thioglycolate stimulation. These cells express high levels of the canonical MØ surface markers, CD11b and F4/80. The second subset, referred to as small peritoneal MØ (SPM), expresses substantially lower levels of CD11b and F4/80 but expresses high levels of MHC-II, which is not expressed on LPM. SPM, which predominates in PerC after LPS or thioglycolate stimulation, does not derive from LPM. Instead, it derives from blood monocytes that rapidly enter the PerC after stimulation and differentiate to mature SPM within 2 to 4 d. Both subsets show clear phagocytic activity and both produce nitric oxide (NO) in response to LPS stimulation in vivo. However, their responses to LPS show key differences: in vitro, LPS stimulates LPM, but not SPM, to produce NO; in vivo, LPS stimulates both subsets to produce NO, albeit with different response patterns. These findings extend current models of MØ heterogeneity and shed new light on PerC MØ diversity, development, and function. Thus, they introduce a new context for interpreting (and reinterpreting) data from ex vivo studies with PerC MØ.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0915000107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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    detail.hit.zdb_id: 1461794-8
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  • 4
    Online Resource
    Online Resource
    Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 10 ( 2009-03-10), p. 3941-3945
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 10 ( 2009-03-10), p. 3941-3945
    Abstract: Disorders affecting mitochondria, including those that directly affect the respiratory chain function or result from abnormalities in branched amino acid metabolism (organic acidemias), have been shown to be associated with impaired redox balance. Almost all of the evidence underlying this conclusion has been obtained from studies on patient biopsies or animal models. Since the glutathione (iGSH) system provides the main protection against oxidative damage, we hypothesized that untreated oxidative stress in individuals with mitochondrial dysfunction would result in chronic iGSH deficiency. We confirm this hypothesis here in studies using high-dimensional flow cytometry (Hi-D FACS) and biochemical analysis of freshly obtained blood samples from patients with mitochondrial disorders or organic acidemias. T lymphocyte subsets, monocytes and neutrophils from organic acidemia and mitochondrial patients who were not on antioxidant supplements showed low iGSH levels, whereas similar subjects on antioxidant supplements showed normal iGSH. Measures of iROS levels in blood were insufficient to reveal the chronic oxidative stress in untreated patients. Patients with organic acidemias showed elevated plasma protein carbonyls, while plasma samples from all patients tested showed hypocitrullinemia. These findings indicate that measurements of iGSH in leukocytes may be a particularly useful biomarker to detect redox imbalance in mitochondrial disorders and organic acidemias, thus providing a relatively non-invasive means to monitor disease status and response to therapies. Furthermore, studies here suggest that antioxidant therapy may be useful for relieving the chronic oxidative stress that otherwise occurs in patients with mitochondrial dysfunction.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0813409106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
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    detail.hit.zdb_id: 1461794-8
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  • 5
    Online Resource
    Online Resource
    Phenotypically distinct B cell development pathways map to the three B cell lineages in the mouse
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 16 ( 2006-04-18), p. 6293-6298
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 16 ( 2006-04-18), p. 6293-6298
    Abstract: A recent article by Montecino-Rodriguez et al. [Montecino-Rodriguez, E., Leathers, H. & Dorshkind, K. (2006) Nat. Immunol. 7, 293–301] has distinguished the early progenitors for B-1 cells, which principally develop in neonates, from early progenitors for B-2 cells, which principally develop in adult bone marrow. Here we introduce syndecan-1 (CD138) and MHC class II (I-A) as markers of early B cell development [Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D. & Hayakawa, K. (1991) J. Exp. Med. 173, 1213–1225; Hardy fractions B – D ] and show that the expression of these markers distinguishes the predominant B cell development pathway in neonates from the corresponding predominant pathway in adults (both progenitors are present but differently represented in each case). We show that pre-B cells (Hardy fraction D ) in the predominant adult pathway express high levels of CD138 and intermediate levels of I-A, whereas the corresponding pre-B cells in the pathway that predominates in neonates do not express either of these markers. As expected, because most of the pre-B cells in adults express CD138, we find that sorted CD138 + adult pre-B cells differentiate to IgM + B cells in vitro . Sorted CD138 − pre-B cells from neonates, the majority subset at this age, also mature to IgM + cells (without passing through a CD138 + stage). Importantly, our studies here confirm the differential representation of adult and neonatal progenitor populations and further demonstrate that CD138 expression subdivides the adult CD19 + , B220–6B2 −/low population shown to contain B-1 progenitors in a way consistent with the predominance of B-1b progenitors in adults. Thus, CD138 expression provides a key route to distinguishing early B cell development pathway for what now are clearly three B cell lineages.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0511305103
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
    detail.hit.zdb_id: 209104-5
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  • 6
    Online Resource
    Online Resource
    CD4 + T cells derived from B cell-deficient mice inhibit the establishment of peripheral B cell pools
    Proceedings of the National Academy of Sciences ; 2000
    In:  Proceedings of the National Academy of Sciences Vol. 97, No. 9 ( 2000-04-25), p. 4766-4771
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 9 ( 2000-04-25), p. 4766-4771
