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Träfflista för sökning "LAR1:gu ;mspu:(researchreview);pers:(Lycke Nils Y 1954)"

Sökning: LAR1:gu > Forskningsöversikt > Lycke Nils Y 1954

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2.
  • Akhiani, Aliasghar, 1957, et al. (författare)
  • Vaccine-induced immunity against Helicobacter pylori infection is impaired in IL-18-deficient mice.
  • 2004
  • Ingår i: Journal of immunology. - 0022-1767. ; 173:5, s. 3348-56
  • Forskningsöversikt (refereegranskat)abstract
    • Protective immunity against Helicobacter pylori infection in mice has been associated with a strong Th1 response, involving IL-12 as well as IFN-gamma, but recent studies have also demonstrated prominent eosinophilic infiltration, possibly linked to local Th2 activity in the gastric mucosa. In this study we investigated the role of IL-18, because this cytokine has been found to be a coregulator of Th1 development as well as involved in Th2-type responses with local eotaxin production that could influence gastric eosinophilia and resistance to infection. We found that IL-18(-/-) mice failed to develop protection after oral immunization with H. pylori lysate and cholera toxin adjuvant, indicating an important role of IL-18 in protection. Well-protected C57BL/6 wild-type (WT) mice demonstrated substantial influx of CD4(+) T cells and eosinophilic cells in the gastric mucosa, whereas IL-18(-/-) mice had less gastritis, few CD4(+) T cells, and significantly reduced numbers of eosinophilic cells. T cells in well-protected WT mice produced increased levels of IFN-gamma and IL-18 to recall Ag. By contrast, unprotected IL-18(-/-) mice exhibited significantly reduced gastric IFN-gamma and specific IgG2a Ab levels. Despite differences in gastric eosinophilic cell infiltration, protected WT and unprotected IL-18(-/-) mice had comparable levels of local eotaxin, suggesting that IL-18 influences protection via Th1 development and IFN-gamma production rather than through promoting local production of eotaxin and eosinophilic cell infiltration.
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3.
  • Eriksson, Anna M, et al. (författare)
  • The cholera toxin-derived CTA1-DD vaccine adjuvant administered intranasally does not cause inflammation or accumulate in the nervous tissues.
  • 2004
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 173:5, s. 3310-9
  • Forskningsöversikt (refereegranskat)abstract
    • Although highly effective, the use of GM1-receptor binding holotoxins as nasal mucosal adjuvants has recently been cautioned due to the risk for their accumulation in the brain and other nervous tissues. Therefore we have explored the efficacy of the CTA1-DD adjuvant for its ability to enhance nasal immune responses in mice. We found that despite the lack of a mucosal binding element, the B cell-targeted CTA1-DD molecule was an equally strong adjuvant as cholera toxin (CT). The potency of CTA1-DD was not a result of endotoxin contamination because more than a 50-fold higher dose of LPS was needed to achieve a similar enhancement. Moreover, the adjuvant effect was TLR4-independent and absent in mutant CTA1-E112K-DD, lacking enzymatic activity. The CTA1-DD adjuvant augmented germinal center formations and T cell priming in the draining lymph nodes, and contrary to CT, promoted a balanced Th1/Th2 response with little effect on IgE Ab production. CTA1-DD did not induce inflammatory changes in the nasal mucosa, and most importantly did not bind to or accumulate in the nervous tissues of the olfactory bulb, whereas CT bound avidly to the nervous tissues. We believe that the nontoxic CTA1-DD adjuvant is an attractive solution to the current dilemma between efficacy and toxicity encountered in CT-holotoxin adjuvant or Escherichia coli heat-labile toxin-holotoxin adjuvant strategies and provides a safe and promising candidate to be included in future vaccines for intranasal administration.
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4.
  • Grdic, Dubravka, 1968, et al. (författare)
  • Splenic marginal zone dendritic cells mediate the cholera toxin adjuvant effect: dependence on the ADP-ribosyltransferase activity of the holotoxin.
