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1.
Clin Cancer Res ; 26(3): 588-597, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31558479

RESUMO

PURPOSE: Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors. PATIENTS AND METHODS: INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan-Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry. RESULTS: Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 µg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed. CONCLUSIONS: INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond.See related commentary by Slingluff Jr, p. 529.


Assuntos
Vacinas Anticâncer , Neoplasias , Telomerase , Vacinas de DNA , DNA , Humanos , Vacinação
2.
J Clin Invest ; 128(4): 1627-1640, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29553486

RESUMO

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV-infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Inibidores de Caspase/farmacologia , Quinolinas/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/metabolismo , Síndrome da Imunodeficiência Adquirida/enzimologia , Síndrome da Imunodeficiência Adquirida/patologia , Animais , Relação CD4-CD8 , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/patologia , Progressão da Doença , Feminino , Depleção Linfocítica , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/enzimologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia
3.
Genes Cancer ; 6(5-6): 241-253, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26124923

RESUMO

Members of the Bcl-2 family are key elements of the apoptotic machinery. In mammals, this multigenic family contains about twenty members, which either promote or inhibit apoptosis. We have previously shown that the mammalian pro-apoptotic Bcl-2 family member Bax is very efficient in inducing apoptosis in Drosophila, allowing the study of bax-induced cell death in a genetic animal model. We report here the results of the screening of a P[UAS]-element insertion library performed to identify gene products that modify the phenotypes induced by the expression of bax in Drosophila melanogaster. We isolated 17 putative modifiers involved in various function or process: the ubiquitin/proteasome pathway; cell growth, proliferation and death; pathfinding and cell adhesion; secretion and extracellular signaling; metabolism and oxidative stress. Most of these suppressors also inhibit debcl-induced phenotypes, suggesting that the activities of both proteins can be modulated in part by common signaling or metabolic pathways. Among these suppressors, Glycerophosphate oxidase-1 is found to participate in debcl-induced apoptosis by increasing mitochondrial reactive oxygen species accumulation.

4.
Apoptosis ; 19(10): 1444-56, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25208640

RESUMO

The ubiquitin-proteasome system is one of the main proteolytic pathways. It inhibits apoptosis by degrading pro-apoptotic regulators, such as caspases or the tumor suppressor p53. However, it also stimulates cell death by degrading pro-survival regulators, including IAPs. In Drosophila, the control of apoptosis by Bcl-2 family members is poorly documented. Using a genetic modifier screen designed to identify regulators of mammalian bax-induced apoptosis in Drosophila, we identified the ubiquitin activating enzyme Uba1 as a suppressor of bax-induced cell death. We then demonstrated that Uba1 also regulates apoptosis induced by Debcl, the only counterpart of Bax in Drosophila. Furthermore, we show that these apoptotic processes involve the same multimeric E3 ligase-an SCF complex consisting of three common subunits and a substrate-recognition variable subunit identified in these processes as the Slimb F-box protein. Thus, Drosophila Slimb, the homologue of ß-TrCP targets Bax and Debcl to the proteasome. These new results shed light on a new aspect of the regulation of apoptosis in fruitfly that identifies the first regulation of a Drosophila member of the Bcl-2 family.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas de Membrana/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Apoptose , Proteínas de Ciclo Celular/genética , Drosophila/citologia , Drosophila/enzimologia , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Membrana/genética , Complexo de Endopeptidases do Proteassoma/genética , Ligação Proteica , Transporte Proteico , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
5.
Virol J ; 9: 220, 2012 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23021024

RESUMO

BACKGROUND: Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART). RESULTS: We demonstrated that rIL-2 induced a dose dependent expansion of CD4+ and CD8+ T cells without affecting viral load. rIL-2 increased CD4 and CD8 Treg cells as defined by the expression of CD25(high)FoxP3(+)CD127(low). We also showed that rIL-2 modulated spontaneous and Fas-mediated CD4(+) and CD8(+) T cell apoptosis. The higher dose exhibited a dramatic pro-apoptotic effect on both CD4(+) and CD8(+) T cell populations. Finally, all the animals treated with rIL-2 developed a wasting syndrome in the month following treatment simultaneously to a dramatic decrease of circulating effector T cells. CONCLUSION: These data contribute to the understanding of the homeostatic and dosage effects of IL-2 in the context of SIV/HIV infection.


