Amelioration of Mas-related G protein-coupled receptor X2-mediated itch and reduced mast cell degranulation by a single-stranded oligonucleotide
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BACKGROUND: HIV preferentially infects activated, memory CD4+ lymphocytes expressing requisite co-receptors. The gut mucosa is the body s largest immune organ, which in the healthy, normal condition is characterised by low-level... more
BACKGROUND: HIV preferentially infects activated, memory CD4+ lymphocytes expressing requisite co-receptors. The gut mucosa is the body s largest immune organ, which in the healthy, normal condition is characterised by low-level inflammation and constitutive expression of chemokines and cytokines. The gut contains the body s largest number of activated, memory T cells, which express high levels of CCR5 and CXCR4 A. Inflammation with chemotactic chemokines recruiting additional activated immune cells, would potentially further increase infectible targets for HIV spread. METHODS: Colon biopsies from 6 HIV-infected individuals, 8 Inflammatory Bowel Disease (IBD) patients and 5 seronegative, healthy controls without organic bowel disease were compared. All but one HIV infected was on HAART. Plasma viral load was undetectable in three patients and differed between 4.4 5.7 logs in three patients. IBD patients included 5 with active disease, 3 in remission. Samples were immunohistochemically stained with monoclonal antibodies against CCR5, CXCR4, RANTES, MlP-l a and MIP-l f3 with expression evaluated at the single cell level by computerized in situ imaging. RESULTS: The expression of chemokine receptors CCR5 and CXCR4 was significantly increased in HIV-infected mucosal sections compared to both IBD in remission (IBDr) and seronegative controls (p<0.05). Sections from patients with active IBD showed a similar pattern of increased chemokine receptor expression. f3-chemokines including RANTES and MIPlf3, were significantly upregulated in HIV compared to IBDr and healthy controls (p<0.05). In active IBD there was increased expression of RANTES, compared to IBDr (p<O.OI). The chemokine MIP-l a was expressed at low levels in all samples. CONCLUSIONS: HIV is characterized by a significant degree of mucosal inflammation. Our findings show that the levels of chemokines and chemokine receptors in HIV are similar to those levels seen in active IBD and are significantly higher than those from IBDr and healthy controls. This suggests that the inflammatory response in HIV is at least as potent as in IBD. Topical anti-inflammatories lead to remission and reduction in soluble and cellular markers of inflammation in IBD. Given the presence of marked inflammation, further investigation of the role of adjunctive treatment of HIV-patients with local anti-inflammatory drugs targeting the host immune response, deserves attention.
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MRL lpr/lpr mice develop a generalized autoimmune disease associated with a massive accumulation in the peripheral lymphoid organs of abnormal, phenotypically immature T cells. Both the lymphoadenopathy and the autoimmunity are... more
MRL lpr/lpr mice develop a generalized autoimmune disease associated with a massive accumulation in the peripheral lymphoid organs of abnormal, phenotypically immature T cells. Both the lymphoadenopathy and the autoimmunity are thymus-dependent and likely to arise from an aberrant pathway of intrathymic differentiation. We here present the marked beneficial effects acquired in MRL lpr/lpr mice after in vivo administration of a novel immunomodulator called linomide. The highly altered pattern of thymic subpopulations in MRL lpr/lpr mice is normalized after linomide-treatment. Concomitantly, the peripheral T cell compartment, which in MRL lpr/lpr is highly deficient in producing and responding to IL-2, gains substantial functional reactivities. We propose that linomide acts by correcting the abnormal T cell development in autoimmune MRL lpr/lpr mice. This new immunomodulator may be a useful tool for providing insight into both the pathogenesis of autoimmune disorders and intrathymic differentiation.
