44 results on '"Pierre Bobé"'
Search Results
2. The Smoothened agonist SAG Modulates the Male and Female Peripheral Immune Systems Differently in an Immune Model of Central Nervous System Demyelination
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Abdelmoumen Kassoussi, Amina Zahaf, Tom Hutteau-Hamel, Claudia Mattern, Michael Schumacher, Pierre Bobé, and Elisabeth Traiffort
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oligodendrocyte ,microglia ,myelination ,Hedgehog signaling ,androgen ,cytokine ,Cytology ,QH573-671 - Abstract
Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination.
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- 2024
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3. P2X7 purinergic receptor plays a critical role in maintaining T-cell homeostasis and preventing lupus pathogenesis
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Amine Mellouk, Tom Hutteau-Hamel, Julie Legrand, Hanaa Safya, Mohcine Benbijja, Françoise Mercier-Nomé, Karim Benihoud, Jean M. Kanellopoulos, and Pierre Bobé
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SLE (systemic lupus erythematosus) ,ALPS (autoimmune lymphoproliferative syndrome) ,p2x7 (purino) receptor ,fas (APO-1/CD95) ,lpr mice ,T cell ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The severe lymphoproliferative and lupus diseases developed by MRL/lpr mice depend on interactions between the Faslpr mutation and MRL genetic background. Thus, the Faslpr mutation causes limited disease in C57BL/6 mice. We previously found that accumulating B220+ CD4–CD8– double negative (DN) T cells in MRL/lpr mice show defective P2X7 receptor ( P2X7)-induced cellular functions, suggesting that P2X7 contributes to T-cell homeostasis, along with Fas. Therefore, we generated a B6/lpr mouse strain (called B6/lpr-p2x7KO) carrying homozygous P2X7 knockout alleles. B6/lpr-p2x7KO mice accumulated high numbers of FasL-expressing B220+ DN T cells of CD45RBhighCD44high effector/memory CD8+ T-cell origin and developed severe lupus, characterized by leukocyte infiltration into the tissues, high levels of IgG anti-dsDNA and rheumatoid factor autoantibodies, and marked cytokine network dysregulation. B6/lpr-p2x7KO mice also exhibited a considerably reduced lifespan. P2X7 is therefore a novel regulator of T-cell homeostasis, of which cooperation with Fas is critical to prevent lymphoaccumulation and autoimmunity.
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- 2022
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4. Hypercholesterolemia Negatively Regulates P2X7-Induced Cellular Function in CD4+ and CD8+ T-Cell Subsets from B6 Mice Fed a High-Fat Diet
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Tom Hutteau-Hamel, Amine Mellouk, Nicolas Trainel, Anne-Marie Cassard, and Pierre Bobé
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cholesterol ,high fat diet ,P2X7 receptor ,T-cell subsets ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4+ and CD8+ T cells to ATP depends on their stage of differentiation. Here, we show that CD4+ and CD8+ T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol. Thus, in CD4+ T cells, membrane cholesterol content negatively correlated with ATP/P2X7-induced CD62L shedding but positively correlated with pore formation, phosphatidylserine externalization, and cell death. By contrast, in CD8+ T cells, cholesterol, GM1, and P2X7 levels negatively correlated with all these ATP/P2X7-induced cellular responses. The relationship between cholesterol and P2X7-induced cellular responses was confirmed by modulating cholesterol levels either ex vivo or through a high-fat diet. Membrane cholesterol enrichment ex vivo led to a significant reduction in all P2X7-induced cellular responses in T cells. Importantly, diet-induced hypercholesterolemia in B6 mice was also associated with decreased sensitivity to ATP in CD4+ and CD8+ T cells, highlighting the relationship between cholesterol intake and the amplitudes of P2X7-induced cellular responses in T cells.
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- 2022
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5. A2A adenosine receptors are involved in the reparative response of tendon cells to pulsed electromagnetic fields
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Alessandra Colombini, Carlotta Perucca Orfei, Fabrizio Vincenzi, Paola De Luca, Enrico Ragni, Marco Viganò, Stefania Setti, Katia Varani, Laura de Girolamo, and Pierre Bobé
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Medicine ,Science - Abstract
Tendinopathy is a degenerative disease in which inflammatory mediators have been found to be sometimes present. The interaction between inflammation and matrix remodeling in human tendon cells (TCs) is supported by the secretion of cytokines such as IL-1β, IL-6 and IL-33. In this context, it has been demonstrated that pulsed electromagnetic fields (PEMFs) were able to reduce inflammation and promote tendon marker synthesis. The aim of this study was to evaluate the anabolic and anti-inflammatory PEMF-mediated response on TCs in an in vitro model of inflammation. Moreover, since PEMFs enhance the anti-inflammatory efficacy of adenosine through the adenosine receptors (ARs), the study also focused on the role of A2AARs. Human TCs were exposed to PEMFs for 48 hours. After stimulation, A2AAR saturation binding experiments were performed. Along with 48 hours PEMF stimulation, TCs were treated with IL-1β and A2AAR agonist CGS-21680. IL-1Ra, IL-6, IL-8, IL-10, IL-33, VEGF, TGF-β1, PGE2 release and SCX, COL1A1, COL3A1, ADORA2A expression were quantified. PEMFs exerted A2AAR modulation on TCs and promoted COL3A1 upregulation and IL-33 secretion. In presence of IL-1β, TCs showed an upregulation of ADORA2A, SCX and COL3A1 expression and an increase of IL-6, IL-8, PGE2 and VEGF secretion. After PEMF and IL-1β exposure, IL-33 was upregulated, whereas IL-6, PGE2 and ADORA2A were downregulated. These findings demonstrated that A2AARs have a role in the promotion of the TC anabolic/reparative response to PEMFs and to IL-1β.
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- 2020
6. Variations in Cellular Responses of Mouse T Cells to Adenosine-5′-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage
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Hanaa Safya, Amine Mellouk, Julie Legrand, Sylvain M. Le Gall, Mohcine Benbijja, Colette Kanellopoulos-Langevin, Jean M. Kanellopoulos, and Pierre Bobé
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P2X7 ,CD39 ,CD73 ,regulatory T lymphocyte ,CD62L shedding ,pore formation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5′-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlow Tconvs, but not CD45RBhigh Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlow Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RBhighCD44low to effector/memory CD45RBlowCD44high stage. Maximum levels of upregulation are reached on recently activated CD69+ naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69+ CD45RBhighCD44low Tconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RBhighCD44low Tconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RBlow Tconvs, CD45RBlowFoxp3+ Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the different abilities of ATP-treated Tconvs to form pore or cleave CD62L depending on their activation and differentiation state suggests that P2X7R signaling varies according to the physiological role of T convs during antigen activation in secondary lymphoid organs or trafficking to inflammatory sites.
