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  • 1
    Online Resource
    Online Resource
    Dendritic cell targeting anti-CD40 antibody-CD40L-HIV-1 vaccines are adjuvant intrinsic
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 167.2-167.2
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 167.2-167.2
    Abstract: Soluble CD40L and agonistic anti-CD40 monoclonal antibody are adjuvants used in vaccination settings. Vaccines based on anti-CD40 antibodies fused to HIV-1 antigens are in clinical development. Studies with current anti-CD40-based dendritic cell (DC) targeting vaccines show that co-administration of an adjuvant is needed for maximal immune responses. We show that by fusing CD40L to CD40-targeting antibodies, activation of DCs concomitant with antigen uptake and processing is maximized, and this provides a context CD40-targeting vaccines with intrinsic adjuvant activity. Direct fusion of CD40L to L or H chain C-termini results in CD40 agonists with ‘superagonist’ properties. Especially on DCs, both potency and efficacy for induction of cytokine secretion and activation markers is greatly enhanced compared to known strong agonists like Pfizer’s anti-CD40 CP-870-89 antibody. This potency was maintained by anti-CD40-CD40L constructs fused to HIV-1 antigens from Gag, Nef, and Pol regions (HIV5pep). Anti-CD40-CD40L-HIV5pep preferentially expanded CD8+ T cells from HIV-1+ donor PBMCs compared to the same antibody-antigen fusions without attached CD40L. Anti-CD40-CD40L-TEα and anti-CD40-TEα both evoked robust proliferation of TEα-specific CD4+ T cells in human CD40 transgenic mice, but only anti-CD40-CD40L-TEα vaccine elicited TEα-specific CD4+ T cells producing IFNγ. Also, anti-CD40-CD40L-Env gp140 vaccine without adjuvant in human CD40 transgenic mice elicited stronger anti-Env gp140 antibody responses than anti-CD40-Env gp140 vaccine. Thus superagonist anti-CD40 antibodies directly fused to the natural ligand show great advantage in inducing immune responses without the use of an extrinsic adjuvant.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.167.2
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Magnetron Sputtering of Au-Based Alloys on NiTi Elements: Surface Investigation for New Products in SMA-Based Fashion and Luxury Accessories and Watchmaking
    MDPI AG ; 2022
    In:  Coatings Vol. 12, No. 2 ( 2022-01-24), p. 136-
    Details
    In: Coatings, MDPI AG, Vol. 12, No. 2 ( 2022-01-24), p. 136-
    Abstract: A novel approach for the deposition of Au-based coatings on NiTi components was proposed to give rise to innovative SMA-based products for the fashion, luxury, and watchmaking fields. Different Au-Cu and Au-Ag-Cu alloys (with confidential compositions within the color designations 2N, 4N, and 5N) were deposited by magnetron sputtering on superelastic and shape-memory NiTi ribbons. After preliminary morphological and microstructural characterizations, the influence of the film deposition on the functional, mechanical, and tribological behavior was deeply investigated. The macroscopic mechanical properties, including the damping, superelastic, and shape recovery characteristics, were not affected since the behavior upon both small and severe deformations was unchanged and the coatings were not damaged. Indeed, both the film adhesion and the precious aspect were maintained. Furthermore, a more detailed surface characterization, through nanoindentation, tribocorrosion, and scratch and wear tests, was performed. This experimental investigation evidenced the ductile behavior of the Au-based films and their good adhesion on NiTi substrates. Moreover, the coatings exhibited a good wear resistance, both in dry conditions and simulated body fluids, which proved to be suitable for fashion and watchmaking fields. Despite slight differences being observed within the films’ responses, all of them could be considered suitable and interesting for the design of smart luxury accessories, proving that the chosen deposition process is sound and reliable for these applications.
