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V Quesniaux

Publications and source records attributed to V Quesniaux.

At least 19 recordsLinked to original sources
PubMed2006

Acute and chronic vascular rejection in nonhuman primate kidney transplantation.

A nonhuman primate (NHP) study was designed to evaluate in nonlife-supporting kidney allografts the progression from acute rejection with transplant endarteritis (TXA) to chronic rejection (CR) with sclerosing vasculopathy. Group G1 (n = 6) received high cyclosporine A (CsA) immunosuppression and showed neither TXA nor CR during 90 days post-transplantation. Group G2 (n = 6) received suboptimal CsA immunosuppression and showed severe TXA with graft loss within 46 days (median). Arterial intimal changes included infiltration of macrophages and T lymphocytes (CD3, CD4, CD8) with few myofibroblasts, abundant fibronectin/collagen IV, scant collagens I/III, high rate of cellular proliferation and no C4d accumulation along peritubular capillaries. Group G3 (n = 12) received suboptimal CsA and anti-rejection therapy (rabbit ATG + methylprednisolone + CsA) of TXA. Animals developed CR and lost grafts within 65 days (median). As compared to G2, the arterial intimal changes showed less macrophages and T lymphocytes, an increased number of myofibroblasts, abundant fibronectin/collagen IV and scar collagens I/III, C4d deposition along capillaries in 60% of animals and transplant glomerulopathy in 80% of animals. In conclusion, CR is an immune stimulated process initiated during TXA with the accumulation and proliferation of myofibroblasts, and progressive deposition of collagens in the intima. Our experimental design appears well suited to study events leading to CR.

Acute Disease↗
PubMed2001

Use of transgenic animals to investigate drug hypersensitivity.

Hypersensitivity reactions to drugs and environmental agents are often due to exaggerated humoral (Th(2)) or cell mediated (Th(1)) immune responses with typical cytokine profiles. Overexpression of Th(2) cytokines, such as IL-4, IL-5 or IL-13 in mice, enhances an IgE antibody mediated response, while deletion of these cytokines attenuates and/or prevents allergic responses. Conversely, modulation of Th(1) cytokine gene expression may affect cell-mediated immune responses. Therefore, cytokine transgenic mice are used as investigative tools to study potential chemicals and/or drug allergies. In addition to cytokines and chemokines, other factors are important for the development of allergic responses, such as IgE, Fc receptors, vasopressin and several other factors, which can be tested in transgenic mice.

Allergens↗
PubMed1999

A novel immunosuppressant, FTY720, induces peripheral lymphodepletion of both T- and B cells and immunosuppression in baboons.

OBJECTIVE: FTY720, a new immunosuppressant active in transplantation models, modulates lymphocyte re-circulation, leading to peripheral lymphopenia and increased lymphocytes in lymph nodes and Peyer's patches. Here, we investigated the susceptibility of baboons to FTY720 as an introductory study to transplantation protocols. METHODS: FTY720 was administered orally to Chacma baboons at 0.3 or 0.1 mg/kg/day for 3 days or at 0.03 mg/kg/day for 10 days. Haematological parameters, lymphocyte phenotype (CD3, CD4, CD8, CD20), cell apoptosis, ex vivo blood cell proliferation in response to mitogens and drug blood levels were monitored during treatment and up to 4 weeks thereafter. MAIN FINDINGS: FTY720 administered p.o. in baboons at 0.3 mg/kg/day caused a marked decrease in circulating lymphocytes within 4 h of treatment, reaching 60-80% decrease within 24-48 h. The effect of FTY720 was seen both on T- and B cells, although it was slightly more rapid/pronounced on T cells. CD4+ cells were slightly more affected than CD8+ cells. The response onset was faster and the duration longer at higher dose, but the maximal peripheral lymphodepletion achieved was similar within the dose range 0.03-0.3 mg/kg tested. Ex vivo mitogen-induced lymphoproliferation was drastically decreased after FTY720 treatment, corresponding to the reduced blood lymphocyte counts. The blood drug levels measured after FTY720 administration correlated well with the dose applied but there was a poor correlation between FTY720 blood levels and the extent of peripheral lymphodepletion, suggestive of a high tissue distribution of the drug. When compared with cynomolgus monkeys treated in the same way, baboons had a lower initial exposure and a slightly lower response 24 h after one or two doses of FTY720 0.03-0.3 mg/kg. However, the stabilized drug blood levels and peripheral lymphodepletion achieved after 7 days of FTY720 0.03 mg/kg/day were similar in both nonhuman primate species. CONCLUSIONS: FTY720 was well tolerated and was effective in terms of peripheral T- and B lymphodepletion in baboons, indicating that it could be used in protocols of allo- and xenotransplantation. The pharmacokinetic and pharmacodynamic profiles of FTY720 in baboons suggest the use of high induction doses to optimize immediate response followed by a reduced dose regimen for drug maintenance.