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- 2018
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7. Leukocyte population dynamics and detection of IL-9 as a major cytokine at the mouse fetal-maternal interface.
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Mohamed Habbeddine, Philippe Verbeke, Sonia Karaz, Pierre Bobé, and Colette Kanellopoulos-Langevin
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Medicine ,Science - Abstract
Despite much interest in the mechanisms regulating fetal-maternal interactions, information on leukocyte populations and major cytokines present in uterus and placenta remains fragmentary. This report presents a detailed and quantitative study of leukocyte populations at the mouse fetal-maternal interface, including a comparison between pregnancies from syngeneic and allogeneic crosses. Our results provide evidence for drastic differences not only in the composition of leukocyte populations in the uterus during pregnancy, but also between uterine and placental tissues. Interestingly, we have observed a significant decrease in the number of myeloid Gr1+ cells including monocytes, and myeloid CD11c+ cells including DCs in placenta from an allogeneic pregnancy. In addition, we have compared the expression levels of a panel of cytokines in non-pregnant (NP) or pregnant mouse uterus, in placenta, or in their isolated resident leukocytes. Qualitative and quantitative differences have emerged between NP, pregnant uterus and placenta. Unexpectedly, IL-9 was the major cytokine in NP uterus, and was maintained at high levels during pregnancy both in uterus and placenta. Moreover, we have found that pregnancy is associated with an increase in uterine IL-1a and a significant decrease in uterine G-CSF and GM-CSF. Comparing allogeneic versus syngeneic pregnancy, less allogeneic placental pro-inflammatory cytokines CCL2 (MCP-1), CXCL10 (IP-10) and more IL1-α in whole uterus was reproducibly observed. To our knowledge, this is the first report showing a detailed overview of the leukocyte and cytokine repertoire in the uterus of virgin females and at the fetal-maternal interface, including a comparison between syngeneic and allogeneic pregnancy. This is also the first evidence for the presence of IL-9 in NP uterus and at the maternal-fetal interface, suggesting a major role in the regulation of local inflammatory or immune responses potentially detrimental to the conceptus.
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- 2014
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8. Loss of P2X7 receptor plasma membrane expression and function in pathogenic B220+ double-negative T lymphocytes of autoimmune MRL/lpr mice.
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Sylvain M Le Gall, Julie Legrand, Mohcine Benbijja, Hanaa Safya, Karim Benihoud, Jean M Kanellopoulos, and Pierre Bobé
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Medicine ,Science - Abstract
Lupus is a chronic inflammatory autoimmune disease influenced by multiple genetic loci including Fas Ligand (FasL) and P2X7 receptor (P2X7R). The Fas/Fas Ligand apoptotic pathway is critical for immune homeostasis and peripheral tolerance. Normal effector T lymphocytes up-regulate the transmembrane tyrosine phosphatase B220 before undergoing apoptosis. Fas-deficient MRL/lpr mice (lpr mutation) exhibit lupus and lymphoproliferative syndromes due to the massive accumulation of B220(+) CD4(-)CD8(-) (DN) T lymphocytes. The precise ontogeny of B220(+) DN T cells is unknown. B220(+) DN T lymphocytes could be derived from effector CD4(+) and CD8(+) T lymphocytes, which have not undergone activation-induced cell death due to inactivation of Fas, or from a special cell lineage. P2X7R is an extracellular ATP-gated cell membrane receptor involved in the release of proinflammatory cytokines and TNFR1/Fas-independent cell death. P2X7R also regulate early signaling events involved in T-cell activation. We show herein that MRL/lpr mice carry a P2X7R allele, which confers a high sensitivity to ATP. However, during aging, the MRL/lpr T-cell population exhibits a drastically reduced sensitivity to ATP- or NAD-mediated stimulation of P2X7R, which parallels the increase in B220(+) DN T-cell numbers in lymphoid organs. Importantly, we found that this B220(+) DN T-cell subpopulation has a defect in P2X7R-mediated responses. The few B220(+) T cells observed in normal MRL(+/+) and C57BL/6 mice are also resistant to ATP or NAD treatment. Unexpectedly, while P2X7R mRNA and proteins are present inside of B220(+) T cells, P2X7R are undetectable on the plasma membrane of these T cells. Our results prompt the conclusion that cell surface expression of B220 strongly correlates with the negative regulation of the P2X7R pathway in T cells.
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- 2012
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9. TGF-β : un acteur essentiel de la perte d’immunité innée du tissu cutané au cours du vieillissement
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Pierre Bobé and Emie Gutierrez-Mateyron
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Age related ,Philosophy ,General Medicine ,Humanities ,General Biochemistry, Genetics and Molecular Biology ,030215 immunology - Abstract
Title TGF-β : un acteur essentiel de la perte d’immunite innee du tissu cutane au cours du vieillissement - L’actualite scientifique vue par les etudiants du Master Biologie Sante, module physiopathologie de la signalisation, Universite Paris-Saclay. Abstract Pour la sixieme annee, dans le cadre du module d’enseignement « Physiopathologie de la signalisation » propose par l’universite Paris-sud, les etudiants du Master « Biologie Sante » de l’universite Paris-Saclay se sont confrontes a l’ecriture scientifique. Ils ont selectionne une quinzaine d’articles scientifiques recents dans le domaine de la signalisation cellulaire presentant des resultats originaux, via des approches experimentales variees, sur des themes allant des relations hote-pathogene aux innovations therapeutiques, en passant par la signalisation hepatique et le metabolisme. Apres un travail preparatoire realise avec l’equipe pedagogique, les etudiants, organises en binomes, ont ensuite redige, guides par des chercheurs, une Nouvelle soulignant les resultats majeurs et l’originalite de l’article etudie. Ils ont beaucoup apprecie cette initiation a l’ecriture d’articles scientifiques et, comme vous pourrez le lire, se sont investis dans ce travail avec enthousiasme ! Trois de ces Nouvelles sont publiees dans ce numero, les autres le seront dans des prochains numeros.