    Abstract: We demonstrate that adoptive transfer of peritoneal cavity B cells fails to replenish the peripheral B-1 cells in adult B cell-deficient (μ −/− ) mice but does replenish adult RAG-1 −/− mice. We show that this lack of self-replenishment in μ −/− mice is mediated by strongly inhibitory, radiation-sensitive CD4 + T cells that also function in cotransfer studies to block the reconstitution of B-1 cells and inhibit accumulation of bone marrow-derived B-2 cells in the periphery in irradiated recipients. CD8 + T cells from μ −/− do not mediate this inhibition. The inhibitory CD4 + T cells develop early in life, because B-1 cell replenishment occurs normally when B-1 cells are transferred into μ −/− neonates. Thus, we conclude that the presence of B cells in the neonate conditions the CD4 + T-cell population to permit the establishment and maintenance of normal B cell pools throughout life.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.97.9.4766
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2000
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  • 7
    Online Resource
    Online Resource
    Antigen-specific antibody responses in B-1a and their relationship to natural immunity
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 14 ( 2012-04-03), p. 5382-5387
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 14 ( 2012-04-03), p. 5382-5387
    Abstract: B-1a cells are primarily thought of as natural antibody-producing cells. However, we now show that appropriate antigenic stimulation induces IgM and IgG B-1a antibody responses and long-lived T-independent antigen-specific B-1a memory that differs markedly from canonical B-2 humoral immunity. Thus, we show here that in the absence of inflammation, priming with glycolipid (FtL) from Francisella tularensis live vaccine strain induces splenic FtL-specific B-1a to mount dominant IgM and activation-induced cytidine deaminase-dependent IgG anti-FtL responses that occur within 3–5 d of FtL priming and fade within 1 wk to natural antibody levels that persist indefinitely in the absence of secondary FtL immunization. Equally surprising, FtL priming elicits long-term FtL-specific B-1a memory cells (IgM 〉 〉 IgG) that migrate rapidly to the peritoneal cavity and persist there indefinitely, ready to respond to appropriately administrated secondary antigenic stimulation. Unlike B-2 responses, primary FtL-specific B-1a responses and establishment of persistent FtL-specific B-1a memory occur readily in the absence of adjuvants, IL-7, T cells, or germinal center support. However, in another marked departure from the mechanisms controlling B-2 memory responses, rechallenge with FtL in an inflammatory context is required to induce B-1a secondary antibody responses. These findings introduce previously unexplored vaccination strategies for pathogens that target the B-1a repertoire.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1121631109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
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    detail.hit.zdb_id: 1461794-8
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  • 8
    Online Resource
    Online Resource
    Culturing of human peripheral blood cells reveals unsuspected lymphocyte responses relevant to HIV disease
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 13 ( 2008-04), p. 5111-5116
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 13 ( 2008-04), p. 5111-5116
    Abstract: Recombinant HIV-Tat (Tat) induces extensive apoptosis in peripheral blood mononuclear cells (PBMCs) cultured in typical CO 2 incubators, which are equilibrated with air (21% O 2 ). However, as we show here, Tat apoptosis induction fails in PBMCs cultured at physiological oxygen levels (5% O 2 ). Under these conditions, Tat induces PBMCs to divide, efficiently primes them for HIV infection, and supports virus production by the infected cells. Furthermore, Tat takes only 2 h to prime PBMCs under these conditions. In contrast, PHA/IL-2, which is widely used to prime cells for HIV infection, takes 2–3 days. These findings strongly recommend culturing primary cells at physiological oxygen levels. In addition, they suggest HIV-Tat as a key regulator of HIV disease progression.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0712363105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
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  • 9
    Online Resource
    Online Resource
    Importance of culturing primary lymphocytes at physiological oxygen levels
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 11 ( 2007-03-13), p. 4547-4552
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 11 ( 2007-03-13), p. 4547-4552
    Abstract: Although studies with primary lymphocytes are almost always conducted in CO 2 incubators maintained at atmospheric oxygen levels (atmosO 2 ; 20%), the physiological oxygen levels (physO 2 ; 5%) that cells encounter in vivo are 2–4 times lower. We show here that culturing primary T cells at atmosO 2 significantly alters the intracellular redox state (decreases intracellular glutathione, increases oxidized intracellular glutathione), whereas culturing at physO 2 maintains the intracellular redox environment (intracellular glutathione/oxidized intracellular glutathione) close to its in vivo status. Furthermore, we show that CD3/CD28-induced T cell proliferation (based on proliferation index and cell yield) is higher at atmosO 2 than at physO 2 . This apparently paradoxical finding, we suggest, may be explained by two additional findings with CD3/CD28-stimulated T cells: ( i ) the intracellular NO (iNO) levels are higher at physO 2 than at atmosO 2 ; and ( ii ) the peak expression of CD69 is significantly delayed and more sustained at physO 2 that at atmosO 2 . Because high levels of intracellular NO and sustained CD69 tend to down-regulate T cell responses in vivo , the lower proliferative T cell responses at physO 2 likely reflect the in vitro operation of the natural in vivo regulatory mechanisms. Thus, we suggest caution in culturing primary lymphocytes at atmosO 2 because the requisite adaptation to nonphysiological oxygen levels may seriously skew T cell responses, particularly after several days in culture.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0611732104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
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  • 10
    Online Resource
    Online Resource
    Fluorescence-Activated Cell Sorting
    Springer Science and Business Media LLC ; 1976
    In:  Scientific American Vol. 234, No. 3 ( 1976-3), p. 108-117
    Details
    In: Scientific American, Springer Science and Business Media LLC, Vol. 234, No. 3 ( 1976-3), p. 108-117
    Type of Medium: Online Resource
    ISSN: 0036-8733
    URL: Article
    DOI: 10.1038/scientificamerican0376-108
    RVK:
    TA 1000
    RVK:
    WA 15000
    RVK:
    TA 7375
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1976
    detail.hit.zdb_id: 246-X
    detail.hit.zdb_id: 1413371-4
    SSG: 11
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