Animals↗
PubMed1999

Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp. A92-308110. I. Taxonomy, fermentation, isolation and biological activity.

A novel class of macrolides for which the name sanglifehrins is proposed, has been discovered from actinomycete strains based on their high affinity binding for cyclophilin A (CypA), an immunophilin originally identified as a cytosolic protein binding cyclosporin A (CsA). The sanglifehrins were produced by Streptomyces sp. A92-308110. They were isolated and purified by extraction and several chromatographic, activity-guided steps. Sanglifehrins A and B exhibit a 10 to approximately 20 fold higher affinity for CypA than CsA, whereas the affinity of sanglifehrins C and D for CypA is comparable to that of CsA. Sanglifehrins exhibit a lower immunosuppressive activity than CsA when tested in the mixed lymphocyte reaction. Their in vitro activity indicates that they belong to a novel class of immunosuppressants.

Animals↗
PubMed1997

Malaria toxins from P. chabaudi chabaudi AS and P. berghei ANKA cause dyserythropoiesis in C57BL/6 mice.

The lack of correlation between parasitaemia and anaemia in severe malaria indicates that factors in addition to schizont rupture or erythrophagocytosis contribute to anaemia. We asked whether malaria toxin (MT) from Plasmodium berghei or P. chabaudi might impair erythropoiesis. Daily intraperitoneal injection of MT into C57BL/6 mice induced a transient reduction of RBC values by 25-30% after about 2 weeks, followed by increased haematopoiesis in the spleen as compared to mice receiving uninfected RBC preparations. There was a 3 (P. berghei) to 8-fold (P. chabaudi) increase of total proliferative activity in the spleen. Flow cytometric analyses showed that this was accompanied by some differentiation of TER-119 positive erythroid cells and of Gr-1 positive myeloid cells. Erythroid and myeloid progenitor cell-derived colony assays confirmed these results and revealed an increase in the number of CFU-E (< or = 200-fold), BFU-E (< or = 10-fold) and CFU-GM (< or = 20-fold) in the spleen of MT treated mice, as compared to controls.

Anemia↗
PubMed1995

Mode of action of SDZ NIM 811, a nonimmunosuppressive cyclosporin A analog with activity against human immunodeficiency virus (HIV) type 1: interference with HIV protein-cyclophilin A interactions.

Cyclosporins, in particular the nonimmunosuppressive derivative SDZ NIM 811, exhibit potent anti-human immunodeficiency virus type 1 (HIV-1) activity in vitro. SDZ NIM 811 interferes at two stages of the viral replication cycle: (i) translocation of the preintegration complex to the nucleus and (ii) production of infectious virus particles. Immunosuppressive activity is not correlated with anti-HIV-1 activity of cyclosporins. However, binding to cyclophilin A, the major cellular receptor protein of cyclosporins, is a prerequisite for HIV inhibition: all structural changes of the cyclosporin A molecule leading to loss of affinity to cyclophilin abolished the antiviral effect. Cyclosporin derivatives did not interact directly with HIV-1 proteins; cyclophilin was the only detectable receptor protein for antivirally active cyclosporins. There is no evidence that inhibition of HIV occurs via a gain of function of cyclophilin in the presence of cyclosporins: the complex of cyclophilin A with SDZ NIM 811 does not bind to calcineurin or to any other viral or cellular proteins under conditions in which calcineurin binding to the cyclophilin A-cyclosporin A complex is easily detectable. Thus, the loss of function caused by binding of cyclosporins to cyclophilin seems to be sufficient for the anti-HIV effect. Cyclophilin A was demonstrated to bind to HIV-1 p24gag, and the formation of complexes was blocked by cyclosporins with 50% inhibitory concentrations of about 0.7 microM. HIV-2 and simian immunodeficiency virus are only weakly or not at all inhibited by cyclosporins. For gag-encoded proteins derived from HIV-1, HIV-2, or simian immunodeficiency virus particles, cyclophilin-binding capacity correlated with sensitivity of the viruses to inhibition by cyclosporins. Cyclophilin A also binds to HIV-1 proteins other than gag-encoded proteins, namely, p17gag, Nef, Vif, and gp120env; the biological significance of these interactions is questionable. We conclude that HIV-1 Gag-cyclophilin A interaction may be essential in HIV-1 replication, and interference with this interaction may be the molecular basis for the antiviral activity of cyclosporins.

Amino Acid Isomerases↗
PubMed1993

Cyclosporins. Structure-activity relationships.

Cyclosporin A (Sandimmun) achieves immunosuppressive activity by complex formation with cyclophilin and subsequent binding of the binary complex to and inhibiting protein phosphatase 2B (calcineurin). Complexes of nonimmunosuppressive cyclophilin binding cyclosporin analogues do not inhibit protein phosphatase 2B, suggesting a crucial role for this enzyme in T cell activation. Binding of cyclosporin A to cyclophilins A, B, and C, respectively, results in complexes of significantly different inhibitory potency. The cyclosporin molecule thus has two functional domains, one mediating cyclophilin binding and a second one endowing affinity of the complex to calcineurin, thereby inhibiting its enzyme activity. Structure-activity studies and x-ray crystallography of cyclosporin-cyclophilin complexes indicate a crucial role of leucine side chains in positions 4 and 6 of the cyclosporin macrocycle for the calcineurin interaction.