- Published
- 2021
10. Functional cooperation of the hedgehog and androgen signaling pathways during developmental and repairing myelination
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Yousra Laouarem, Pierre Bobé, Elisabeth Traiffort, Amine Mellouk, Michael Schumacher, Claudia Mattern, Tom Hutteau-Hamel, Amina Zahaf, and Abdelmoumen Kassoussi
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0301 basic medicine ,Regulatory T cell ,CNS demyelination ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Myelin ,0302 clinical medicine ,medicine ,Animals ,Hedgehog Proteins ,Testosterone ,Hedgehog ,Myelin Sheath ,Neuroinflammation ,FOXP3 ,Oligodendrocyte ,Hedgehog signaling pathway ,Cell biology ,Oligodendroglia ,030104 developmental biology ,medicine.anatomical_structure ,Neurology ,Neuroinflammatory Diseases ,Androgens ,030217 neurology & neurosurgery ,Demyelinating Diseases ,Signal Transduction - Abstract
Hedgehog morphogens control fundamental cellular processes during tissue development and regeneration. In the central nervous system (CNS), Hedgehog signaling has been implicated in oligodendrocyte and myelin production, where it functions in a concerted manner with other pathways. Since androgen receptor (AR) plays a key role in establishing the sexual phenotype of myelin during development and is required for spontaneous myelin regeneration in the adult CNS, we hypothesized the existence of a possible coordination between Hedgehog and androgen signals in oligodendrocyte and myelin production. Here, we report complementary activities of both pathways during early postnatal oligodendrogenesis further revealing that persistent Hedgehog signaling activation impedes myelin production. The data also uncover prominent pro-myelinating activity of testosterone and involvement of AR in the control of neural stem cell commitment toward the oligodendroglial lineage. In the context of CNS demyelination, we provide evidence for the functional cooperation of the pathways leading to acceleration of myelin regeneration that might be related to their respective role on microglial and astroglial responses, higher preservation of axonal integrity, lower neuroinflammation, and functional improvement of animals in an immune model of CNS demyelination. Strong decreases of deleterious cytokines in the CNS (GM-CSF, TNF-α, IL-17A) and spleen (IL-2, IFN-γ) stand as unique features of the combined drugs while the potent therapeutic activity of testosterone on peripheral immune cells contributes to increase tolerogenic CD11c+ dendritic cells, reduce the clonal expansion of conventional CD4+ T cells and increase CD4+ Foxp3+ regulatory T cells. Altogether, these data might open promising perspectives for demyelinating diseases.
- Published
- 2021
11. Alphafetoprotein Down-Regulates ia Antigen Expression on Thyroid Cells
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Jean Salamero, Pierre Bobé, Jeannine Charreire, and Nicole Kiger
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Antigen ,business.industry ,Cancer research ,Medicine ,Thyroid cells ,business - Published
- 2020
12. Modulation of Immune Responses by Different Factors Extracted from Placenta
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Pierre Bobé, Christian Bleux, and Colette Kanellopoulos-Langevin
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Immune system ,medicine.anatomical_structure ,Modulation ,Placenta ,medicine ,Biology ,Cell biology - Published
- 2020
13. Quand les microbes se mêlent de la maladie de Parkinson
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Esther Lutete, Pierre Bobé, and Yanis Khenniche
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,General Medicine ,Biology ,General Biochemistry, Genetics and Molecular Biology - Published
- 2017
14. P2X7 receptor promotes intestinal inflammation in chemically induced colitis and triggers death of mucosal regulatory T cells
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Vanessa Ribeiro Figliuolo, Heitor Siffert Pereira de Souza, Pierre Bobé, Claudio Bernardazzi, Hanaa Safya, Cláudia Mara Lara Melo Coutinho, Hayandra F. Nanini, Jean Kanellopoulos, Luiz Eduardo Baggio Savio, Robson Coutinho-Silva, Alessandra Alves Abalo, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), and Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,colitis ,Regulatory T cell ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Inflammation ,Biology ,Inflammatory bowel disease ,regulatory T cells ,Mice ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Mesenteric lymph nodes ,IL-2 receptor ,Intestinal Mucosa ,Colitis ,Immunity, Mucosal ,Molecular Biology ,Mice, Knockout ,Oxazolone ,FOXP3 ,Inflammatory Bowel Diseases ,medicine.disease ,3. Good health ,ATP ,030104 developmental biology ,medicine.anatomical_structure ,Trinitrobenzenesulfonic Acid ,P2X7 receptor ,Immunology ,Molecular Medicine ,Female ,Receptors, Purinergic P2X7 ,medicine.symptom - Abstract
P2X7 receptor activation contributes to inflammation development in different pathologies. We previously reported that the P2X7 receptor is over-expressed in the gut mucosa of patients with inflammatory bowel disease, and that P2X7 inhibition protects against chemically induced colitis. Here, we investigated in detail the role of the P2X7 receptor in inflammatory bowel disease development, by treating P2X7 knockout (KO) and WT mice with two different (and established) colitis inductors. P2X7 KO mice were protected against gut inflammation induced by 2,4,6-trinitrobenzenesulfonic acid or oxazolone, with no weight loss or gut histological alterations after treatment. P2X7 receptor knockout induced regulatory T cell accumulation in the colon, as evaluated by qRT-PCR for FoxP3 expression and immunostaining for CD90/CD45RB(low). Flow cytometry analysis of mesenteric lymph node cells showed that P2X7 activation (by ATP) triggered regulatory T cell death. In addition, such cells from P2X7 KO mice expressed more CD103, suggesting increased migration of regulatory T cells to the colon (relative to the WT). Our results show that the P2X7 has a key role during inflammation development in inflammatory bowel disease, by triggering the death and retention in the mesenteric lymph nodes of regulatory T cells that would otherwise promote immune system tolerance in the gut.
