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51.
Miller JD Clabaugh SE Smith DR Stevens RB Wrenshall LE 《Immunology and cell biology》2012,90(2):159-167
Interleukin-2 (IL-2) is a multifaceted cytokine with immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2-dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2-deficient mice were normal. The aortas of IL-2-deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems. 相似文献
52.
Lucile Garidou Sara Heydari Phi Truong David G. Brooks Dorian B. McGavern 《Journal of virology》2009,83(17):8905-8915
Persistent viral infections are a major health concern worldwide. During persistent infection, overwhelming viral replication and the rapid loss of antiviral T-cell function can prevent immune-mediated clearance of the infection, and therapies to reanimate the immune response and purge persistent viruses have been largely unsuccessful. Adoptive immunotherapy using memory T cells is a highly successful therapeutic approach to eradicate a persistent viral infection. Understanding precisely how therapeutically administered memory T cells achieve clearance should improve our ability to terminate states of viral persistence in humans. Mice persistently infected from birth with lymphocytic choriomeningitis virus are tolerant to the pathogen at the T-cell level and thus provide an excellent model to evaluate immunotherapeutic regimens. Previously, we demonstrated that adoptively transferred memory T cells require recipient dendritic cells to effectively purge an established persistent viral infection. However, the mechanisms that reactivate and sustain memory T-cell responses during clearance of such an infection remain unclear. Here we establish that therapeutic memory T cells require CD80 and CD86 costimulatory signals to efficiently clear an established persistent viral infection in vivo. Early blockade of costimulatory pathways with CTLA-4-Fc decreased the secondary expansion of virus-specific CD8+ and CD4+ memory T cells as well as their ability to produce antiviral cytokines and purge the persistent infection. Late costimulation blockade also reduced virus-specific T-cell numbers, illustrating that sustained interactions with costimulatory molecules is required for efficient T-cell expansion. These findings indicate that antiviral memory T cells require costimulation to efficiently clear a persistent viral infection and that costimulatory pathways can be targeted to modulate the magnitude of an adoptive immunotherapeutic regimen.Persistent viruses, such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, cause major health problems worldwide and are extraordinarily difficult to clear following the establishment of persistence. Given the challenges associated with clearing persistent infections, it is important to develop and mechanistically understand therapeutic strategies that successfully achieve viral eradication without inducing permanent damage in the host. Studies using the lymphocytic choriomeningitis virus (LCMV) model system have convincingly demonstrated that a systemic persistent viral infection can be completely purged from a murine host by using a therapeutic approach referred to as adoptive immunotherapy (1, 15, 22, 29, 30). Remarkably, total body control of multiple persistent viral infections in both the mouse (1, 15, 22, 29, 30) and humans (8, 14, 24, 26, 31) can be achieved using adoptive immunotherapy. When mice are persistently infected at birth or in utero with LCMV (referred to as carrier mice), the virus establishes systemic persistence (6). Adult LCMV carrier mice are tolerant to the virus at the T-cell level and thus are unable to eradicate the pathogen (23), which provides an excellent model to study immunotherapeutic regimens. Immunocytotherapy relies on the adoptive transfer of virus-specific memory CD8 and CD4 T cells from LCMV-immune donor mice into recipient carrier mice (1, 15, 22, 29, 30). Following the therapeutic administration of memory cells, LCMV is purged from most peripheral tissues of carrier mice in 14 days, whereas more than 100 days are required to clear virus from the central nervous system (CNS) and kidneys (1, 15, 22). Furthermore, successful viral clearance requires antiviral “memory” but not “effector” T cells (11). Thus, in addition to its proven therapeutic relevance, this model also provides a paradigm to understand factors that regulate memory T cells following secondary exposure to pathogens in vivo.The mechanisms leading to activation of naïve T cells have been well described and involve recognition of major histocompatibility complex (MHC) peptide through the T-cell receptor (TCR) as well as costimulation (e.g., CD80 and CD86 interactions) (4, 25, 27). On the other hand, the factors that govern the activation and secondary expansion of memory CD8+ and CD4+ T cells are less clearly defined, particularly