Biomedical subjects

C Théry

Publications and source records attributed to C Théry.

At least 19 recordsLinked to original sources

PubMed2001

Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles.

Dendritic cells constitutively secrete a population of small (50-90 nm diameter) Ag-presenting vesicles called exosomes. When sensitized with tumor antigenic peptides, dendritic cells produce exosomes, which stimulate anti-tumor immune responses and the rejection of established tumors in mice. Using a systematic proteomic approach, we establish the first extensive protein map of a particular exosome population; 21 new exosomal proteins were thus identified. Most proteins present in exosomes are related to endocytic compartments. New exosomal residents include cytosolic proteins most likely involved in exosome biogenesis and function, mainly cytoskeleton-related (cofilin, profilin I, and elongation factor 1alpha) and intracellular membrane transport and signaling factors (such as several annexins, rab 7 and 11, rap1B, and syntenin). Importantly, we also identified a novel category of exosomal proteins related to apoptosis: thioredoxin peroxidase II, Alix, 14-3-3, and galectin-3. These findings led us to analyze possible structural relationships between exosomes and microvesicles released by apoptotic cells. We show that although they both represent secreted populations of membrane vesicles relevant to immune responses, exosomes and apoptotic vesicles are biochemically and morphologically distinct. Therefore, in addition to cytokines, dendritic cells produce a specific population of membrane vesicles, exosomes, with unique molecular composition and strong immunostimulating properties.

Animals↗

PubMed2001

The cell biology of antigen presentation in dendritic cells.

Dendritic cells are the most efficient antigen-presenting cells. They take up antigens and pathogens, generate MHC-peptide complexes, migrate from the sites of antigen acquisition to secondary lymphoid organs and, finally, they physically interact with and stimulate T lymphocytes. Indeed, dendritic cells are the only antigen-presenting cells that induce the activation of resting T cells, both in vitro and in vivo. Thus, dendritic cells initiate adaptive immune responses and determine tolerance. To do so, dendritic cells have developed unique membrane transport pathways. The molecular mechanisms responsible for the control of antigen uptake and processing, for the generation of MHC-peptide complexes and for their transport to the cell surface have been partially unraveled in the past two years.

Animals↗

PubMed2001

Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.

The initiation of T-cell-mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8+ T-cell-dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions.

Animals↗

PubMed2001

Secretory granules of mast cells accumulate mature and immature MHC class II molecules.

Bone marrow-derived mast cells as well as dendritic cells, macrophages and B lymphocytes express major histocompatibility complex (MHC) class II molecules. In mast cells, the majority of MHC class II molecules reside in intracellular cell type-specific compartments, secretory granules. To understand the molecular basis for the localisation of MHC class II molecules in secretory granules, MHC class II molecules were expressed, together with the invariant chain, in the mast cell line, RBL-2H3. Using electron and confocal microscopy, we observed that in RBL-2H3 cells, mature and immature class II molecules accumulate in secretory granules. Two particular features of class II transport accounted for this intracellular localization: first, a large fraction of newly synthesized MHC class II molecules remained associated with invariant chain fragments. This defect, resulting in a slower rate of MHC class II maturation, was ascribed to a low cathepsin S activity. Second, although a small fraction of class II dimers matured (i.e. became free of invariant chain), allowing their association with antigenic peptides, they were retained in secretory granules. As a consequence of this intracellular localization, cell surface expression of class II molecules was strongly increased by cell activation stimuli which induced the release of the contents of secretory granules. Our results suggest that antigen presentation, and thereby antigen specific T cell stimulation, are regulated in mast cells by stimuli which induce mast cell activation.

Animals↗

PubMed1999

Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73.

Exosomes are membrane vesicles secreted by hematopoietic cells upon fusion of late multivesicular endosomes with the plasma membrane. Dendritic cell (DC)-derived exosomes induce potent antitumor immune responses in mice, resulting in the regression of established tumors (Zitvogel, L., A. Regnault, A. Lozier, J. Wolfers, C. Flament, D. Tenza, P. Ricciardi-Castagnoli, G. Raposo, and S. Amigorena. 1998. Nat. Med. 4:594-600). To unravel the molecular basis of exosome-induced immune stimulation, we now analyze the regulation of their production during DC maturation and characterize extensively their protein composition by peptide mass mapping. Exosomes contain several cytosolic proteins (including annexin II, heat shock cognate protein hsc73, and heteromeric G protein Gi2alpha), as well as different integral or peripherally associated membrane proteins (major histocompatibility complex class II, Mac-1 integrin, CD9, milk fat globule-EGF-factor VIII [MFG-E8]). MFG-E8, the major exosomal component, binds integrins expressed by DCs and macrophages, suggesting that it may be involved in exosome targeting to these professional antigen-presenting cells. Another exosome component is hsc73, a cytosolic heat shock protein (hsp) also present in DC endocytic compartments. hsc73 was shown to induce antitumor immune responses in vivo, and therefore could be involved in the exosome's potent antitumor effects. Finally, exosome production is downregulated upon DC maturation, indicating that in vivo, exosomes are produced by immature DCs in peripheral tissues. Thus, DC-derived exosomes accumulate a defined subset of cellular proteins reflecting their endosomal biogenesis and accounting for their biological function.