- Published
- 2017
15. CD8
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Amine, Mellouk and Pierre, Bobé
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CD4-Positive T-Lymphocytes ,Mice, Knockout ,Aging ,Cell Differentiation ,CD8-Positive T-Lymphocytes ,Mice, Inbred C57BL ,Mice ,Adenosine Triphosphate ,Hyaluronan Receptors ,Phenotype ,T-Lymphocyte Subsets ,Animals ,Leukocyte Common Antigens ,Calcium Signaling ,Receptors, Purinergic P2X7 ,L-Selectin ,Immunologic Memory - Abstract
Previously we reported that the sensitivity of CD4
- Published
- 2018
16. Crystal Wars: la nécroptose contre-attaque
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Charlotte Duwat, Pierre Bobé, and Diana García García
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0301 basic medicine ,03 medical and health sciences ,chemistry.chemical_compound ,Mtor signaling ,030104 developmental biology ,chemistry ,Cysteine sulfinic acid ,General Medicine ,mTORC1 ,Nutrient sensing ,Molecular biology ,General Biochemistry, Genetics and Molecular Biology ,PI3K/AKT/mTOR pathway - Abstract
m/s n° 6-7, vol. 32, juin-juillet 2016 DOI : 10.1051/medsci/20163206019 2. Budanov AV, Lee JH, Karin M. Stressin’ sestrins take an aging fight. EMBO Mol Med 2010 ; 2 : 388-400. 3. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008 ; 134 : 451-60. 4. Budanov AV, Shoshani T, Faerman A, et al. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 2002 ; 21 : 6017-31. 5. Kim H, An S, Ro SH, et al. Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun 2015 ; 6 : 10025. 6. Woo H, Bae S, Park S, et al. Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. Antioxid Redox Signal 2009 ; 11 : 739-45. 7. Bae SH, Sung SH, Oh SY, et al. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liverdamage. Cell Metab 2013 ; 17 : 73-84. 8. Duran A, Amanchy R, Linares JF, et al. p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol Cell 2011 ; 44 : 134-46. Par son expression ubiquitaire et la pluralite de ses actions, la Sesn2 apparait comme un effecteur d’un grand interet dans l’homeostasie metabolique et la prevention du vieillissement. D’autres etudes sont encore necessaires pour mieux comprendre toutes les facettes de cette proteine. ‡ The two-faced Sestrin2 against age-related pathologies
- Published
- 2016
17. De nouvelles perspectives thérapeutiques pour l’arsenic
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Mounira K. Chelbi-Alix and Pierre Bobé
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Autoimmune disease ,Acute promyelocytic leukemia ,Acute leukemia ,Lupus erythematosus ,business.industry ,Autoantibody ,General Medicine ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Fas ligand ,chemistry.chemical_compound ,Leukemia ,chemistry ,Immunology ,medicine ,Arsenic trioxide ,skin and connective tissue diseases ,business - Abstract
Since 1996, arsenic trioxide (As2O3) is used to treat patients with acute promyelocytic leukemia. We have recently shown that As2O3 is a novel promising therapeutic agent for the autoimmune diseases (human lupus-like syndrome) and the massive lymphoproliferation (human autoimmune lymphoproliferative-like syndrome) developed by MRL/lpr mice. As2O3 is able to achieve an almost complete regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions. This treatment also markedly reduced anti-DNA autoantibodies, rheumatoid factor, IL-18, IFN-gamma, nitric oxide metabolites, TNF-alpha, Fas ligand and IL-10 levels, and immune-complex deposits in glomeruli, leading to significantly prolonged survival rates.
- Published
- 2008
18. An Essential Role for IFN-α in the Overexpression of Fas Ligand on MRL/lpr Lymphocytes and on Their Spontaneous Fas-Mediated Cytotoxic Potential
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Réda Hadj-Slimane, Mounira K. Chelbi-Alix, Michael G. Tovey, and Pierre Bobé
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Virology ,Immunology ,Cell Biology - Published
- 2004
19. Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain
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Ingrid Durand-Gasselin, Pierre Bobé, Emmanuelle Soual-Hoebeke, Nicole Kiger, Dominique Emilie, Danielle Bonardelle, and Karim Benihoud
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Transposable element ,Mice, Inbred MRL lpr ,Cancer Research ,Lymphoid Tissue ,Gene Expression ,Endogenous retrovirus ,Retrotransposon ,Biology ,Autoimmune Diseases ,Immunoenzyme Techniques ,Epitopes ,Mice ,Mice, Inbred AKR ,Capsid ,Transcription (biology) ,Gene expression ,Genetics ,Animals ,RNA, Messenger ,Molecular Biology ,Glycoproteins ,Mice, Inbred C3H ,Histocompatibility Antigens Class I ,Blotting, Northern ,Molecular biology ,Lymphoproliferative Disorders ,Reverse transcriptase ,Mice, Inbred C57BL ,Blot ,Open reading frame ,Long Interspersed Nucleotide Elements ,Liver ,Mice, Inbred DBA ,DNA Transposable Elements ,Mice, Inbred CBA ,Capsid Proteins ,Spleen - Abstract
LINE-1 are endogenous mobile genetic elements that have dispersed and accumulated in the genomes of eukaryotes via germline transposition, with up to 100,000 copies in mammalian genomes. LINE-1 elements transpose by reverse transcription of their own transcript. Transposition requires synthesis of a full-length, sense-strand transcripts and proteins encoded by open reading frame (ORF) 1 and ORF2. Although severely repressed in most normal tissues, LINE-1 occasionally leads to disease by insertional mutagenesis. In the present study, Northern blot and in situ hybridization analyses revealed a template-strand transcription of LINE-1 ORF2 (encoding reverse transcriptase, RT) in lymphoid organs and the liver from MRL-+/+ and Fas-deficient MRL/lpr strains and their normal ancestors. While these sense transcripts are restricted to the nucleus in hepatocytes, they are also found in the cytoplasm in splenocytes. In contrast to transcription, ORF2 translation was detected only in MRL strains, as shown by the cytoplasmic labelling of splenic cells obtained with a monoclonal antibody recognizing the LINE-1 RT. This antibody coprecipitated two proteins of 45 and 12 kDa from MRL/lpr lymphoid organ lysates that were removed by pretreatment with anti-beta2-microglobulin antiserum, suggesting a structural association between a LINE-1 product and a major histocompatibility complex class I or class I-like molecule.