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Research Interests: Immunology, Medicine, Pregnancy, Humans, Female, and 15 moreAnimals, DNA vaccines, Oryctolagus cuniculus, Standard Operating Procedure, Optometry and Ophthalmology, Time Factors, Reproducibility of Results, DNA vaccine, Parity, Rabbits, Reliability Assessment, Immunogenicity, Immunoglobulin A, Antibody Response, and Vaginal smears
Research Interests: Biology, Cytokines, Cell Biology, Apoptosis, Medicine, and 15 moreMultidisciplinary, Dendritic Cells, Cell Differentiation, Humans, Polymerase Chain Reaction, Research article, Dendritic cell, Hiv Infection, CD, PLoS one, DNA isolation, Monoclonal Antibody, Base Sequence, Chemokines, and coculture techniques
Dendritic cell derived IL-12p70 stimulates IFN-γ production in naïve T cells, thereby promoting Th1 responses, which counteracts induction of tolerance. Uptake of apoptotic cells by dendritic cells is generally considered to induce... more
Dendritic cell derived IL-12p70 stimulates IFN-γ production in naïve T cells, thereby promoting Th1 responses, which counteracts induction of tolerance. Uptake of apoptotic cells by dendritic cells is generally considered to induce tolerance rather than immune activation and has been shown to specifically inhibit IL-12 production. However, we previously demonstrated that the activation state of apoptotic PBMC influence their immunogenic potential. Here we investigated whether dendritic cells that have engulfed apoptotic PBMC are able to produce IL-12p70 after a secondary signal. We show that dendritic cell ability to produce IL-12p70 after uptake of allogeneic apoptotic cells is dependent on the activation state of the apoptotic cells and subsequent CD40 ligation. CD40 ligation by a CD40L-transfected cell-line induced IL-12p70 in DC regardless of previous apoptotic cell uptake. Moreover, dendritic cells that were exposed to allogeneic activated apoptotic PBMC, but not to resting apoptotic PBMC, were able to produce IL-12p70 after co-culture with autologous T cells. These findings show that dendritic cells are able to produce IL-12p70 upon engulfment of apoptotic cells provided that a secondary activating signal such as CD40-ligand is delivered. In addition, resting apoptotic cell but not activated apoptotic cells reduced ongoing IL-12p70 production suggesting that the balance of activated and resting apoptotic lymphocytes influence the amount of IL-12p70 being produced.
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Research Interests: Biology, Cell Biology, Biological Chemistry, Apoptosis, Medicine, and 15 moreDendritic Cells, Biological Sciences, Cell Differentiation, Humans, Mice, Animals, Dendritic cell, Phenotype, CHEMICAL SCIENCES, Monocytes, Integrin, Cell Adhesion Molecules, Intracellular, coculture techniques, and Medical and Health Sciences
Research Interests: Biology, Medicine, Multidisciplinary, Signal Transduction, Cell Differentiation, and 14 moreHumans, cyclic AMP, Infant, T lymphocytes, Calcineurin, Amino Acid Sequence, Base Sequence, DNA binding proteins, Interleukin, Molecular Sequence Data, Child preschool, Signaling pathway, conserved sequence , and In Vitro Techniques
Research Interests: Immunology, Biology, Cytokines, Medicine, Dendritic Cells, and 15 moreHIV, Humans, Blood, Dendritic cell, CD, Clinical Sciences, Immune system, Stimulation, Immunophenotyping, Cell Surface Markers, Interleukin, Cardiovascular medicine and haematology, Paediatrics and reproductive medicine, HIV infections, and Protein subunits
Treatment with a novel immunomodulator called linomide resulted in highly reduced levels of pathogenic anti-DNA antibodies in MRL-lpr/lpr mice compared to untreated mice. This reduction occurred without altering the total levels of serum... more
Treatment with a novel immunomodulator called linomide resulted in highly reduced levels of pathogenic anti-DNA antibodies in MRL-lpr/lpr mice compared to untreated mice. This reduction occurred without altering the total levels of serum immunoglobulins, implying that the compound does not have any direct B-cell suppressive effect. The possible role of T cells in regulating autoreactive B-cell clones is discussed.
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Research Interests: Chemistry, Biology, Cell Biology, Medicine, Internalization, and 3 moreEndocytosis, Endosome, and TLR
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Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core–shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS‐CoV‐2. Macromolecular... more
Inhibitors of viral cell entry based on poly(styrene sulfonate) and its core–shell nanoformulations based on gold nanoparticles are investigated against a panel of viruses, including clinical isolates of SARS‐CoV‐2. Macromolecular inhibitors are shown to exhibit the highly sought‐after broad‐spectrum antiviral activity, which covers most analyzed enveloped viruses and all of the variants of concern for SARS‐CoV‐2 tested. The inhibitory activity is quantified in vitro in appropriate cell culture models and for respiratory viral pathogens (respiratory syncytial virus and SARS‐CoV‐2) in mice. Results of this study comprise a significant step along the translational path of macromolecular inhibitors of virus cell entry, specifically against enveloped respiratory viruses.
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Research Interests: Biology, Medicine, Population, Gene, Phenotype, and 4 moreGenes, Immune system, Phagocytosis, and Innate Immune System
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Thymocytes differentiate upon interactions with microenvironmental components, but the precise role of different stromal cells, or other T cells, in early differentiative events remains unclear. Here we have analyzed the in vitro... more
Thymocytes differentiate upon interactions with microenvironmental components, but the precise role of different stromal cells, or other T cells, in early differentiative events remains unclear. Here we have analyzed the in vitro differentiation of double‐negative (DN) thymocytes from young adult mice. We demonstrate that a substantial proportion of DN thymocytes differentiate into CD8+ γ/δ T cells upon stimulation with concanavalin A and recombinant interleukin 2. However, if α/β T cells are excluded from the initial population of DN thymocytes, the CD8+ γ/δ T cells do not appear in the cultures. These results suggest a role for T‐T cell interactions in thymic differentiative events, and provide evidence for physiological interactions between the α/β and γ/δ T cell compartments within the thymus.