    Type of Medium: Online Resource
    ISSN: 2079-6412
    URL: Article
    DOI: 10.3390/coatings12020136
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662314-6
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  • 3
    Online Resource
    Online Resource
    DataSheet_1.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-11-30)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-11-30)
    Abstract: Common approaches for monitoring T cell responses are limited in their multiplexity and sensitivity. In contrast, deep sequencing of the T Cell Receptor (TCR) repertoire provides a global view that is limited only in terms of theoretical sensitivity due to the depth of available sampling; however, the assignment of antigen specificities within TCR repertoires has become a bottleneck. This study combines antigen-driven expansion, deep TCR sequencing, and a novel analysis framework to show that homologous ‘Clusters of Expanded TCRs (CETs)’ can be confidently identified without cell isolation, and assigned to antigen against a background of non-specific clones. We show that clonotypes within each CET respond to the same epitope, and that protein antigens stimulate multiple CETs reactive to constituent peptides. Finally, we demonstrate the personalized assignment of antigen-specificity to rare clones within fully-diverse uncultured repertoires. The method presented here may be used to monitor T cell responses to vaccination and immunotherapy with high fidelity.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.735584
    DOI: 10.3389/fimmu.2021.735584.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 4
    Online Resource
    Online Resource
    HIV Protease Inhibitors Apoptotic Effect in SH-SY5Y Neuronal Cell Line
    S. Karger AG ; 2016
    In:  Cellular Physiology and Biochemistry Vol. 39, No. 4 ( 2016), p. 1463-1470
    Details
    In: Cellular Physiology and Biochemistry, S. Karger AG, Vol. 39, No. 4 ( 2016), p. 1463-1470
    Abstract: Background: Prophylactic treatment regimens to prevent mother-to-child HIV transmission include protease inhibitors Lopinavir and Ritonavir. Lopinavir and Ritonavir have been reported to be able to induce intracellular oxidative stress in diverse cellular models, however scarce informations are available about protease inhibitor effects of in the central nervous system (CNS). In our study we evaluated the impact of protease inhibitors on a cell neuronal model. Methods: We treated a neuroblastoma cell line (SH-SY5Y) with increasing doses of Lopinavir and Ritonavir (0.1-1-10-25-50 µM), used alone or in combination, evaluating the impact of these drugs in terms of mitochondrial activity, with MTT cell proliferation assay; mRNA expression of heme oxygenase (HemeOH) and reactive oxygen species (ROS) levels with 2',7'-dichlorofluorescin diacetate (H2DCFDA) in order to assess oxidative stress; apoptotic cell death with flow cytometry. Results: We observed that Lopinavir and Ritonavir treatment, at 25 and/or 50 µM concentrations, induced mitochondrial damage, increase of heme oxygenase RNA expression levels and ROS generation, followed by apoptosis in SH-SY5Y. Conclusions: Our in vitro model demonstrates a damaging effect of HIV protease inhibitors on the neuroblastoma cell line, thus partially mimicking the impact of these drugs on the CNS of children born to HIV positive mothers undergone to antiretroviral treatment.