Animals↗

PubMed1999

Free-floating thrombi in the right heart: diagnosis, management, and prognostic indexes in 38 consecutive patients.

BACKGROUND: Floating right heart thrombi (FRHTS) are a rare phenomenon, encountered almost exclusively in patients with suspected or proven pulmonary embolism and diagnosed by transthoracic echocardiography. Their management remains controversial. METHODS AND RESULTS: We report on a series of 38 consecutive patients encountered over the past 12 years. Thirty-two patients were in NYHA class IV, 20 in cardiogenic shock. Echocardiography usually demonstrated signs of cor pulmonale: right ventricular overload (91.7% of the population), paradoxical interventricular septal motion (75%), and pulmonary hypertension (86. 1%). The thrombus was typically wormlike (36 of 38 patients). It extended from the left atrium through a patent foramen ovale in 4 patients. Pulmonary embolism was confirmed in all but 1. Mortality was high (17 of 38 patients) irrespective of the therapeutic option chosen: surgery (8 of 17), thrombolytics (2 of 9), heparin (5 of 8), or interventional percutaneous techniques (2 of 4). The in-hospital mortality rate was significantly linked with the occurrence of cardiac arrest. Conversely, the outcome after discharge was usually good, because 18 of 21 patients were still alive 47.2 months later (range, 1 to 70 months). CONCLUSIONS: Severe pulmonary embolism was the rule in our series of FRHTS (mortality rate, 44.7%). The choice of therapy had no effect on mortality. Emergency surgery is usually advocated. However, thrombolysis is a faster, readily available treatment and seems promising either as the only treatment or as a bridge to surgery. In patients with contraindications to surgery or lytic therapy, interventional techniques may be proposed.

Adult↗

PubMed1999

Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization.

Dendritic cells (DCs) express several receptors for the Fc portion of immunoglobulin (Ig)G (FcgammaR), which mediate internalization of antigen-IgG complexes (immune complexes, ICs) and promote efficient major histocompatibility complex (MHC) class II-restricted antigen presentation. We now show that FcgammaRs have two additional specific attributes in murine DCs: the induction of DC maturation and the promotion of efficient MHC class I-restricted presentation of peptides from exogenous, IgG-complexed antigens. Both FcgammaR functions require the FcgammaR-associated gamma chain. FcgammaR-mediated MHC class I-restricted antigen presentation is extremely sensitive and specific to immature DCs. It requires proteasomal degradation and is dependent on functional peptide transporter associated with antigen processing, TAP1-TAP2. By promoting DC maturation and presentation on both MHC class I and II molecules, ICs should efficiently sensitize DCs for priming of both CD4(+) helper and CD8(+) cytotoxic T lymphocytes in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

[Pheochromocytoma simulating myocardial infarct. Apropos of a case].

The authors report the case of a pheochromocytoma in a 67 year old man in whom the initial clinical presentation suggested myocardial infarction. Pheochromocytoma is usually an adrenal tumour with a very variable clinical symptomatology. It is very rare for cardiac disease to be a presenting symptom. The diagnosis was suggested by major blood pressure abnormalities occurring after starting medical treatment for infarction. Pheochromocytomas may cause serious cardiovascular disorders. The diagnosis must be suspected in the presence of atypical signs, an essential requirement to reduce the mortality of the disease.

Adrenal Gland Neoplasms↗

PubMed1998

MHC class II transport from lysosomal compartments to the cell surface is determined by stable peptide binding, but not by the cytosolic domains of the alpha- and beta-chains.

