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Sandrine Delignat

Publications and source records attributed to Sandrine Delignat.

16 recordsLinked to original sources
PubMed2006

VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors.

Von Willebrand factor (VWF) is a chaperone molecule for procoagulant factor VIII (FVIII). Its role in the reduction of the immunogenicity of therapeutic FVIII in patients with hemophilia A has been evoked but lacks clear cellular and molecular rationale. Here, we demonstrate that VWF protects FVIII from being endocytosed by human dendritic cells (DCs) and subsequently presented to FVIII-specific T cells. The immunoprotective effect of VWF requires a physical interaction with FVIII because the endocytosis of FVIII was significantly restored on hindering the formation of the VWF-FVIII complex. Interestingly, VWF had no direct inhibitory effect either on the ability of DCs to present antigenic peptides or on the activation potency of CD4+ T cells. We thus propose that VWF may reduce the immunogenicity of FVIII by preventing, upstream from the activation of immune effectors, the entry of FVIII in professional antigen-presenting cells.

Antigen Presentation↗
PubMed2006

Comparative study of the anti-inflammatory effect of two intravenous immunoglobulin preparations manufactured by different processes.

Intravenous immunoglobulin (IVIG) is increasingly used in the treatment of diverse immune-mediated disorders. Since several preparations of IVIG are available for therapy, it is possible that different manufacturing processes might influence clinical efficacy of IVIG. An insight into the mechanisms of action of such different IVIG preparations is therefore necessary that will provide further guidelines for the utility of IVIG preparations in autoimmune and inflammatory diseases. Since endothelial cells (EC) influence the inflammatory process via production of cytokines, chemokines and expression of adhesive molecules, we analyzed the anti-inflammatory effect on EC of two IVIG preparations: caprylated IVIG (IVIG-C) versus solvent/detergent-treated IVIG (IVIG-SD) preparation. We found that both IVIG preparations inhibit in an equivalent manner, the expression of different pro-inflammatory factors such as IL-6, IL-8, GM-CSF, IL-1beta and TNF-alpha and the adhesion molecules ICAM-1 and VCAM-1. Our results thus suggest that the caprylate while inactivating the virus and enhancing the yield of IgG during IVIG formulation, does not modulate the immunomodulatory properties of IVIG at EC level and that the two preparations show similar anti-inflammatory effects.

Caprylates↗
PubMed2006

Direct and indirect effects of alloantibodies link neointimal and medial remodeling in graft arteriosclerosis.

OBJECTIVE: Chronic vascular rejection, the main cause of allograft failure, is characterized by the destruction of smooth muscle cells (SMCs) in the media concomitantly with the proliferation of SMCs in the adjacent neointima. We hypothesized that alloantibodies might be responsible for these 2 opposite but coordinated events. METHODS AND RESULTS: We used the rat aortic interposition model of chronic vascular rejection. During the rejection process, a neointima composed of proliferating SMCs from the recipient developed, whereas the SMCs in the media, all of donor origin, underwent apoptosis. Alloantibody deposition was detected only in the media. Using in vitro cultures experiments, we observed that alloantibody binding to donor SMCs exerts (1) a rapid upregulation of the transcription of growth factors genes, followed by (2) the induction of apoptosis after 24 hours. The transient production of growth factors by donor SMCs in response to the binding of alloantibodies induced the proliferation of recipient SMCs in culture supernatant transfer experiments. Additional data suggest that among the repertoire of alloantibodies, those directed against major histocompatibility complex I might carry the remodeling effect. CONCLUSIONS: Our data suggest that during chronic vascular rejection, alloantibody binding to donor medial SMCs is a crucial event that links neointimal and medial remodeling.

Animals↗
PubMed2006

Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII.

Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitor-negative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIII-hydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids.

Adolescent↗
PubMed2006

Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma.

Viscum album (VA) preparations consist of aqueous extracts of different types of lectins of mistletoe. VA exert cytotoxic and immunomodulatory properties that may be relevant for the inhibition of tumor growth. We addressed the effects of VA preparation VA Qu FrF on growth of B16F1 melanoma implanted in mice and on proliferation and cytokine synthesis of splenocytes. In C57BL6 mice, inhibition of tumor growth by VA was associated with an enhancement of splenocyte proliferation and with an up-regulation of IL-12 secretion. In IL-12-deficient strain of mice the inhibition of melanoma growth by VA and the splenocyte proliferation were abrogated. Results from the present study strongly suggest a crucial role of IL-12 in the anti-tumor properties of VA extracts.

Animals↗
PubMed2006

Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador.