    Type of Medium: Online Resource
    ISSN: 1015-8987 , 1421-9778
    URL: Article
    DOI: 10.1159/000447849
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2016
    detail.hit.zdb_id: 1482056-0
    SSG: 12
    SSG: 15,3
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  • 5
    Online Resource
    Online Resource
    Disrupted filamin A/αIIbβ3 interaction induces macrothrombocytopenia by increasing RhoA activity
    American Society of Hematology ; 2019
    In:  Blood Vol. 133, No. 16 ( 2019-04-18), p. 1778-1788
    Details
    In: Blood, American Society of Hematology, Vol. 133, No. 16 ( 2019-04-18), p. 1778-1788
    Abstract: Filamin A (FLNa) links the cell membrane with the cytoskeleton and is central in several cellular processes. Heterozygous mutations in the X-linked FLNA gene are associated with a large spectrum of conditions, including macrothrombocytopenia, called filaminopathies. Using an isogenic pluripotent stem cell model derived from patients, we show that the absence of the FLNa protein in megakaryocytes (MKs) leads to their incomplete maturation, particularly the inability to produce proplatelets. Reduction in proplatelet formation potential is associated with a defect in actomyosin contractility, which results from inappropriate RhoA activation. This dysregulated RhoA activation was observed when MKs were plated on fibrinogen but not on other matrices (fibronectin, vitronectin, collagen 1, and von Willebrand factor), strongly suggesting a role for FLNa/αIIbβ3 interaction in the downregulation of RhoA activity. This was confirmed by experiments based on the overexpression of FLNa mutants deleted in the αIIbβ3-binding domain and the RhoA-interacting domain, respectively. Finally, pharmacological inhibition of the RhoA-associated kinase ROCK1/2 restored a normal phenotype and proplatelet formation. Overall, this work suggests a new etiology for macrothrombocytopenia, in which increased RhoA activity is associated with disrupted FLNa/αIIbβ3 interaction.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-07-861427
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
    Online Resource
    Online Resource
    Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity
    Oxford University Press (OUP) ; 2012
    In:  Brain Vol. 135, No. 11 ( 2012-11), p. 3320-3335
    Details
    In: Brain, Oxford University Press (OUP), Vol. 135, No. 11 ( 2012-11), p. 3320-3335
    Type of Medium: Online Resource
    ISSN: 1460-2156 , 0006-8950
    URL: Article
    DOI: 10.1093/brain/aws194
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2012
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    DataSheet_1.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 12 ( 2022-1-13)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2022-1-13)
    Abstract: CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant  in vivo  efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses  in vitro  and  in vivo . In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8 +  T cells versus CD4 +  T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4 +  T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were  in vitro  skewing responses towards CD8 +  T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4 +  T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.786144
    DOI: 10.3389/fimmu.2021.786144.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 8
    Online Resource
    Online Resource
    Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis
    Elsevier BV ; 2011
    In:  Brain, Behavior, and Immunity Vol. 25, No. 5 ( 2011-7), p. 947-956
    Details
    In: Brain, Behavior, and Immunity, Elsevier BV, Vol. 25, No. 5 ( 2011-7), p. 947-956
    Type of Medium: Online Resource
    ISSN: 0889-1591
    URL: Article
    DOI: 10.1016/j.bbi.2010.10.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2011
    detail.hit.zdb_id: 1462491-6
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  • 9
    Online Resource
    Online Resource
    Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 207, No. 8 ( 2021-10-15), p. 2060-2076
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 207, No. 8 ( 2021-10-15), p. 2060-2076
    Abstract: CD40 is a potent activating receptor within the TNFR family expressed on APCs of the immune system, and it regulates many aspects of B and T cell immunity via interaction with CD40 ligand (CD40L; CD154) expressed on the surface of activated T cells. Soluble CD40L and agonistic mAbs directed to CD40 are being explored as adjuvants in therapeutic or vaccination settings. Some anti-CD40 Abs can synergize with soluble monomeric CD40L. We show that direct fusion of CD40L to certain agonistic anti-CD40 Abs confers superagonist properties, reducing the dose required for efficacy, notably greatly increasing total cytokine secretion by human dendritic cells. The tetravalent configuration of anti-CD40–CD40L Abs promotes CD40 cell surface clustering and internalization and is the likely mechanism of increased receptor activation. CD40L fused to either the L or H chain C termini, with or without flexible linkers, were all superagonists with greater potency than CD40L trimer. The increased anti-CD40–CD40L Ab potency was independent of higher order aggregation. Moreover, the anti-CD40–CD40L Ab showed higher potency in vivo in human CD40 transgenic mice compared with the parental anti-CD40 Ab. To broaden the concept of fusing agonistic Ab to natural ligand, we fused OX40L to an agonistic OX40 Ab, and this resulted in dramatically increased efficacy for proliferation and cytokine production of activated human CD4+ T cells as well as releasing the Ab from dependency on cross-linking. This work shows that directly fusing antireceptor Abs to ligand is a useful strategy to dramatically increase agonist potency.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2000704
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2021
    detail.hit.zdb_id: 1475085-5
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