  • 2005
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 175:8, s. 5192-202
  • Forskningsöversikt (refereegranskat)abstract
    • The in vivo mechanisms of action of most vaccine adjuvants are poorly understood. In this study, we present data in mice that reveal a series of critical interactions between the cholera toxin (CT) adjuvant and the dendritic cells (DC) of the splenic marginal zone (MZ) that lead to effective priming of an immune response. For the first time, we have followed adjuvant targeting of MZ DC in vivo. We used CT-conjugated OVA and found that the Ag selectively accumulated in MZ DC following i.v. injections. The uptake of Ag into DC was GM1 ganglioside receptor dependent and mediated by the B subunit of CT (CTB). The targeted MZ DC were quite unique in their phenotype: CD11c(+), CD8alpha(-), CD11b(-), B220(-), and expressing intermediate or low levels of MHC class II and DEC205. Whereas CTB only delivered the Ag to MZ DC, the ADP-ribosyltransferase activity of CT was required for the maturation and migration of DC to the T cell zone, where these cells distinctly up-regulated CD86, but not CD80. This interaction appeared to instruct Ag-specific CD4(+) T cells to move into the B cell follicle and strongly support germinal center formations. These events may explain why CT-conjugated Ag is substantially more immunogenic than Ag admixed with soluble CT and why CTB-conjugated Ag can tolerize immune responses when given orally or at other mucosal sites.
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5.
  • Helgeby, Anja, 1967, et al. (författare)
  • The combined CTA1-DD/ISCOM adjuvant vector promotes priming of mucosal and systemic immunity to incorporated antigens by specific targeting of B cells.
  • 2006
  • Ingår i: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 176:6, s. 3697-706
  • Forskningsöversikt (refereegranskat)abstract
    • The cholera toxin A1 (CTA1)-DD/QuilA-containing, immune-stimulating complex (ISCOM) vector is a rationally designed mucosal adjuvant that greatly potentiates humoral and cellular immune responses. It was developed to incorporate the distinctive properties of either adjuvant alone in a combination that exerted additive enhancing effects on mucosal immune responses. In this study we demonstrate that CTA1-DD and an unrelated Ag can be incorporated together into the ISCOM, resulting in greatly augmented immunogenicity of the Ag. To demonstrate its relevance for protection against infectious diseases, we tested the vector incorporating PR8 Ag from the influenza virus. After intranasal immunization we found that the immunogenicity of the PR8 proteins were significantly augmented by a mechanism that was enzyme dependent, because the presence of the enzymatically inactive CTA1R7K-DD mutant largely failed to enhance the response over that seen with ISCOMs alone. The combined vector was a highly effective enhancer of a broad range of immune responses, including specific serum Abs and balanced Th1 and Th2 CD4(+) T cell priming as well as a strong mucosal IgA response. Unlike unmodified ISCOMs, Ag incorporated into the combined vector could be presented by B cells in vitro and in vivo as well as by dendritic cells; it also accumulated in B cell follicles of draining lymph nodes when given s.c. and stimulated much enhanced germinal center reactions. Strikingly, the enhanced adjuvant activity of the combined vector was absent in B cell-deficient mice, supporting the idea that B cells are important for the adjuvant effects of the combined CTA1-DD/ISCOM vector.
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6.
  • Lycke, Nils Y, 1954 (författare)
  • From toxin to adjuvant: basic mechanisms for the control of mucosal IgA immunity and tolerance.