Inside APCs, MHC class II molecules associate with antigenic peptides before reaching the cell surface. This association takes place in compartments of the endocytic pathway, more related to endosomes or lysosomes depending on the cell type. Here, we compared MHC class II transport from endosomal vs lysosomal compartments to the plasma membrane. We show that transport of MHC class II molecules to the cell surface does not depend on the cytosolic domains of the alpha- and beta-chains. In contrast, the stability of the alphabeta-peptide complexes determined the efficiency of transport to the cell surface from lysosomal, but not from endosomal, compartments. In murine B lymphoma cells, SDS-unstable and -stable complexes were transported to the cell surface at almost similar rates, whereas after lysosomal relocalization or in a cell line in which MHC class II molecules normally accumulate in lysosomal compartments, stable complexes were preferentially addressed to the cell surface. Our results suggest that when peptide loading occurs in lysosomal compartments, selective retention and lysosomal degradation of unstable dimers result in the expression of highly stable MHC class II-peptide complexes at the APC surface.

Amino Acid Sequence↗

PubMed1997

Comparative efficacy of the intravenous administration of linsidomine, a direct nitric oxide donor, and isosorbide dinitrate in severe unstable angina. A French multicentre study. French Group of Investigators.

AIMS: Although linsidomine shares common properties with nitrovasodilators, it releases nitric oxide directly without catalytic involvement by thiols. We conducted a prospective, randomized, multicentre, parallel group, single-blind study to compare the efficacy of intravenous administration of linsidomine with that of isosorbide dinitrate in unstable angina. METHODS AND RESULTS: Between November 1990 and July 1992, 568 patients with suspected unstable angina (class IIIB of the Braunwald classification) received a continuous infusion of either linsidomine (1 mg.h-1 on average) or isosorbide dinitrate (2.5 mg.h-1 on average) for 72 h. All patients received concomitant aspirin and intravenous heparin, 81% beta-blockers and 38% calcium antagonists. Holter monitoring was performed in all patients and analysed blindly. Only 25% of the patients had at least one episode of chest pain during the study (24.6% vs 25.8% in the linsidomine and isosorbide dinitrate groups, P = 0.74), of which 12% were associated with ECG changes. Holter criteria yielded similar results in both groups: 33% of patients presented episodes of myocardial ischaemia (32.6% vs 33.9% in the linsidomine and isosorbide dinitrate groups, P = 0.74), while 45% showed episodes of ventricular arrhythmia (43.5% vs 46.5% in the linsidomine and isosorbide dinitrate groups, P = 0.48). The incidence of serious clinical events at 72 h (death, myocardial infarction or myocardial revascularization) was 6.5% (5% vs 8% in the linsidomine and isosorbide dinitrate groups, P = 0.17). CONCLUSION: Intravenous linsidomine is at least as efficacious as isosorbide dinitrate in the stabilization of patients with severe unstable angina.

Aged↗

PubMed1997

[Mobile thrombi of the right heart in pulmonary embolism].

Systematic transthoracic echocardiography in all cases of pulmonary embolism may demonstrate right heart thrombi. The results of this monocentric series of 28 consecutive cases observed between 1987 and 1996 were analysed. Twenty-four patients were in NYHA Class IV: thirteen were in cardiogenic shock. Echocardiographic signs of acute cor pulmonale were usually observed: 96.3% of patients had right ventricular dilatation, 85.2% paradoxical interventricular septal motion, 88.9% pulmonary hypertension. The thrombus was typical serpentine (27/28 cases) arising from the lower limb veins. Passage into the left heart chambers through a patent foramen ovale was observed in 3 cases. Pulmonary embolism was confirmed in all cases. This is an extreme therapeutic emergency and 13 patients (46.4%) died despite treatment: surgery (7/16), thrombolysis (2/5), heparin (3/4) or interventional radiology (1/3). After the acute phase, the prognosis was generally good, as demonstrated by the 100% survival rate at 28.6 +/- 25 months. This study confirms the gravity of mobile right heart thrombi in pulmonary embolism. The diagnosis is echocardiographic. No significant difference in mortality was observed between the different therapeutic approaches used in this series. The echocardiographic finding of these thrombi is a traditional indication for emergency surgical embolectomy. Thrombolysis is rapid and readily available and seems to provide promising results alone or before surgery. In patients with contraindications to thrombolysis, interventional radiology or simple heparin therapy may be proposed.

Adult↗

PubMed1996

[Current status of treatment of chronic cardiac insufficiency].