Viscum album (VA) preparations (Iscador) consist of aqueous extracts from different types of European mistletoe. Biologically active components of VA extracts include mistletoe lectins (ML) and viscotoxins. The treatment with VA extracts or with purified ML has been shown to be associated with tumor regression in several in vivo experimental models of tumoral implantation. The mechanisms underlying the anti-tumoral activity of VA or ML are complex and involve apoptosis, angiogenesis and immunomodulation. This review provides an account of the current status of the understanding of the VA-associated immunomodulation in various cell types including lymphoblastoid, monocytic or endothelial cell lines.

Angiogenesis Inhibitors↗
PubMed2005

Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms.

Intravenous immunoglobulin (IGIV) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. IGIV is beneficial in several diseases, including acute and chronic/relapsing diseases, autoimmune diseases and inflammatory disorders. Therapeutic efficacy of IGIV has also been established in a number of dermatologic diseases. Although a considerable progress has been made in understanding the mechanisms by which IGIV exerts immunomodulatory functions in autoimmune diseases, they remain not fully elucidated. The mode of action of IGIV is complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network, modulation of idiotype network, regulation of cell growth, alteration of cellular adhesion process, and effects on the activation differentiation and effector functions of T and B cells and of antigen-presenting cells. The therapeutic effects of IGIV most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy people. The ability of IGIV to interact through V regions with complementary V regions of antibodies and antigen receptors as well as with relevant soluble and surface molecules provides the basis for inducing the selection of immune repertoires. Since IGIV is frequently used to treat autoimmune and inflammatory diseases for which evidence of its efficacy is insufficiently documented, controlled trials, particularly of some neurologic and dermatologic diseases, are imperative.

Animals↗
PubMed2005

Pathophysiology of catalytic antibodies.

Immunoglobulins have initially been illustrated as proteins produced by the immune system for binding and neutralizing foreign molecules potentially harmful to the organism. The number of V(H), D(H), J(H), V(L) and J(L) genes that encode the variable regions of immunoglobulins and the junctional diversity that occurs at the time of somatic rearrangement determine the extent of the repertoire of antibodies that may be potentially produced by an organism. This potential repertoire includes antibodies the antigen binding site of which may recognize external as well as autologous antigens, or may structurally resemble the active site of enzymes and be endowed with enzymatic activity. Under physiological conditions, B cell clones that produce antibodies naturally endowed with catalytic activity are negatively regulated and subjected to apoptosis. Catalytic antibodies are expressed only following active immunization, or if the physiological regulatory mechanisms that control the expression of catalytic antibody-producing B cell clones are perturbed, e.g. in the context of pregnancy or in the course of autoimmune diseases.

Antibodies, Catalytic↗
PubMed2005

Intravenous immunoglobulin in neurological disorders: a mechanistic perspective.

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over 25 years. It is a safe preparation with no long-term side effects. IVIg was first demonstrated to be effective in autoimmune disorders, two decades ago, in the treatment of acute immune thrombocytopenia. Since then, the therapeutic efficacy of IVIg has been established in Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), dermatomyositis (DM), Kawasaki syndrome and the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants and reported in a large number of other autoimmune and systemic inflammatory conditions.

Animals↗
PubMed2005

Intravenous immunoglobulin and dendritic cells.

Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases, and in supportive therapy of immunodeficient patients. Available clinical and experimental evidence suggests, however, that a wide spectrum of immune-mediated conditions could benefit from IVIg, including acute and chronic/relapsing diseases and autoimmune diseases mediated by pathogenic autoantibodies or by autoaggressive T-cells. Dendritic cells (DCs) are professional antigen-presenting cells and because of their capacity to stimulate naïve T-cells, they play a central role in the initiation of primary immune responses. Several immunomodulatory agents have been shown to inhibit DC activation. Recently, we examined the effects of IVIg on differentiation, maturation, and functions of DCs. We demonstrate that DCs are one of the targets for the immunomodulatory effects of IVIg.

Animals↗
PubMed2004

Natural antibodies sustain differentiation and maturation of human dendritic cells.

The differentiation and maturation of dendritic cells (DCs) is governed by various signals in the microenvironment. Monocytes and DCs circulate in peripheral blood, which contains high levels of natural antibodies (NAbs). NAbs are germ-line-encoded and occur in the absence of deliberate immunization or microbial aggression. To assess the importance of NAbs in the milieu on DC development, we examined the status of DCs in patients with X-linked agammaglobulinemia, a disease characterized by paucity of B cells and circulating antibodies. We demonstrate that the in vitro differentiation of DCs is severely impaired in these patients, at least in part because of low levels of circulating NAbs. We identified NAbs reactive with the CD40 molecule as an important component that participates in the development of DCs. CD40-reactive NAbs restored normal phenotypes of DCs in patients. The maturation process induced by CD40-reactive NAbs was accompanied by an increased IL-10 and decreased IL-12 production. The transcription factor analysis revealed distinct signaling pathways operated by CD40-reactive NAbs compared to those by CD40 ligand. These results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.