- Published
- 2002
20. Sensitivity of leukemic T-cell lines to arsenic trioxide cytotoxicity is dependent on the induction of phosphatase B220/CD45R expression at the cell surface
- Author
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Pierre Bobé, Mohcine Benbijja, Amine Mellouk, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Régulation de la réponse immune, infection VIH-1 et autoimmunité, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation calcique et interactions cellulaires dans le foie, and Centre National de la Recherche Scientifique (CNRS, Agence Nationale de la Recherche (ANR-07BLAN0089-02)
- Subjects
Caspase activation ,Mice, Inbred MRL lpr ,Cancer Research ,T-Lymphocytes ,Membrane tyrosine-phosphatase B220/CD45R ,As2O3-based therapy ,Apoptosis ,Jurkat cells ,Arsenicals ,Fas ligand ,Jurkat Cells ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Arsenic Trioxide ,immune system diseases ,T lymphocyte ,Arsenic trioxide ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,Leukemia ,medicine.diagnostic_test ,NF-kappa B ,Oxides ,hemic and immune systems ,3. Good health ,medicine.anatomical_structure ,Oncology ,Molecular Medicine ,Fas/Fas ligand pathway ,Cell death ,Programmed cell death ,Membrane-bound HSP70 ,T cell ,NF-κB p50 ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Flow cytometry ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,HSP70 Heat-Shock Proteins ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Propidium iodide ,030304 developmental biology ,Research ,Cell Membrane ,chemistry ,Cancer research ,Leukocyte Common Antigens ,030215 immunology - Abstract
Background Arsenic trioxide (As2O3) is highly effective in treating acute promyelocytic leukemia (APL), but shows more variable therapeutic efficacy for other types of hematological malignancies. Previously, we reported that As2O3 selectively eliminates pathogenic B220-expressing T cells in autoimmune MRL/lpr mice. We investigated herein the relationship between As2O3 sensitivity of leukemic T-cell lines and the expression levels of the B220 isoform of transmembrane tyrosine phosphatase CD45. Methods GSH content, O2- production, and B220, HSP70, Fas and FasL membrane expression was measured by flow cytometry. Subcellular localization of B220 was determined by imaging flow cytometry. Cell death was analyzed by morphological changes, annexin V and propidium iodide staining, and caspase 8 and 9 activation. B220 mRNA expression was analyzed by RT-PCR. Activated NF-κB p50 was quantified by a DNA binding ELISA. Results We selected human (Jurkat, Jurkat variant J45.01, HPB-ALL) and mouse (EL-4, BW5147, L1210) T-cell lines for their marked differences in As2O3 sensitivity over a large range of doses (1 to 20 μM). Differences in redox status cannot explain the dramatic differences in As2O3 sensitivity observed among the T-cell lines. Unexpectedly, we found that B220 is differentially induced on As2O3-treated T-cell lines. As2O3 treatment for 24 h induced low (HPB-ALL), intermediate (Jurkat) and high (EL-4, BW5147) levels of B220 membrane expression, membrane-bound HSP70 and cell death, but inhibited NF-κB p50 nuclear translocation. When high levels of B220 expression were achieved with low doses of As2O3, the T-cell lines died by apoptosis only. When high doses of As2O3 were required to induce B220 expression, leukemic T cells died by both apoptosis and necrosis. Conclusions Cellular redox status is not essential for As2O3 sensitivity of leukemic T cells, suggesting the existence of additional factors determining their sensitivity to As2O3 cytotoxicity. Phosphatase B220 could be such a factor of sensitivity. As2O3 treatment inhibits NF-κB p50 nuclear translocation, and induces B220 expression and cell death in a dose and time dependent manner. The levels of B220 induction on leukemic T cells strictly correlate with both the extent and form of cell death, B220 might therefore play a checkpoint role in death pathways. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-13-251) contains supplementary material, which is available to authorized users.
- Published
- 2014
21. Nitric Oxide Mediation of Active Immunosuppression Associated With Graft-Versus-Host Reaction
- Author
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Linda L. Pritchard, Pierre Bobé, Paule Opolon, Danièle Grandjon, Karim Benihoud, and Roger Huchet
- Subjects
Arginine ,Lymphocyte ,medicine.medical_treatment ,Immunology ,Nitric Oxide Synthase Type II ,Biology ,Nitric Oxide ,Biochemistry ,Nitric oxide ,Minor Histocompatibility Antigens ,Graft vs Host Reaction ,Interferon-gamma ,Mice ,chemistry.chemical_compound ,medicine ,Animals ,Macrophage ,Enzyme Inhibitors ,Immunosuppression Therapy ,Cell Biology ,Hematology ,Molecular biology ,Pimagedine ,Nitric oxide synthase ,medicine.anatomical_structure ,Cytokine ,chemistry ,biology.protein ,Nitric Oxide Synthase ,CD5 - Abstract
In the immunosuppression accompanying the lethal systemic graft-versus-host reaction (GVHR) directed against minor histocompatibility antigens in irradiated adult mice, we previously determined that non-T, non-B, L-leucine methyl ester (LME)-sensitive cells were implicated via two different mechanisms: one, which is interferon-gamma (IFN-gamma)-dependent and affects both T-cell proliferative responses and thymus-independent antibody production by CD5(+) B cells; and a second, which is IFN-gamma-independent and affects B-cell proliferative responses. Because IFN-gamma induces the production of nitric oxide (NO), a potent immunosuppressive molecule, we investigated the involvement of NO in the suppression mediated by the LME-sensitive cells. Inducible NO synthase (iNOS) mRNA, iNOS protein, and the stable end products of iNOS pathway, L-citrulline and nitrite, were detected early in GVHR in LME-sensitive spleen cells taken ex vivo and could be amplified in vitro by T and B mitogens. Inhibition of NO production with arginine analogs (aminoguanidine, N(G)-monomethyl-L-arginine [LMMA]), like anti-IFN-gamma antibodies, reversed suppression of both T-cell responses to concanavalin A and CD5(+) B-cell responses, but not of B-cell response to lipopolysaccharides (LPS). The GVHR-associated, IFN-gamma-dependent immunosuppression of T-cell proliferation and of antibody synthesis by CD5(+) B cells is the consequence of NO production by LME-sensitive cells. Immunohistochemical analyses indicate that these cells belong to the macrophage lineage.
- Published
- 1999
22. MRL/lpr CD4−CD8− and CD8+ T cells, respectively, mediate Fas-dependent and perforin cytotoxic pathways
- Author
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Danielle Bonardelle, Pierre Bobé, Karim Benihoud, and Nicole Kiger
- Subjects
Cytotoxicity, Immunologic ,Pore Forming Cytotoxic Proteins ,Mice, Inbred MRL lpr ,Fas Ligand Protein ,CD8 Antigens ,T cell ,Immunology ,Ligands ,Major histocompatibility complex ,Fas ligand ,Mice ,Antigen ,T-Lymphocyte Subsets ,Concanavalin A ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,fas Receptor ,skin and connective tissue diseases ,Cells, Cultured ,Membrane Glycoproteins ,biology ,Perforin ,Ionomycin ,T-cell receptor ,Fas receptor ,Molecular biology ,Culture Media ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Mice, Inbred DBA ,CD4 Antigens ,biology.protein ,Tetradecanoylphorbol Acetate ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Autoimmune-prone MRL/lpr mice, homozygous for the lpr mutation, exhibit defective apoptosis and develop generalized lymphoproliferation with the accumulation of a double-negative (DN: CD4- CD8-) T cell population. The capacity of lpr T lymphocytes to effectuate Fas- and perforin-mediated cytotoxicity was investigated. Spleen and lymph nodes cells spontaneously lyse Fas- targets (thymocytes) through a Fas-mediated mechanism as a consequence of their overexpression of Fas ligand (FasL) confirmed by semiquantitative reverse transcription (RT)-PCR and immunoprecipitation analysis. This cytotoxicity was greatly increased after stimulation of the effectors by phorbol myristate acetate (PMA) + ionomycin. Under these conditions, MRL/lpr spleen and LN cells exhibited strong Fas-mediated Ca2+-independent cytotoxic activity against wild-type Fas+ (H-2 compatible or incompatible) thymocytes or lipopolysaccharide (LPS)-transformed blast cells. Such Fas-mediated cytotoxic activity was also observed with C57BL/6-lpr, but never with wild-type C57BL/6 or MLR+/+ effectors. Depletion experiments showed that the effector cells of this Fas-mediated cytotoxicity were DN T cells. This subset, which represent in vivo activated T cells, can spontaneously lyse Fas+ targets by a mechanism that does not need the interaction of the T cell receptor (TCR) with major histocompatibility complex molecule plus antigen. This lytic potential is increased by PMA + ionomycin, which sends a second activation signal to these primed T cells. Therefore, the small amounts of Fas receptor expressed on MRL/lpr tissues may account for their nonspecific autoimmune attack by DN cells. In Con A-containing medium, which allows detection of the perforin-mediated pathway against Fas targets, cytotoxic CD8+ effectors were detected that are able to kill lpr thymocytes via a Ca2+-dependent pathway. Thus, in MRL/lpr mice, these CD8+ cells could constitute potent cytotoxic effectors against cells presenting antigen to their TCR.