When there is no correctable cause, cardiac failure continues to progress and outcome is poor. However several controlled clinical trials have shown that several therapeutic agents relieve symptoms, improve exercise tolerance and, for some, reduce mortality. Patients in NYHA functional class II, III and IV, whose systolic function is impaired should be treated by digitalis, diuretics and angiotensin-converting-enzyme inhibitors. These therapeutic agents are complementary and each of them are required. Moreover a study has shown that the impairment of patients in NYHA functional class I (who are still asymptomatic but with a ventricular ejection fraction < 35%) could be slowed by angiotensin-converting-enzyme inhibitors. In each case, it is of paramount importance to exclude treatable causes of heart failure because the best the symptomatic treatment can do is slow the inevitable worsening of the disease.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Involvement of Livertine, a hepatocyte growth factor family member, in neural morphogenesis.

The formulation of the nervous system in vertebrate embryos involves extensive morphogenetic movements that include the folding of the neural tube and the migration of neural crest cells. Changes in cell shape and cell movements underlie neural morphogenesis but the molecular mechanisms involved in these processes in vivo are not well understood. Here, we show that a new member of the hepatocyte growth factor family, which we name Livertine, is expressed in frog embryos in neural cells including neural crest and midline neural plate cells which are undergoing pronounced morphogenetic movements. The ectopic expression of Livertine perturbs gastrulation and leads to positional changes in injected cells without apparently changing cell type. These results suggest that one of the normal functions of Livertine is the control of neural morphogenesis in the vertebrate embryo.

Amino Acid Sequence↗

PubMed1996

Homozygous variant of antithrombin with lack of affinity for heparin: management of severe thrombotic complications associated with intrauterine fetal demise.

Patients with homozygous heparin-binding-site (HBS) qualitative antithrombin deficiencies are at significant risk of venous and arterial thrombosis. We report on the eighth case of homozygous HBS deficiency, and the fourth case concerning the Arg 47-Cys mutation. The proposita is a 25 year old, without known thrombotic antecedent, despite an oral contraceptive therapy for 7 years. After 25 weeks of a first pregnancy, she presented an intrauterine fetal demise complicated with deep vein thrombosis and pulmonary embolism. Heparin therapy was inefficient (no clinical nor angiographic improvement, no biological hypocoagulability). Heparin cofactor activity was < 10%, antigen concentration was normal. The crossed immunoelectrophoresis of patient's plasma, with and without heparin, showed a typical profile of qualitative HBS antithrombin deficiency. The molecular analysis revealed an homozygous Arg 4-Cys mutation. Antithrombotic therapy was achieved with continuous infusion of antithrombin concentrates (80 IU/kg/day) and unfractionated heparin (500 IU/kg/day) during 12 days, leading to clinical improvement, and followed by treatment with vitamin K antagonists. This observation emphasizes the risk of intrauterine fetal demise and the inefficiency of heparin therapy without antithrombin infusion in type II HBS homozygous deficiency. The management of a future pregnancy will probably require repeated infusions of antithrombin.

Adult↗

PubMed1996

Roles of kringle domain-containing serine proteases in epithelial-mesenchymal transitions during embryonic development.

Transformation of an epithelial sheet into a migrating mesenchymal cell population implies the destruction of the basal lamina underlying the epithelium, and the subsequent localized digestion of the extracellular matrix by the migrating cells. Proteases are involved in these processes. Among them, molecules containing both a serine protease domain and at least one kringle domain have been identified as possible important effectors. Interestingly, related proteins containing an inactive serine protease domain also seem to play a role, suggesting that the function of these molecules in epithelial-mesenchymal transformation is not confined to proteolytic digestion of cell attachments. Instead, these molecules act through specific tyrosine kinase receptors in the membrane of the responding cells. In this review, we summarize data implicating this family of molecules in various epithelial-mesenchymal transitions during embryonic development. Our major focus of attention are: hepatocyte growth factor/scatter factor (HGF/SF), its tyrosine kinase receptor proto-oncogene c-met, and the related peptide factor HGF-like/macrophage-stimulating protein (HGF1/MSP), whose receptor is the Ron tyrosine kinase. c-met and Ron also have another close homolog in the chick, called Sea, whose ligand remains unknown. Interestingly, HGF/SF is activated by other plasminogen-related molecules which, apart from a specific activator, include the protease urokinase. HGF/SF, c-met and HGF/MSP are expressed in dynamic ways during early embryonic development, correlating with regions undergoing epithelial/mesenchymal transformations. Moreover, several assays are now starting to reveal great pleiotropism of function during development, including both the loss and the acquisition of epithelial morphology according to the cell type and assay used, as well as angiogenesis, kidney tubule morphogenesis, cell motility, the maintenance of competence for neural induction and some aspects of the later development of the musculoskeletal and nervous systems.