  • 2005
  • Ingår i: Immunology letters. - : Elsevier BV. - 0165-2478. ; 97:2, s. 193-8
  • Forskningsöversikt (refereegranskat)abstract
    • We provide compelling evidence that delivery of Ag in the absence of ADP-ribosylation can promote tolerance, whereas ADP-ribosyltransferase activity induces IgA immunity and prevents tolerance. By linking Ag to the ADP-ribosylating enzyme, cholera toxin subunit A1 (CTA1), we could show that the combination of targeting to antigen-presenting cells (APC) and enzymatic activity is a highly effective means of controlling the induction of tolerance or immunity. Firstly, we demonstrated that cholera toxin (CT), although potentially binding to all nucleated cells, in fact, bound preferentially to dendritic cells (DC) in vivo. Following injection of CT-conjugated Ag, we found that DC in the marginal zone (MZ) of the spleen accumulated Ag, a process that was GM1-ganglioside receptor dependent. Contrary to CTB, which also delivered Ag to the MZ DC, CT matured and activated co-stimulatory functions in the targeted DC and greatly augmented immune responses to Ag. Secondly, when Ag was incorporated into the CTA1-DD fusion protein, which equals the CT in adjuvant function but lacks GM1-ganglioside-binding ability, we greatly augmented specific responses to Ag. The DD-bound Ag was distinctly targeted to B cells and probably also to follicular dendritic cells (FDC) in vivo. Thus, in both constructs Ag was targeted to APC and associated with an ADP-ribosylating enzyme, which resulted in greatly enhanced immunogenicity. When the enzymatic activity was absent, as in CT B-subunit (CTB) or in the inactive CTA1R7K-DD mutant, Ag largely failed to stimulate an active immune response. Rather, this type of Ag exposure resulted in Ag-specific tolerance, especially when mucosal delivery of Ag was attempted. Therefore, targeting to APC in the absence or presence of the CTA1-enzyme appears to be an effective means to control tolerance and active protective IgA immunity.
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7.
  • Lycke, Nils Y, 1954 (författare)
  • From toxin to adjuvant: the rational design of a vaccine adjuvant vector, CTA1-DD/ISCOM.
  • 2004
  • Ingår i: Cellular microbiology. - : Hindawi Limited. - 1462-5814 .- 1462-5822. ; 6:1, s. 23-32
  • Forskningsöversikt (refereegranskat)abstract
    • Mucosally active vaccine adjuvants which will prime a full range of local and systemic immune responses against defined antigenic epitopes are much needed. Cholera toxin (CT) and lipophilic immune stimulating complexes (ISCOMs) containing Quil A can both act as adjuvants for orally administered antigens, but through separate pathways, as evidenced by the dependence on IL-12 for the effect of ISCOMs, whereas CT is independent of this cytokine. Unfortunately the toxicity of CT and recent findings of accumulation of CT in the olfactory nerve and bulb after intranasal administration precludes the clinical use of CT. However, we have been successful in separating the adjuvant and toxic effects of CT, by constructing a gene fusion protein, CTA1-DD, that combines the enzymatically active CTA1-subunit with a B cell targeting moiety, D, derived from Staphylococcus aureus protein A. The present review gives a background to mucosal immunization and the use of -adjuvants in general, followed by a description of a strategy to rationally design a vaccine adjuvant vector that fulfils the criteria of targeting and immunomodulating innate immunity in order to boost a strong adaptive immune response. We have combined CTA1-DD and ISCOMs into a new highly promising vaccine adjuvant vector, CTA1-DD/ISCOMs. The combined vector is immunogenic when given by the subcutaneous, oral or nasal routes, inducing strong cell--mediated and humoral immune responses, including local mucosal IgA. It requires the ADP ribosylating property of the CTA1-enzyme and the effect of the combined vector greatly exceeded the effect of either ISCOMs or CT used alone. Antigens could be incorporated into or just admixed with the new vector. Thus, we have demonstrated that rationally designed vectors consisting of CTA1-DD and ISCOMS may provide a novel strategy for the generation of potent and safe mucosal vaccines.
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10.
  • Lycke, Nils Y, 1954 (författare)
  • Mucosal Lymphoid Tissues
  • 2004
  • Ingår i: Encyclopedia of Life Sciences. - : Wiley.
  • Forskningsöversikt (refereegranskat)abstract
    • The mucosal membranes host the largest component of the immune system and most of our lymphocytes are found there. These tissues are important for host defence against invasive microorganisms and also function as barriers that allow nutrients to be taken up while preventing unwanted substances from entering further into the body.
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