- Published
- 1997
23. A Mouse Placental Immunoregulatory Factor Different from Transforming Growth Factor β
- Author
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Colette Kanellopoulos-Langevin, Pierre Bobé, and Christian Bleux
- Subjects
medicine.drug_class ,Placenta ,Immunoblotting ,Immunology ,Monoclonal antibody ,Chromatography, Affinity ,Cell Line ,Mice ,Immune system ,Pregnancy ,Transforming Growth Factor beta ,Virology ,medicine ,Animals ,Cytotoxic T cell ,Maternal-Fetal Exchange ,biology ,Cell growth ,Antibodies, Monoclonal ,Cell Biology ,Transforming growth factor beta ,Cell biology ,medicine.anatomical_structure ,Transforming growth factor, beta 3 ,Mice, Inbred CBA ,biology.protein ,Female ,Antibody ,Cell Division ,Immunosuppressive Agents - Abstract
Of the growth-promoting factors, transforming growth factor beta (TGF-beta) has been most clearly shown to act as a potent regulator of inflammation and immunity. It is highly suppressive for T and B lymphocyte proliferation, cytotoxic T lymphocyte generation, and lymphokine-activated killer cell development, as well as natural killer cell activity. Moreover, there is accumulating evidence that TGF-beta also may contribute to impaired immune surveillance of tumor development. In previous work, we isolated and described a 40 kD glycoprotein extracted from mouse placenta. This placental factor (PF) is also a potent immune modulator in vivo: it is highly inhibitory of secondary antibody responses as well as cellular responses, such as local graft-versus-host reactions. Because placenta has been shown to be a major source of TGF-beta and several reports have indicated an important role for TGF-beta in the immunosuppressive mechanisms taking place during the course of mammalian gestation, we have looked for the presence of TGF-beta in our placental factor preparations. Our results clearly indicate that they do not contain TGF-beta or TGF-beta-like molecules by the following criteria: (1) no inhibition of Mv-1 Lu cell proliferation at any dose tested; (2) no band detected by immunoblotting using different polyclonal reagents specific for TGF-beta 1; and (3) no activity retained on or eluted from an affinity column made of immobilized monoclonal antibody against TGF-beta 2. Aliquots of the same preparations retained their full immune inhibitory capacity in vivo throughout the various assays.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
24. The Fas - Fas Ligand apoptotic pathway
- Author
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Pierre Bobé
- Subjects
Cancer Research ,Oncology ,Apoptosis ,Chemistry ,Genetics ,Cancer research ,Hematology ,Fas receptor ,Fas ligand - Published
- 2011
25. IMBALANCE OF MHC CLASS I EXPRESSION IN 3LL TUMOUR CELLS
- Author
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Pierre Bobé, Karim Benihoud, Nicole Kiger, and Jean-Michel Lecerf
- Subjects
medicine.drug_class ,Molecular Sequence Data ,Immunology ,Cell ,Gene Expression ,Genes, MHC Class I ,In Vitro Techniques ,Monoclonal antibody ,Interferon-gamma ,Mice ,Antigen ,Interferon ,MHC class I ,Gene expression ,Tumor Cells, Cultured ,Genetics ,medicine ,Animals ,Base Sequence ,biology ,Histocompatibility Antigens Class I ,H-2 Antigens ,Antibodies, Monoclonal ,Blotting, Northern ,Molecular biology ,Recombinant Proteins ,In vitro ,medicine.anatomical_structure ,Cell culture ,biology.protein ,Oligonucleotide Probes ,beta 2-Microglobulin ,medicine.drug - Abstract
SUMMARY Cell lines and a clone established from the C57BL/6 (H-2b) Lewis lung (3LL) tumour were previously characterized with respect to tumour growth and metastatic spread in vivo, and to the expression of a 3LL tumour-specific antigen (3LL TA) using a monoclonal antibody raised in syngeneic mice immunized with 3LL cells. No correlation was observed between the presence of 3LL TA and the prevention of metastatic spread which suggests that the immune recognition of this tumour antigen requires the presence of a self H-2 molecule absent from these tumour cells. Indeed, radioimmunoassay (RIA) and cytofluorometric analysis using specific monoclonal antibodies have shown that the H-2Kb molecule was not expressed at the cell surface of all 3LL cell lines and clones, while the H-2Db molecule was present at normal levels. This defect, which was not the consequence of a lack Of (32m expression, was accompanied by an absence or a marked reduction of the H-2K mRNA level (which has been reversed in the M4 cell line by in vitro gamma interferon treatment), while the H-2D class I gene was normally transcribed. Another defective transcription was also observed for a gene in the Tla region (gene 37). This low‘37’phenotype was corrected by in vitro treatment of the M4 cell line with gamma interferon, which indicates that this class I gene of the Qa/Tla region has an interferon response sequence in the promoter.
- Published
- 1991
26. [New therapeutic perspectives for arsenic: from acute promyelocytic leukemia to autoimmune diseases]
- Author
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Pierre, Bobé and Mounira K, Chelbi-Alix
- Subjects
Antineoplastic Agents ,Oxides ,Arsenicals ,Growth Inhibitors ,Lymphoproliferative Disorders ,Arsenic ,Autoimmune Diseases ,Disease Models, Animal ,Mice ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Animals ,Humans ,Lupus Erythematosus, Systemic - Abstract
Since 1996, arsenic trioxide (As2O3) is used to treat patients with acute promyelocytic leukemia. We have recently shown that As2O3 is a novel promising therapeutic agent for the autoimmune diseases (human lupus-like syndrome) and the massive lymphoproliferation (human autoimmune lymphoproliferative-like syndrome) developed by MRL/lpr mice. As2O3 is able to achieve an almost complete regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions. This treatment also markedly reduced anti-DNA autoantibodies, rheumatoid factor, IL-18, IFN-gamma, nitric oxide metabolites, TNF-alpha, Fas ligand and IL-10 levels, and immune-complex deposits in glomeruli, leading to significantly prolonged survival rates.