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Research Interests: Chemistry, Biology, Cell Biology, Medicine, Internalization, and 3 moreEndocytosis, Endosome, and TLR
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Dendritic cells present microbial antigens to T cells after uptake of apoptotic vesicles from infected cells. We previously reported that immunizations with apoptotic HIV-1/Murine Leukemia virus (MuLV) infected cells lead to induction of... more
Dendritic cells present microbial antigens to T cells after uptake of apoptotic vesicles from infected cells. We previously reported that immunizations with apoptotic HIV-1/Murine Leukemia virus (MuLV) infected cells lead to induction of both cellular and humoral immune responses as well as resistance to mucosal challenge with live HIV-1/MuLV infected cells. Here we extended those studies and investigated whether apoptotic cells from HIV-1/MuLV infected cells stimulate the production of HIV-1 neutralizing activity. We compared different routes of administration and were able to induce p24- and Nef-specific cellular proliferation after intraperitoneal (i.p.), intranasal (i.n.), subcutaneous (s.c) and intramuscular (i.m.) immunizations. Serum IgG and IgA antibodies directed against gp160, p24, or Nef were also produced regardless of immunization route used. However, the induction of mucosa associated IgAs from faeces or vaginal secretions were detected only after either i.p. or i.n. i...
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Insects rely on their innate immune system to successfully mediate complex interactions with their internal microbiota, as well as the microbes present in the environment. Given the variation in microbes across habitats, the challenges to... more
Insects rely on their innate immune system to successfully mediate complex interactions with their internal microbiota, as well as the microbes present in the environment. Given the variation in microbes across habitats, the challenges to respond to them are likely to result in local adaptations in the immune system. Here we focus upon phagocytosis, a mechanism by which pathogens and foreign particles are engulfed in order to be contained, killed, and processed. We investigated the phenotypic and genetic variation related to phagocytosis in two allopatric populations of the butterfly Pieris napi. Populations were found to differ in their hemocyte composition and overall phagocytic capability, driven by the increased phagocytic propensity of each cell type. Yet, genes annotated to phagocytosis showed no large genomic signal of divergence. However, a gene set enrichment analysis on significantly divergent genes identified loci involved in glutamine metabolism, which recently have been...
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Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need... more
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in young children. Currently, there is no RSV vaccine or universally accessible antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Furthermore, we show that ssON’s antiviral activity was length dependent and that both RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON inhibited RSV infection by competing with the virus for binding to the cellular receptor nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo resulted in the upregulati...
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Early clearance of tuberculosis is the successful eradication of inhaled bacteria before the development of an adaptive immune response. We previously showed, by utilizing a non-virulent mycobacteria infection model, that C57BL/6 mice are... more
Early clearance of tuberculosis is the successful eradication of inhaled bacteria before the development of an adaptive immune response. We previously showed, by utilizing a non-virulent mycobacteria infection model, that C57BL/6 mice are more efficient than BALB/c in their control of bacterial growth in the lungs during the first weeks of the infection. Here, we assessed early (within 1-3 days) innate immune events locally in the lungs to identify factors that may contribute to the control of non-virulent mycobacterial burden. We confirmed that C57BL/6 mice are more resistant to infection compared with BALB/c after intranasal inoculation with mycobacterium. Transcriptomic analyses revealed a remarkably silent signature in C57BL/6 mice despite effective control of bacterial growth. In contrast, BALB/c mice up-regulated genes associated with neutrophil and myeloid cell chemotaxis and migration. Flow cytometry analyses corroborated the transcriptomic analyses and demonstrated influx o...
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A key gap in the development and evaluation of HIV-1 vaccines is insufficient knowledge with regard to sampling techniques and assessment of mucosal immune responses required for early prevention and inhibition of viral dissemination. In... more
A key gap in the development and evaluation of HIV-1 vaccines is insufficient knowledge with regard to sampling techniques and assessment of mucosal immune responses required for early prevention and inhibition of viral dissemination. In an attempt to start bridging this gap, the EUROPRISE network of scientists working on HIV-1 vaccine and microbicide research organized a workshop with the aim to review the types of mucosal responses/biomarkers currently measured in mucosal immunology and to define how the mucosal responses/biomarkers are measured and/or the assays and sampling methods used. The Workshop addressed two critical questions: first whether, with current knowledge, it would be possible to define a consensus set of mucosal sampling methods to facilitate cross-species comparisons and ensure standardized implementation in clinical trials; second to determine the remaining challenges (technical and logistical) and their possible solutions for assessing mucosal responses to HIV-1 vaccines.