in an in vivo therapeutic setting. When memory T cells reencounter cognate antigen, they respond rapidly by producing cytokines and dividing. Previous studies indicated that there was no role for dendritic cells or costimulation (4, 27) in the reactivation of memory T cells; however, three recent studies have shown that dendritic cells (DCs) stimulate memory T-cell activity upon antigen rechallenge (2, 33) and during adoptive immunotherapy (15). Because MHC class I antigen (MHC-I) is expressed on nearly all cell types but costimulatory molecules are not, these three studies strongly suggested that DCs were influencing memory T cells with costimulatory pathways thought only to be required during priming. Indeed, when the issue was reexamined, it was revealed that memory CD8+ and CD4+ T cells require CD28-CD80/CD86 costimulation to be fully reactivated upon secondary exposure to antigen (3, 7, 21).Because therapeutically administered memory T cells require effective interactions with the host hematopoietic system (10), in particular dendritic cells (15), to achieve successful viral clearance, we set out to address several unanswered questions. First, is costimulation required for the immunotherapeutic clearance of an established persistent viral infection? This is a particularly important question because the requirements imposed on therapeutically administered memory T cells, which encounter immediate and overwhelmingly high levels of virus, heightened antigenic stimulation, and a unique inflammatory milieu, are likely to be different than those faced by endogenous memory T cells following pathogen rechallenge in an otherwise-quiescent environment. The second question we set out to address in this study was whether costimulation blockade could modulate the activities of an immunotherapeutic regimen consisting of memory T cells. This question is of great importance in a clinical setting where pathogen-specific memory T cells can induce severe tissue pathology through the release of effector molecules (12). Thus, it is critical to have a strategy to limit the magnitude of an undesirable response without impeding viral clearance. 相似文献
53.
54.
Effects of Fungal Bioaugmentation and Cyclodextrin Amendment on Fluorene Degradation in Soil Slurry 总被引:2,自引:0,他引:2
This study assesses the potential of fungal bioaugmentation and the effect of maltosyl-cyclodextrin amendment, as an approach to accelerate fluorene biodegradation in soil slurries. 47 fungal strains isolated from a contaminated site were tested in the biodegradation of fluorene. Results showed the greater efficiency of "adaptated" fungi isolated from contaminated soil vs. reference strains belonging to the collection of the laboratory. These assays allowed us to select the most efficient strain, Absidia cylindrospora, which was used in a bioaugmentation process. In the presence of Absidia cylindrospora, more than 90% of the fluorene was removed in 288 h while 576 h were necessary in the absence of fungal bioaugmentation. Maltosyl-cyclodextrin, a branched-cyclodextrin was chosen in order to optimize fluorene bioavailability and biodegradation in soil slurries. The results of this study indicate that Absidia cylindrospora and maltosyl-cyclodextrin could be used successfully in bioremediation systems. 相似文献
55.
Mucin is the main constituent of gastrointestinal mucus and is responsible for its physicochemical and physiological properties. Previous studies have suggested that this glycoprotein represents a major component of undigested endogenous protein at the ileum. The aim of the study was to estimate the ileal output of this glycoprotein using three methods: direct ELISA, hexosamine-based method and ethanol precipitation. For setting up the ELISA assay, the glycoprotein was isolated from intestinal mucus scraping by cesium chloride density gradient ultracentrifugation and a rabbit hyperimmune plasma was raised against the purified glycoprotein. Ileal outputs of hexosamine and glycoprotein were measured in weaned piglets fed a control diet (C) based on casein or diets which contained 50% crude protein supplied by white (WCP) or black (BCP) chickpea. The hexosamine output was higher (P < 0.05) with the WCP diet (2.3 and 1.5 g x kg(-1) of dry matter intake for glucosamine and galactosamine, respectively) than with diet C (1.1 and 0.7 g x kg(-1) of DMI). The hexosamine-based and ethanol precipitation methods, but not the ELISA, showed significant differences between the diet treatments (P < 0.05). Although hexosamine-based and ethanol precipitation methods for the estimation of ileal glycoprotein appeared to be more satisfactory than the developed ELISA to display diet effects in this study, it remains to be determined whether the higher glycoprotein data variability observed with ELISA reflects the actual biological variability of the phenomenon or not. 相似文献
56.