- Published
- 2008
27. Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice
- Author
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Elisabeth Connault, Barbara Salone, Paule Opolon, Michel Perricaudet, Delphyne Descamps, Pierre Bobé, Stéphanie Esselin, Karim Benihoud, Isabella Saggio, Danielle Bonardelle, Betsy Jullienne, Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes Lasers Intenses et Applications (CELIA), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Oncologie virale (OV), Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB), Faculté des Sciences, Université de Genève (UNIGE), Institut Gustave Roussy (IGR), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], and UPR 9045
- Subjects
TNF-a ,[SDV]Life Sciences [q-bio] ,Adenoviridae Infections ,Genetic enhancement ,medicine.medical_treatment ,Gene Expression ,Antibodies, Viral ,immune response ,Receptors, Tumor Necrosis Factor ,Etanercept ,Hepatitis ,Mice ,0302 clinical medicine ,Transduction, Genetic ,Transgenes ,Mice, Knockout ,Mice, Inbred BALB C ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Immunogenicity ,adenovirus ,gene therapy ,3. Good health ,Cytokine ,Receptors, Tumor Necrosis Factor, Type I ,030220 oncology & carcinogenesis ,Molecular Medicine ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Tumor necrosis factor alpha ,TNF-alpha ,Transgene ,Genetic Vectors ,Biology ,Gene delivery ,Adenoviridae ,Proinflammatory cytokine ,03 medical and health sciences ,Immune system ,Genetics ,medicine ,Animals ,Humans ,RNA, Messenger ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,Autoantibodies ,030304 developmental biology ,IL-6 ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Genetic Therapy ,TNF-a, IL-6, immune response ,Immunoglobulin G ,DNA, Viral ,Immunology - Abstract
International audience; The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding beta-galactosidase or alpha1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6(-/-)) to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha leads to increased transgene expression in both wild-type and IL-6(-/-) mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6(-/-) mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.Gene Therapy advance online publication, 16 November 2006; doi:10.1038/sj.gt.3302885.
- Published
- 2007
28. Arsenic trioxide: a promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice
- Author
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Mounira K. Chelbi-Alix, Paule Opolon, Pierre Bobé, Karim Benihoud, Danielle Bonardelle, Oncologie virale (OV), Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Epigenetique et Cancer, and Harel-Bellan, Annick
- Subjects
Mice, Inbred MRL lpr ,Drug Evaluation, Preclinical ,Apoptosis ,Antigen-Antibody Complex ,Lymphocyte Activation ,Biochemistry ,Arsenicals ,Fas ligand ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Arsenic Trioxide ,Lupus Erythematosus, Systemic ,Arsenic trioxide ,skin and connective tissue diseases ,0303 health sciences ,Systemic lupus erythematosus ,Oxides ,Syndrome ,Hematology ,Glutathione ,3. Good health ,Antibodies, Antinuclear ,Caspases ,Cytokines ,Oxidation-Reduction ,Immunology ,Antineoplastic Agents ,Nitric Oxide ,Nitric oxide ,03 medical and health sciences ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,fas Receptor ,030304 developmental biology ,Lupus erythematosus ,business.industry ,Autoantibody ,Cell Biology ,medicine.disease ,Lymphoproliferative Disorders ,Enzyme Activation ,chemistry ,Autoimmune lymphoproliferative syndrome ,business ,030215 immunology - Abstract
MRL/lpr mice develop a human lupuslike syndrome and, as in autoimmune lymphoproliferative syndrome (ALPS), massive lymphoproliferation due to inactivation of Fas-mediated apoptosis. Presently, no effective therapy exists for ALPS, and long term, therapies for lupus are hazardous. We show herein that arsenic trioxide (As2O3) is able to achieve quasi-total regression of antibody- and cell-mediated manifestations in MRL/lpr mice. As2O3 activated caspases and eliminated the activated T lymphocytes responsible for lymphoproliferation and skin, lung, and kidney lesions, leading to significantly prolonged survival rates. This treatment also markedly reduced anti-DNA autoantibody, rheumatoid factor, IL-18, IFN-γ, nitric oxide metabolite, TNF-α, Fas ligand, and IL-10 levels and immune-complex deposits in glomeruli. As2O3 restored cellular reduced glutathione levels, thereby limiting the toxic effect of nitric oxide, which is overproduced in MRL/lpr mice. Furthermore, As2O3 protected young animals against developing the syndrome and induced almost total disease disappearance in older affected mice, thereby demonstrating that it is a novel promising therapeutic agent for autoimmune diseases.
- Published
- 2006
29. B lymphocytes mediate Fas-dependent cytotoxicity in MRL/lpr mice
- Author
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Danielle Bonardelle, Karim Benihoud, Nicole Kiger, and Pierre Bobé
- Subjects
Cytotoxicity, Immunologic ,Mice, Inbred MRL lpr ,Fas Ligand Protein ,T-Lymphocytes ,Immunology ,Naive B cell ,Cell ,Population ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Fas ligand ,Mice ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,RNA, Messenger ,Cytotoxicity ,education ,B cell ,education.field_of_study ,B-Lymphocytes ,Membrane Glycoproteins ,Cell Biology ,Molecular biology ,Cell biology ,Up-Regulation ,Killer Cells, Natural ,medicine.anatomical_structure ,Gene Expression Regulation ,Tumor Necrosis Factors ,Ex vivo ,Spleen - Abstract
The Fas/Fas ligand (FasL) pathway is one of the two major effector mechanisms of T cell-mediated cytotoxicity. To prevent nonspecific killing by lymphoid cells, FasL expression on the cell surface of immune effector cells is strictly regulated. However, MRL/lpr autoimmune-prone mice massively overexpress FasL on their T lymphocytes, which render them able to kill Fas+ targets in vitro and in vivo. It is surprising that we show in the present work that B lymphocytes purified from MRL/lpr spleen cells express FasL to the same extent as T cells at the mRNA and protein level. These B cells are potent cytotoxic effectors against Fas+ but not Fas− targets. The B lymphocyte effectors were used ex vivo without any in vitro activation by B cell stimuli. Furthermore, we found that MRL/lpr B lymphocytes have the same cytotoxic potential as natural killer cells, which have been characterized as potent, Fas-mediated, cytotoxic effectors. The level of membrane-anchored FasL increases with the size of the B cell and cell-surface activation marker CD69 expression, indicating that the expression of FasL is up-regulated in parallel with the activation state of the B cell. The activated B cell population contained the major cytotoxic activity, and a minor part was associated with CD138/Syndecan-1+ plasma cells.