Adolescent↗
PubMed2004

Dendritic cells and autoimmunity.

Dendritic cells (DC) are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. Because of their capacity to stimulate naive T cells, DC have a central role in the initiation of primary immune responses and are considered promising tools and targets for immunotherapy. Emerging data suggest a role for DC in initiating autoimmune attacks. Direct analysis of DC phenotypes and DC-T-cell interactions in rodent and human autoimmune diseases should shed light on how pathogenesis occurs, and suggest novel avenues of treatment aimed at alleviating deviant DC function.

Animals↗
PubMed2003

Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon-alpha present in serum from patients with systemic lupus erythematosus.

OBJECTIVE: Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune responses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (IVIG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon-alpha (IFNalpha), on the activity of DCs, we investigated the effects of IVIG on the differentiation of DCs mediated by serum from SLE patients. METHODS: DCs were differentiated from peripheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. IVIG was used at a concentration of 0.15 mM. A functional assay was performed to assess the inhibitory effect of IVIG on the uptake of nucleosomes by DCs. RESULTS: IVIG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with IVIG inhibited the ingestion of nucleosomes by immature DCs, by up to 36%. CONCLUSION: The present findings indicate that IVIG, by down-regulating the IFNalpha-mediated differentiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by IVIG offers a plausible explanation for the efficacy of IVIG in SLE and other immune-mediated inflammatory conditions.

Adult↗
PubMed2003

Comparative study of the sensitivity of lymphoblastoid and transformed monocytic cell lines to the cytotoxic effects of Viscum album extracts of different origin.

Viscum album (VA) preparations consist of aqueous extracts of V. album, the European mistletoe. VA extracts contain mistletoe lectins, which are members of the ribosome-inactivating protein type II family. VA preparations have cytotoxic and immunomodulatory properties. Cytotoxicity induced by VA extracts may differ greatly according to the origin of the preparation (host tree, fermented extract) and the cell type. This work was performed to assess the cytotoxicity of various VA preparations, i.e. VA Qu FrF, Qu Spez, M Spez and VA P, in lymphoblastoid and monocytic cell lines. VA Qu FrF, Qu Spez and M Spez induced dose-dependent cell death and inhibition of cell proliferation in lymphoblastoid T cell lines and in transformed monocytic lines. In contrast, the majority of B cell lines tested were resistant to cytotoxicity induced by VA extracts. While VA Qu FrF, Qu Spez and M Spez were potent inducers of cell death, extracts of VA P, derived from mistletoe plants growing on pine trees, failed to induce any cell death in any of the cell lines examined.

Cell Death↗
PubMed2002

Induction of apoptosis of endothelial cells by Viscum album: a role for anti-tumoral properties of mistletoe lectins.

BACKGROUND: Viscum album (VA) preparations consist of aqueous extracts of different types of lectins of VA. Mistletoe lectins have both cytotoxic and immunomodulatory properties that support their study for the development for cancer therapy. However, the mechanisms of the anti- tumoral properties in vivo of mistletoe lectins are not fully understood. Because endothelial cells (EC) play a pivotal role in tumor angiogenesis, we tested the hypothesis that VA extracts induce endothelial cell death and apoptosis. MATERIALS AND METHODS: We investigated the effect of various VA preparations on both human venous endothelial cell (HUVEC) and immortalized human venous endothelial cell line (IVEC) using morphologic assessment of EC, FACScan analysis after propidium iodine and annexin V labeling, and detection of cleavage of poly(A)DP-ribose polymerase (PARP). RESULTS: All tested VA preparations, except Iscador P, were cytotoxic in IVEC. Apoptosis, assessed by morphologic examination, annexin V labeling, and Western blot analysis for PARP cleavage, was involved in HUVEC cell death induced by VA preparations derived from plants that grow on oak trees (VA Qu FrF). CONCLUSIONS: Results from the present study suggest that VA extract-induced endothelial apoptosis may explain the tumor regression associated with the therapeutic use of VA preparations and support further investigations to develop novel anti-angiogenic compounds based on mistletoe compounds.

Antineoplastic Agents, Phytogenic↗