Disruption of focal adhesions by integrin cytoplasmic domain-associated protein-1 alpha 总被引:1,自引:0,他引:1
Bouvard D Vignoud L Dupé-Manet S Abed N Fournier HN Vincent-Monegat C Retta SF Fassler R Block MR 《The Journal of biological chemistry》2003,278(8):6567-6574
Regulation of integrin affinity and clustering plays a key role in the control of cell adhesion and migration. The protein ICAP-1 alpha (integrin cytoplasmic domain-associated protein-1 alpha) binds to the cytoplasmic domain of the beta(1A) integrin and controls cell spreading on fibronectin. Here, we demonstrate that, despite its ability to interact with beta(1A) integrin, ICAP-1 alpha is not recruited in focal adhesions, whereas it is colocalized with the integrin at the ruffling edges of the cells. ICAP-1 alpha induced a rapid disruption of focal adhesions, which may result from the ability of ICAP-1 alpha to inhibit the association of beta(1A) integrin with talin, which is crucial for the assembly of these structures. ICAP-1 alpha-mediated dispersion of beta(1A) integrins is not observed with beta(1D) integrins that do not bind ICAP. This strongly suggests that ICAP-1 alpha action depends on a direct interaction between ICAP-1 alpha and the cytoplasmic domain of the beta(1) chains. Altogether, these results suggest that ICAP-1 alpha plays a key role in cell adhesion by acting as a negative regulator of beta(1) integrin avidity. 相似文献
57.
Lucile Plourde-Owobi Sophie Durner Jean-Luc Parrou Roman Wieczorke Gerard Goma Jean Franois 《Journal of bacteriology》1999,181(12):3830-3832
The trehalose content in Saccharomyces cerevisiae can be significantly manipulated by including trehalose at an appropriate level in the growth medium. Its uptake is largely dependent on the expression of AGT1, which encodes an alpha-glucoside transporter. The trehalose found in a tps1 mutant of trehalose synthase may therefore largely reflect its uptake from the enriched medium that was employed. 相似文献
58.
Thierry Prang Marc Schiltz Lucile Pernot Nathalie Colloc'h Sonia Longhi William Bourguet Roger Fourme 《Proteins》1998,30(1):61-73
X-ray diffraction is used to study the binding of xenon and krypton to a variety of crystallised proteins: porcine pancreatic elastase; subtilisin Carlsberg from Bacillus licheniformis; cutinase from Fusarium solani; collagenase from Hypoderma lineatum; hen egg lysozyme, the lipoamide dehydrogenase domain from the outer membrane protein P64k from Neisseria meningitidis; urate-oxidase from Aspergillus flavus, mosquitocidal δ-endotoxin CytB from Bacillus thuringiensis and the ligand-binding domain of the human nuclear retinoid-X receptor RXR-α. Under gas pressures ranging from 8 to 20 bar, xenon is able to bind to discrete sites in hydrophobic cavities, ligand and substrate binding pockets, and into the pore of channel-like structures. These xenon complexes can be used to map hydrophobic sites in proteins, or as heavy-atom derivatives in the isomorphous replacement method of structure determination. Proteins 30:61–73, 1998. © 1998 Wiley-Liss, Inc. 相似文献
59.
60.
Fran?ois Lahaye Fran?oise Lespinasse Pascal Staccini Lucile Palin Véronique Paquis-Flucklinger Sabine Santucci-Darmanin 《Nucleic acids research》2010,38(11):3655-3671
MSH5 is a MutS-homologous protein required for meiotic DNA recombination. In addition, recent studies suggest that the human MSH5 protein (hMSH5) participates to mitotic recombination and to the cellular response to DNA damage and thus raise the possibility that a tight control of hMSH5 function(s) may be important for genomic stability. With the aim to characterize mechanisms potentially involved in the regulation of hMSH5 activity, we investigated its intracellular trafficking properties. We demonstrate that hMSH5 possesses a CRM1-dependent nuclear export signal (NES) and a nuclear localization signal that participates to its nuclear targeting. Localization analysis of various mutated forms of hMSH5 by confocal microscopy indicates that hMSH5 shuttles between the nucleus and the cytoplasm. We also provide evidence suggesting that hMSH5 stability depends on its subcellular compartmentalization, hMSH5 being much less stable in the nucleus than in the cytoplasm. Together, these data suggest that hMSH5 activity may be regulated by nucleocytoplasmic shuttling and nuclear proteasomal degradation, both of these mechanisms contributing to the control of nuclear hMSH5 content. Moreover, data herein also support that in tissues where both hMSH5 and hMSH4 proteins are expressed, hMSH5 might be retained in the nucleus through masking of its NES by binding of hMSH4. 相似文献