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Nicol X Voyatzis S Muzerelle A Narboux-Nême N Südhof TC Miles R Gaspar P 《Nature neuroscience》2007,10(3):340-347
Spontaneous activity generated in the retina is necessary to establish a precise retinotopic map, but the underlying mechanisms are poorly understood. We demonstrate here that neural activity controls ephrin-A-mediated responses. In the mouse retinotectal system, we show that spontaneous activity of the retinal ganglion cells (RGCs) is needed, independently of synaptic transmission, for the ordering of the retinotopic map and the elimination of exuberant retinal axons. Activity blockade suppressed the repellent action of ephrin-A on RGC growth cones by cyclic AMP (cAMP)-dependent pathways. Unexpectedly, the ephrin-A5-induced retraction required cAMP oscillations rather than sustained increases in intracellular cAMP concentrations. Periodic photo-induced release of caged cAMP in growth cones rescued the response to ephrin-A5 when activity was blocked. These results provide a direct molecular link between spontaneous neural activity and axon guidance mechanisms during the refinement of neural maps. 相似文献
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Comparison of 60 or 90 mg/m2 of daunorubicin in induction therapy for acute myeloid leukemia with intermediate or unfavorable cytogenetics 下载免费PDF全文
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Patrice Chevallier Francoise Huguet Emmanuel Raffoux Anne Etienne Thibaut Leguay Francoise Isnard Nelly Robillard Thierry Guillaume Jacques Delaunay Aude Charbonnier Arnaud Pigneux Pierre Peterlin Marie C. Bené William A. Wegener David M. Goldenberg Hervé Dombret 《Haematologica》2015,100(4):e128-e131
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The immunosuppressive enzyme IL4I1 promotes FoxP3+ regulatory T lymphocyte differentiation 下载免费PDF全文
Céline Cousin Aude Aubatin Sabine Le Gouvello Lionel Apetoh Valérie Molinier‐Frenkel 《European journal of immunology》2015,45(6):1772-1782
IL4I1 (interleukin‐4‐induced gene 1) is a phenylalanine oxidase produced mainly by APCs of myeloid origin, and converts phenylalanine (Phe) to phenylpyruvate, hydrogen peroxide, and ammonia. We have previously shown that IL4I1 is highly expressed by tumor‐associated macrophages from various human cancers and facilitates immune evasion from the cytotoxic response in a murine tumor model. Indeed, IL4I1 inhibits T‐cell proliferation via hydrogen peroxide toxicity on effector/memory T cells. Here, we explored the effect of IL4I1 on naïve CD4+ T‐cell differentiation. We show that IL4I1 stimulates the generation of Foxp3+ regulatory T (Treg) cells in vitro from human and mouse T cells. This effect was observed with IL4I1 from different sources, including the naturally produced enzyme. Conversely, IL4I1 limits Th1 and Th2 polarization while modifying the Th17 phenotype, in particular, by inducing its own production. Analysis of Treg‐cell induction under conditions of Phe deprivation and hydrogen peroxide addition suggests that Phe consumption by the enzyme participates in Treg‐cell enrichment. In line with this hypothesis, IL4I1 inhibits mTORC1 signaling shortly after T‐cell activation. Thus, the IL4I1 enzyme may act on T cells both by direct inhibition of effector cell proliferation and by indirect immunoregulation mediated by Treg‐cell induction. 相似文献
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Mélanie Roriz Mickael Landais Jonathan Desprez Christelle Barbet Elie Azoulay Lionel Galicier Alain Wynckel Jean-Luc Baudel Fran?ois Prov?t Frédéric Pène Jean-Paul Mira Claire Presne Pascale Poullin Yahsou Delmas Tarik Kanouni Amélie Seguin Christiane Mousson Aude Servais Dominique Bordessoule Pierre Perez Dominique Chauveau Agnès Veyradier Jean-Michel Halimi Mohamed Hamidou Paul Coppo the French Thrombotic Microangiopathies Reference Center 《Medicine》2015,94(42)
Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjögren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64–15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59–27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications. 相似文献
90.
STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity
Olivier Demaria Aude De Gassart Sanja Coso Nicolas Gestermann Jeremy Di Domizio Lukas Flatz Olivier Gaide Olivier Michielin Patrick Hwu Tatiana V. Petrova Fabio Martinon Robert L. Modlin Daniel E. Speiser Michel Gilliet 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(50):15408-15413
Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.Metastatic melanoma is a highly aggressive cancer with a fast increasing incidence worldwide. Unless diagnosed early and surgically resected, the disease becomes metastatic and life threatening. Both chemotherapy and irradiation are ineffective. Novel therapies that target oncogenic drivers have brought some improvements, but tumor cells escape regularly (1). Melanoma is a prototypical immunogenic tumor, as shown by the occurrence of spontaneous CD8 T-cell responses that drive tumor regressions and by the identification of CD8 T cells that recognize melanoma antigens (2, 3). Although many immunotherapeutic strategies have been developed to induce such responses, clinical efficacies have been poor. More recently, “checkpoint blockade” therapies that target T-cell–inhibitory pathways mediated by CTLA4 (4) and PD1 (5) have yielded encouraging clinical results and demonstrated that spontaneous CD8 T-cell responses in tumors can be boosted to treat melanoma.The mechanisms that drive spontaneous antitumor immune responses are poorly understood. Type I IFNs (IFN-α and IFN-β) may play a role as the expression type I IFN-related genes in primary melanoma has been associated with spontaneous tumor regressions (6) and correlated to the tumor infiltration by specific CD8+ T cells (6, 7). Furthermore, the lack of type I IFN signaling or IFN-β expression inhibited the generation of tumor-specific CD8 T cells and accelerated tumor growth in a murine melanoma model (7–9).Type I IFNs are typically induced upon recognition of nucleic acids in intracellular compartments. Several cytosolic DNA receptors have been identified and include DNA-dependent activator of IFN-regulatory factors (DAI) (10), gamma-interferon-inducible protein-16 (IFI16) (11), and the helicase DEAD (Asp-Glu-Ala-Asp) box protein 41 (DDX41) (12). These cytosolic receptors trigger IFN-β production via a signaling cascade that involves the master adaptor molecule stimulator of IFN genes (STING), which binds to tank-binding kinase 1 (TBK1) and induces phosphorylation of the interferon regulatory factor 3 (IRF3) (13). STING associates weakly to dsDNA (14) but strongly binds the endogenous cyclic dinucleotide GMP-AMP (cGAMP) synthesized by the cGMP-AMP synthase (cGAS) (15, 16).Recently, spontaneous STING activation was found to be required for the spontaneous induction of antitumor immunity (17). Activation of STING occurred via tumor DNA-dependent cGAS activation and generation of endogenous cGAMP (17, 18). However, the cellular mechanism underlying this response and whether this mechanism could be exploited to generate more efficient antitumor immune responses is currently unknown.Here, we show that intratumoral injection of exogenous cGAMP enhanced STING activation and strongly promoted the generation of antitumor CD8 T-cell responses leading to efficient growth control of injected and contralateral tumors. This response was dependent on IFN-β produced by tumor endothelial cells. In fact, endothelial cells were found to be the principal producers of type I IFN in response to both spontaneous and enforced STING activation, suggesting a role of the tumor vasculature in the initiation of antitumor immunity. 相似文献