Assuntos
Fatores Imunológicos/administração & dosagem , Interleucina-2/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Animais , Apoptose , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Imunoterapia/métodos , Contagem de Linfócitos , Macaca mulatta , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , Carga Viral
6.
Cell Signal ; 22(3): 467-75, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19895884

RESUMO

Verotoxin (VT-1) is a cytotoxin, produced by Shigella dysenteriae type 1 or by Shiga toxin-producing Escherichia coli, which binds specifically to globotriaosylceramide (Gb3). This glycosphingolipid is a B cell differentiation antigen (Gb3/CD77) strongly expressed on Burkitt's lymphoma cells. We have previously shown that, in these cells, VT-1 induces apoptosis via a caspase- and mitochondria-dependent pathway. In this report, we provide new insights into this signal transduction pathway. First, we demonstrate that VT-1-induced apoptosis requires degradation of the caspase-8 inhibitory molecule c-FLIPL and that this degradation occurs through the ubiquitin-proteasome pathway. Furthermore, we show that mitochondrial activation is mainly due to i) cleavage and activation of the pro-apoptotic Bcl-2 family member Bid by caspase-8 and ii) Bax relocalization to mitochondrial membranes which lead to cytochrome c release. However, tBid is not involved in Bax relocalization, and relocalization is most likely controlled by the extent of Bax phosphorylation: in non-treated BL cells, p38 MAPK participates in the retention of Bax in the cytoplasm in an inactive form whereas in VT-1 treated cells, protein phosphatase 2A is activated and induces Bax relocalization to mitochondria.


Assuntos
Apoptose , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Linfoma de Burkitt/metabolismo , Caspase 8/metabolismo , Proteína Fosfatase 2/metabolismo , Toxina Shiga I/farmacologia , Proteína X Associada a bcl-2/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Linhagem Celular , Citocromos c/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Shigella dysenteriae/metabolismo , Transdução de Sinais , Triexosilceramidas/metabolismo , Ubiquitina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
J Virol ; 81(14): 7598-607, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17494066

RESUMO

The Epstein-Barr virus (EBV)-encoded leader protein, EBNA-LP, strongly activates the EBNA2-mediated transcriptional activation of cellular and viral genes and is therefore important for EBV-induced B-cell transformation. However, a truncated form of EBNA-LP is produced in cells infected with variant EBV strains lacking EBNA2 due to a genetic deletion. The function of this truncated form is unknown. We show here that some Burkitt's lymphoma cells harboring defective EBV strains are specifically resistant to the caspase-dependent apoptosis induced by verotoxin 1 (VT-1) or staurosporine. These cells produced low-molecular-weight Y1Y2-truncated isoforms of EBNA-LP, which were partly localized in the cytoplasm. The transfection of sensitive cells with constructs encoding truncated EBNA-LP isoforms, but not full-length EBNA-LP, induced resistance to caspase-mediated apoptosis. Furthermore, VT-1 induced protein phosphatase 2A (PP2A) activation in sensitive cells but not in resistant cells, in which the truncated EBNA-LP interacted with this protein. Thus, the resistance to apoptosis observed in cells harboring defective EBV strains most probably results from the inactivation of PP2A via interactions with low-molecular-weight Y1Y2-truncated EBNA-LP isoforms.


Assuntos
Apoptose/fisiologia , Caspases/fisiologia , Fosfoproteínas Fosfatases/antagonistas & inibidores , Proteínas Virais/fisiologia , Linhagem Celular , Humanos , Proteína Fosfatase 2 , Transfecção , Proteínas Virais/química
8.
J Biol Chem ; 278(46): 45200-8, 2003 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-12944404

RESUMO

Globotriasosylceramide (Gb3), a neutral glycosphingolipid, is the B-cell differentiation antigen CD77 and acts as the receptor for most Shiga toxins, including verotoxin-1 (VT-1). We have shown that both anti-Gb3/CD77 mAb and VT-1 induce apoptosis in Burkitt's lymphoma cells. We compared the apoptotic pathways induced by these two molecules by selecting cell lines sensitive to only one of these inducers or to both. In all these cell lines (including the apoptosis-resistant line), VT-1 was transported to the endoplasmic reticulum and inhibited protein synthesis similarly, suggesting that VT-1-induced apoptosis is dissociated from these processes. VT-1 triggered a caspase- and mitochondria-dependent pathway (rapid activation of caspases 8 and 3 associated with a loss of mitochondrial membrane potential (Deltapsim) and the release of cytochrome c from mitochondria). In contrast, the anti-Gb3/CD77 mAb-induced pathway was caspase-independent and only involved partial depolarization of mitochondria. Antioxidant compounds had only marginal effects on VT-1-induced apoptosis but strongly protected cells from anti-Gb3/CD77 mAb-induced apoptosis. VT-1- and anti-Gb3/CD77 mAb-treated cells displayed very different features on electron microscopy. These results clearly indicate that the binding of different ligands to Gb3/CD77 triggers completely different apoptotic pathways.


Assuntos
Apoptose , Toxinas Shiga/metabolismo , Transdução de Sinais , Triexosilceramidas/metabolismo , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Transporte Biológico , Western Blotting , Linfoma de Burkitt/metabolismo , Caspase 3 , Caspase 8 , Caspase 9 , Caspases/metabolismo , Morte Celular , Linhagem Celular Tumoral , Citosol/metabolismo , Retículo Endoplasmático/metabolismo , Glicosilação , Humanos , Ligantes , Potenciais da Membrana , Microscopia Eletrônica , Fatores de Tempo , Transfecção
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