Animals↗

PubMed1996

[Aortitis in Horton disease. Review of the literature].

First described in 1937, giant cell aortitis (aortitis associated with giant cell arteritis) occurs in 20 to 40% of patients with giant cell arteritis and is often clinically silent. Temporal involvement usually precedes aortic involvement. The process may involve the entire aorta, but complications are usually related to thoracic involvement. Patients with giant cell aortitis may be asymptomatic, or present with aortic arch syndrome, dilation of the aorta, aortic aneurysm, aortic dissection, sudden rupture of the aorta, or aortic valve incompetence. Thoracic aneurysms are usually fusiform and can be complicated by dissection in up to 50% of patients. Aortic involvement may be the presenting feature of giant cell arteritis: it may also occur in patients with preexisting temporal arteritis, often when corticosteroid therapy is reduced or discontinued. Aortic rupture complicating aortitis may be the cause of death in 3-12% of patients with giant cell arteritis. Clinical follow-up with assessment of disease activity by chest X-ray and biological markers of inflammation should be performed yearly in giant cell arteritis. Aortic involvement should be suspected if cardiac or vascular echo-Doppler shows evidence of an aortic arch syndrome, aortic dilation, aneurysm, or of aortic valve incompetence. Corticosteroid therapy, beginning with a dose of 1 mg/kg/day remains the key point of therapy. The dose is subsequently adjusted based on the clinical course and the results of ancillary tests. This treatment might prevent fatal outcome with aortic rupture. Long-term follow-up of all patients with giant cell arteritis or polymyalgia rheumatica is essential, as complications may develop late in the course of the disease.

Aortitis↗

PubMed1995

Expression of HGF/SF, HGF1/MSP, and c-met suggests new functions during early chick development.

We report the cloning of fulllength cDNAs for a plasminogen-related growth factor, hepatocyte growth factor/scatter factor (HGF/SF), its tyrosine kinase receptor, c-met, and a close member of the same family, hepatocyte growth factor-like/macrophage stimulating protein (HGF1/MSP), from the chick. We have used these cDNAs to provide the first report of the expression of this family of growth factors and the c-met receptor at early stages of vertebrate development. RNAase protection and wholemount in situ hybridization were used on chick embryos between formation of the primitive streak and early organogenesis. We find patterns of expression for HGF/SF and its receptor c-met consistent with their known roles in epithelial-mesenchymal transformation and angiogenesis. In addition, these genes and HGF1/MSP are expressed in discrete locations within developing somites, suggesting a role in paraxial mesodermal development. Very strong and early expression of HGF/SF in the elevating limb buds suggests its involvement in limb outgrowth. HGF1/MSP is expressed in the notochord and then in the prospective floor plate region and could play a role in development of the neural tube. Interestingly, c-met is often more closely associated with HGF1/MSP than with its known ligand, HGF/SF, raising the possibility that c-met expression may be induced by HGF1/MSP.

Amino Acid Sequence↗

PubMed1995

A role for HGF/SF in neural induction and its expression in Hensen's node during gastrulation.

It was previously shown (Roberts, C., Platt, N., Streit, A., Schachner, M. and Stern, C. D. (1991) Development 112, 959-970) that grafts of Hensen's node into chick embryos enhanced and maintain expression of the L5 carbohydrate in neighbouring epiblast cells, and that antibodies against L5 inhibit neural induction by such a graft. We now show that L5 is initially widely expressed in the epiblast, but as neural induction proceeds it gradually becomes confined to and up-regulated in the early neural plate. L5 can therefore be considered as a marker for cells that are competent to respond to neural induction. We also show that Hepatocyte Growth Factor/Scatter Factor (HGF/SF) promotes the expression of L5 by extraembryonic epiblast in collagen gels after overnight culture. Explants cultured for several days in the presence of HGF/SF, as well as explants of prospective neural plate, can differentiate into cells with neuronal morphology expressing neuronal markers. To investigate whether HGF/SF is expressed in the chick embryo at appropriate stages of development, we produced specific cDNA probes and used them for in situ hybridization. We find that at the primitive streak stage, HGF/SF is expressed specifically in Hensen's node. We therefore propose that HGF/SF plays a role during the early steps of neural induction, perhaps by inducing or maintaining the competence of the epiblast to respond to neural inducing signals.

Animals↗