Research Interests: Electron Microscopy, Biology, Inflammation, Immunohistochemistry, Medicine, and 15 moreMotility, Mice, Animals, Explant Culture, Clinical Sciences, Enteric Nervous System, Time Factors, Gastrointestinal Tract, Gastrointestinal motility, Muscle contraction, Network structure, Cellular and Molecular Medicine, Cell Proliferation, Biochemistry and cell biology, and Interleukin
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Research Interests: Immunology, Biology, Immunology of the Gut, Leishmania, Innate immunity, and 15 moreMedicine, Disease susceptibility, Signal Transduction, Leishmaniasis, Mice, Nitric oxide, Animals, Immunization, Immune system, Cutaneous Leishmaniasis, DNA binding proteins, Leishmania Major, Autoantibodies, Interleukin, and Macrophage activation
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Research Interests: Immunology, RNA, Flow Cytometry, Biomarkers, Immunohistochemistry, and 15 moreMedicine, Humans, COPD, Female, Male, Polymerase Chain Reaction, Epithelium, Epithelial cells, Respiratory Epithelium, Enzyme Linked Immunosorbent Assay, Case Control Studies, Interleukin, Immunoglobulin A, Medical and Health Sciences, and Pulmonary Disease Chronic Obstructive
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The dimeric cytokine IL‐12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is... more
The dimeric cytokine IL‐12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines: p40 in IL‐23 and p35 in IL‐35. This has led to erroneous conclusions like the alleged implication of IL‐12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti‐mouse IL‐12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL‐35) but specifically recognize and functionally inhibit the IL‐12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN‐γ production and LPS‐induced septic shock after viral infection, we demonstrate the critical role played by IL‐12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG‐induced EAE, which was clearly prevented by anti‐p40 mAb C17.8. Given this selective inhibition of IL‐12, these mAbs provide new options for reassessing IL‐12 function in vivo.
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The effects of IL-6 on plasmacytomas and on normal B and T cells were examined. Evidence was presented to indicate that, in the mouse, IL-6 not only supports the growth of plasmacytomas in vitro, but also that it significantly enhances... more
The effects of IL-6 on plasmacytomas and on normal B and T cells were examined. Evidence was presented to indicate that, in the mouse, IL-6 not only supports the growth of plasmacytomas in vitro, but also that it significantly enhances tumor progression in vivo. Analysis of the response of normal mouse B cells to IL-6 revealed the existence of a unique synergy between IL-6 and IL-1. The results obtained with T cells also highlighted the remarkable effects of the IL-1-IL-6 combination. In several experimental systems, including the generation of allogeneic cytolytic T cell responses, it appeared that accessory cells could be completely replaced by IL-1 and IL-6, whereas either cytokine used by itself was completely inactive. Analysis of the mode of action of IL-6 in T cell activation demonstrated the existence of two distinct mechanisms: induction of IL-2 biosynthesis and enhancement of T cell responsiveness to IL-2 and IL-4. Finally, it was reported that IL-6 is essential only during the early phases of T cell activation, thus indicating as far as T cells are concerned that IL-6 must be considered as a competence factor.
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In the study we report here we investigated the colony-stimulating activities of interleukin-9 (IL-9). In the presence of erythropoietin, IL-9 was found to stimulate the proliferation of relatively early erythroid progenitor cells (BFU-E)... more
In the study we report here we investigated the colony-stimulating activities of interleukin-9 (IL-9). In the presence of erythropoietin, IL-9 was found to stimulate the proliferation of relatively early erythroid progenitor cells (BFU-E) from normal human bone marrow cells depleted of mononuclear phagocytes and T lymphocytes. Neutralization experiments demonstrated that the observed BFU-E-stimulating effect was not the result of intermediate production of IL-3 or GM-CSF by residual accessory cells in response to IL-9. Accordingly, the effects of IL-9 were preserved when cell suspensions were further depleted of accessory cells using CD34 enrichment of progenitor cells. Furthermore, IL-9 did not stimulate bone marrow mononuclear cells to express mRNA for IL-3, GM-CSF, EPA (erythroid-promoting activity), or IL-4, as determined by a cDNA-PCR method. IL-9 is likely to act on a subpopulation of IL-3-responsive erythroid progenitor cells that are not stimulated by GM-CSF, since plateau concentration of IL-9 and GM-CSF had additive effects on BFU-E formation, whereas a combination of IL-9 and IL-3 did not. In addition to its burst-promoting activity, IL-9 was found to have a modest stimulatory activity on myeloid progenitor cells (CFU-GM) in some experiments, suggesting that this effect may be donor related.