Amino Acid Sequence↗
PubMed1993

Molecular mechanisms of immunosuppression by cyclosporins.

Despite the successful clinical application of the immunosuppressive drug cyclosporin A (CsA, Sandimmun), its precise mechanism of action in the process of T cell activation remains elusive. CsA binds to the high-affinity cytosolic receptor cyclophilin whose peptidyl-prolyl cis-trans isomerase activity is inhibited upon binding. The linkage of this effect with the inhibition of the T cell receptor-mediated signal transduction pathway, which leads to a suppression of lymphokine gene transcription, is still unclear. We analyzed the relationship between cyclophilin-binding and immunosuppressive activity (e.g., effect on IL-2 transcription) of cyclosporin derivatives in vitro. The results show that binding to cyclophilin is required, but not sufficient for immunosuppression. Cyclosporin analogues which completely lack immunosuppressive activity but fully retained their cyclophilin-binding capacity antagonize the immunosuppressive activity of CsA. These derivatives inhibit the isomerase activity of cyclophilin, which clearly demonstrates that inhibition of the cyclophilin isomerase activity does not lead to immunosuppression. In analogy to the other immunosuppressants of microbial origin, FK-506 and rapamycin, a specific structure of the "effector" domain of CsA, which is unrelated to the cyclophilin-binding domain, determines the biological activity. In the nucleus, CsA interferes with the DNA-binding of inducible transcription factors to their respective DNA motifs within lymphokine promoters by affecting intracellular translocation of transcription factor subunits.

Amino Acid Isomerases↗
PubMed1992

Molecular mechanisms of immunosuppression.

The immunosuppressive drug cyclosporin A (CsA, Sandimmun, SIM) is currently being evaluated in a variety of autoimmune disorders with some remarkable successes. Despite the wide empiric application of CsA, the precise mechanism of action of this drug remains elusive. To identify the molecular mode of action of CsA in the process of T cell activation, we have compared the biological profile of cyclophilin-binding cyclosporin analogues (CBCA), which lack immunosuppressive properties, with CsA. We have found that CsA binding to its intracellular receptor (cyclophilin) is required but not sufficient for immunosuppression. Moreover, inhibition of the peptidyl-prolyl cis-trans isomerase activity of cyclophilin does not seem to be relevant for the inhibitory effects of CsA. In analogy to the immunosuppressants FK506 and rapamycin, a specific structure at the 'effector' domain of the CsA molecule different from the immunophilin 'binding' domain determines the biological activity. Overall, a significant understanding of the structure-activity relationship of CsA has emerged. This will have a major impact on the identification of the precise mechanism of action of CsA and its side effects in the process of immunosuppression.

Amino Acid Isomerases↗
PubMed1991

Human B-lymphopoiesis is supported by bone marrow-derived stromal cells.

We have recently reported an in vitro culture system that allows the clonal growth and differentiation of normal human bone marrow B-lineage cells. In the report presented here, we have used this B-cell colony assay to study the influence of cellular components of the human bone marrow microenvironment on B-lymphopoiesis. It is demonstrated that bone marrow stromal cells were able to provide all the necessary requirements for the growth and differentiation of B-lineage cells under the conditions of the B-cell colony assay. These stromal cells were obtained from long-term bone marrow cultures (LTBMC) that had been established from the spicules in human bone marrow. When these stromal cells were plated as an adherent underlayer in the double-agar B-cell colony assay, both immature and mature B-lineage cells were induced to differentiate into colonies containing cells that secreted immunoglobulin. The stromal cells from these spicule-derived LTBMCs maintained the capacity to support B-cell colony formation for up to 9 months.

Antigens, CD↗
PubMed1987

Potential of monoclonal antibodies to improve therapeutic monitoring of cyclosporine.

We show that monitoring of cyclosporine by immunoassay could be improved by using monoclonal antibodies (MAbs) of restricted specificity instead of polyclonal antisera that recognize both unmodified cyclosporine and its metabolites. MAbs with high affinity for cyclosporine have been prepared and characterized. We tested their ability to discriminate between native cyclosporine and its metabolites in indirect solid-phase enzyme immunoassay with a set of cyclosporine metabolites modified at residues 1, 4, 6, and 9 (corresponding to the six known sites of metabolism of cyclosporine). All the metabolites tested were detected by MAb1 at least 15- to 1000-fold less well than unmodified cyclosporine. A second MAb recognized unmodified cyclosporine and most of its metabolites equally well. Both MAbs retained their activity when coupled to alkaline phosphatase and could therefore be used in a direct solid-phase enzyme immunoassay.

Alkaline Phosphatase↗