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Background Allergic diseases are believed to be due to T helper (Th)2‐like immunity to allergens in affected tissues, and immune responses to allergens are characterized by a cross‐regulation between Th1 and Th2 cells. Atopic individuals... more
Background Allergic diseases are believed to be due to T helper (Th)2‐like immunity to allergens in affected tissues, and immune responses to allergens are characterized by a cross‐regulation between Th1 and Th2 cells. Atopic individuals may develop IgE antibodies to only one or more allergens. However, the mechanisms behind sensitization to a specific allergen, e.g. why an individual develops IgE to cat but not birch, are not known. Our aim was to study birch‐ and cat‐induced Th1 and Th2 cytokine secretion in children who were sensitized to birch but not to cat, and vice versa.Materials and methods The subjects in the study were 60 12‐year‐old children. Seventeen of the children were sensitized (skin prick test and circulating IgE positive) to birch but not cat, 13 were sensitized to cat but not birch, 11 were sensitized both to birch and cat, and 19 children were skin prick test and circulating IgE negative. Forty‐six children had a history of atopic symptoms, and 42 of them had current symptoms. Peripheral blood mononuclear cells were separated from venous blood and stimulated with cat or birch allergen. The levels of IL‐4, IL‐5, IL‐9, IL‐10, IL‐13 and IFN‐γ in the cell supernatants were analysed by ELISA.Results Sensitized children produced more of the Th2 cytokines IL‐4, IL‐5, IL‐9 and IL‐13 than non‐sensitized atopic and non‐atopic children in response to stimulation with the allergen they were sensitized to. High levels of the Th2 cytokines IL‐4 and IL‐5 and low levels of the anti‐inflammatory cytokine IL‐10 were associated with atopic symptoms, and high cat‐induced IL‐9 levels with asthma.Conclusions The Th2 cytokines IL‐4, IL‐5, IL‐9 and IL‐13 were all commonly detected in sensitized children after stimulation with the specific, in contrast to an unrelated, allergen. Atopic symptoms were associated with increased levels of IL‐4 and IL‐5 and tended to be associated with low levels of IL‐10, and asthma with high cat‐induced IL‐9 levels.
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The first description of IL9 was based on the observation that supernatants of activated helper T-cell clones were capable of supporting the long term growth of certain T-cell clones in the absence of antigen and antigen presenting cells... more
The first description of IL9 was based on the observation that supernatants of activated helper T-cell clones were capable of supporting the long term growth of certain T-cell clones in the absence of antigen and antigen presenting cells (Uyttenhove 1988). The protein responsible for this activity, designated P40 on the basis of its apparent size in gel filtration, was characterized by an elevated pI (~10) and a high level of glycosylation. Partial amino acid sequences allowed the screening of a cDNA library with oligonucleotides and the cloning of a full length clone encoding the murine P40 protein (Van Snick 1989). Subsequently, the cDNA of the human homologue was isolated by cross-species hybridization (Renauld 1990a,b), while Yang (1989) isolated the human IL9 cDNA by expression cloning of a factor stimulating the growth of the Mo7E megakaryoblastic leukemia line.
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By in vitro mutagenesis of mastocytoma P815, it is possible to obtain tumor cell variants that are rejected by syngeneic mice (tum-). Most of these variants carry new individual antigens and stimulate a specific cytolytic T cell (CTL)... more
By in vitro mutagenesis of mastocytoma P815, it is possible to obtain tumor cell variants that are rejected by syngeneic mice (tum-). Most of these variants carry new individual antigens and stimulate a specific cytolytic T cell (CTL) response in mixed leukocyte tumor cell culture (MLTC). The H-2 associativity of this response was examined for six different variants by measuring the inhibition of cell-mediated cytolysis by antibodies directed against products of the K or the D end of the H-2d complex. The lysis was either not inhibited (variants P91 and P116) or inhibited selectively by anti-Kd (variants P21, P32 and P198) or anti-Dd antibodies (variant P35). All these tum- variants expressed Kd and Dd antigens as measured by absorption of H-2 alloantisera. Long-term CTL clones can be obtained that are specific for individual tum- antigens. The pattern of H-2 associativity obtained with MLTC-derived CTL against four tum- variants was verified with CTL clones directed against the specific antigens of these variants. Concordant results were observed in all cases. In addition to CTL clones specific for tum- antigens, it is possible to isolate clones against a P815 tumor-associated antigen found on all P815 tum- variants. For these clones no clear associativity with either Kd or Dd products was found.
Research Interests: Immunology, Molecular Biology, Biology, Medicine, Mutagenesis, and 7 moreMutation, Mice, Animals, CTL, Antigen, mastocytoma, and cytolysis
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Research Interests: Medical Microbiology, Biology, Toxoplasma, Medicine, Toxoplasmosis, and 14 moreToxoplasma gondii, Biological Sciences, Spleen, Virulence, Mice, Female, Animals, Cytokine, Tumor necrosis factor-alpha, Enzyme Linked Immunosorbent Assay, Interleukin, Medical, Interferon gamma, and Medical and Health Sciences
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Research Interests: Biology, Macrophages, Medicine, Cell Division, Cell Differentiation, and 15 moreArticles, Mice, Female, Animals, The, T lymphocytes, Interleukins, Experimental Medicine, Growth Factor, Antigen presenting cells, Interleukin, Cell Growth, Drug synergism, phytohemagglutinins, and Medical and Health Sciences
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For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild... more
For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild symptoms, 68 severe cases, and 20 healthy controls for the first time in Rwanda. Pro-inflammatory (IFNγ, IL-6, TNFα), Treg (IL-10, TGFβ1, TGFβ3), Th9 (IL-9), Th17 (IL-17), and Th2 (IL-4, IL-13) cytokines, total IgM and IgG, as well as gene expressions of FoxP3, STAT5+, IFNγ-R1, and ROR alpha+, were measured at day 1, day 7, day 14, day 21, and day 28 post-infection. Severe cases showed a significantly stronger increase than mild patients in levels of all cytokines (except IL-9) and all gene expression on day 1 of infection. Some cytokine levels dropped to levels comparable to mild cases at later time points. Further analysis identified IFNγ as a marker of severity throughout the disease course, while TGFβ1, IL-6, and IL-17 were markers of severity only at...
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IntroductionNatural prevention of cancer development depends on an efficient immunosurveillance that may be modulated by environmental factors, including infections. Innate lymphoid cytotoxic cells have been shown to play a major role in... more
IntroductionNatural prevention of cancer development depends on an efficient immunosurveillance that may be modulated by environmental factors, including infections. Innate lymphoid cytotoxic cells have been shown to play a major role in this immunosurveillance. Interleukin-12 (IL-12) has been suggested to be a key factor in the activation of innate cytotoxic cells after infection, leading to the enhancement of cancer immunosurveillance.MethodsThe aim of this work was to analyze in mouse experimental models by which mechanisms the interaction between infectious agent molecules and the early innate responses could enhance early inhibition of cancer growth and especially to assess the role of IL-12 by using novel antibodies specific for IL-12 heterodimers.ResultsLigation of toll-like receptor (TLR)9 by CpG-protected mice against plasmacytoma TEPC.1033.C2 cell early growth. This protection mediated by innate cytolytic cells was strictly dependent on IL-12 and partly on gamma-interferon...
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We have previously reported that cytokines such as IL-9, IL-4, and IL-6 protect murine thymic lymphoma cell lines against dexamethasone-induced apoptosis. A similar activity, which could not be ascribed to any of these factors, was found... more
We have previously reported that cytokines such as IL-9, IL-4, and IL-6 protect murine thymic lymphoma cell lines against dexamethasone-induced apoptosis. A similar activity, which could not be ascribed to any of these factors, was found in a number of human T cell supernatants that enabled mouse BW5147 thymic lymphoma not only to escape apoptosis but also to maintain proliferation. The protein responsible for this activity was purified to homogeneity from the culture medium of activated leukemic T cells and was found to be identical with the I-309 chemokine. Half-maximal anti-apoptotic activity was obtained with approximately 1 ng/ml, a concentration considerably lower than that required for the monocyte chemotactic activity of this molecule, as measured on THP-1 cells. The purified I-309 also improved the survival of two other mouse thymic lymphoma cell lines. This activity was as potent as that of IL-9, which was the strongest anti-apoptotic factor found to date for these cells. ...
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Mouse plasmacytoma FLOPC21 was adapted to culture in the presence of a mouse Th cell supernatant. A stable factor-dependent cell line was derived from this culture and the factor responsible for its growth was identified as... more
Mouse plasmacytoma FLOPC21 was adapted to culture in the presence of a mouse Th cell supernatant. A stable factor-dependent cell line was derived from this culture and the factor responsible for its growth was identified as granulocyte-macrophage colony-stimulating factor.
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The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-β1 and TGF-β3 in this process using novel monoclonal antibodies to measure their plasma concentrations in... more
The proper control of Plasmodium infection requires a finely balanced immune response. Here, we evaluated the implication of TGF-β1 and TGF-β3 in this process using novel monoclonal antibodies to measure their plasma concentrations in comparison with other cytokines and the expression of FOXP3 mRNA. Plasma cytokine levels were measured in 80 patients with severe anaemic malaria and 186 with a mild presentation using ELISA, and rtPCR was used to measure FOXP3 mRNA expression. While no mature TGF-β isoforms were detected in the plasma, the latent TGF-β1 and TGF-β3 were strongly upregulated in patients with mild malaria and nearly undetected in patients with severe disease. Similar selective upregulation in mild patients was observed for IL-9 and FOXP3 mRNA, while IL-7, IL-10, IL-17, and IL-27, although higher in mild cases, were also detected in severe disease. In contrast, a clearly skewed trend of severe cases towards higher pro-inflammatory (IL-6, IL-13, TNF-α) and Th1 (IFN-γ) resp...