- Published
- 2005
30. An essential role for IFN-alpha in the overexpression of Fas ligand on MRL/lpr lymphocytes and on their spontaneous Fas-mediated cytotoxic potential
- Author
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Pierre Bobé, Michael G. Tovey, Mounira K. Chelbi-Alix, and Réda Hadj-Slimane
- Subjects
Cytotoxicity, Immunologic ,Transcriptional Activation ,Mice, Inbred MRL lpr ,DNA, Complementary ,Fas Ligand Protein ,Transcription, Genetic ,animal diseases ,Immunology ,Receptor, Interferon alpha-beta ,urologic and male genital diseases ,Fas ligand ,Mice ,Downregulation and upregulation ,immune system diseases ,Virology ,Gene expression ,Splenocyte ,Cytotoxic T cell ,Animals ,Lupus Erythematosus, Systemic ,Lymphocytes ,RNA, Messenger ,Phosphorylation ,skin and connective tissue diseases ,Gene ,Cells, Cultured ,Receptors, Interferon ,Membrane Glycoproteins ,Chemistry ,Reverse Transcriptase Polymerase Chain Reaction ,Interferon-alpha ,Membrane Proteins ,Nucleic Acid Hybridization ,Cell Biology ,Molecular biology ,female genital diseases and pregnancy complications ,DNA-Binding Proteins ,STAT1 Transcription Factor ,Gene Expression Regulation ,Suppression subtractive hybridization ,Trans-Activators ,After treatment ,Spleen - Abstract
Lymphocytes from aged autoimmune MRL/lpr mice overexpress Fas ligand (FasL), and are cytotoxic against Fas+ target cells. This cytotoxic potential is only partly due to FasL, as wild-type MRL+/+ lymphocytes are not able to kill Fas+ targets after induction of FasL. In addition, serum levels of interferon-alpha (IFN-alpha) increase in parallel with the Fas-dependent cytotoxic potential of lymphocytes from MRL/lpr mice as they age. To understand the mechanisms underlying these observations, combined suppression subtractive hybridization (SSH) and RT-PCR were used to study differential gene expression in splenocytes from MRL/lpr mice compared with splenocytes from MRL+/+ mice. Twenty-two genes were upregulated transcriptionally in MRL/lpr splenocytes compared with their MRL+/+ counterparts. Furthermore, 9 of these genes were also upregulated after treatment of MRL/lpr splenocytes with IFN-alpha, and 4 were strongly downregulated. MRL/lpr lymphocytes were also found to be hyperresponsive to IFN-alpha. Thus, MRL/lpr lymphocytes overexpressed mRNA for the IFN-alpha receptor (IFNAR-1 and IFNAR-2) chains of the IFN-alpha/beta receptor and exhibited high endogenous levels of both Stat1 and phosphorylated Stat1 proteins. Lymphocytes from young MRL/lpr mice, with low Fas-dependent cytotoxic activity, were found to become highly cytotoxic against Fas+ targets after treatment with IFN-alpha. These data suggest that IFN-alpha plays an important role in the physiopathology of the systemic lupus erythematosus (SLE)-like syndrome that occurs in MRL/lpr mice.
- Published
- 2005
31. Arsenic enhances the activation of Stat1 by interferon gamma leading to synergistic expression of IRF-1
- Author
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Pierre Bobé, Richard Pine, Antony Canova, Mounira K. Chelbi-Alix, and Gérard Benoit
- Subjects
inorganic chemicals ,Cancer Research ,medicine.medical_treatment ,chemistry.chemical_element ,Apoptosis ,Tretinoin ,Arsenicals ,Arsenic ,Interferon-gamma ,Interferon γ ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Interferon ,Superoxides ,Genetics ,medicine ,Tumor Cells, Cultured ,Humans ,STAT1 ,Promoter Regions, Genetic ,Molecular Biology ,integumentary system ,biology ,Cell Differentiation ,Drug Synergism ,Oxides ,Phosphoproteins ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Cytokine ,STAT1 Transcription Factor ,chemistry ,Drug Resistance, Neoplasm ,biology.protein ,Cancer research ,Trans-Activators ,medicine.drug ,Interferon Regulatory Factor-1 ,Signal Transduction - Abstract
Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia (APL), including those who have relapsed after treatment with all-trans-retinoic acid (RA). In vitro studies with the APL-derived NB4 cell line showed that As2O3 exerts a dose-dependent dual effect, which induces apoptosis at 1 microM, whereas at a lower concentration of 0.1 microM, a partial differentiation of APL is observed. In non-APL cells, interferon (IFN) alpha and 1 microM As2O3 act synergistically to induce apoptosis. In this report, we show that in NB4 cells and in two RA-resistant NB4-derived cell lines, NB4-R1 and NB4-R2, IFNalpha or IFNgamma combined with 0.1 microM As2O3 lead to an increased maturation effect. Moreover, IFNgamma alone is able to differentiate RA-sensitive and -resistant cells with a higher maturation effect on NB4-R2 cells. In contrast, all these cells underwent apoptosis in the presence of the cytokine and a higher concentration of As2O3. IFNgamma boosted As2O3-induced apoptosis in APL cells as tested by TUNEL, Annexin V staining and activation of caspase 3. As2O3 differently altered IFN-induced gene products; it downregulated PML/RARalpha and PML, did not alter PKR and Stat1, and upregulated interferon regulatory family (IRF)-1. Synergism by IFNgamma and arsenic on IRF-1 expression is mediated by a composite element in the IRF-1 promoter that includes an IFNgamma-activation site (GAS) overlapped by a nonconsensus site for nuclear factor kappa B (NFkappaB). Arsenic has no effect on NFkappaB, whereas it enhances the activation of Stat1 by IFNgamma in NB4 cells leading to an increase in IRF-1 expression.
- Published
- 2003
32. Leukocyte Population Dynamics and Detection of IL-9 as a Major Cytokine at the Mouse Fetal-Maternal Interface
- Author
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Philippe Verbeke, Pierre Bobé, Colette Kanellopoulos-Langevin, Sonia Karaz, Mohamed Habbeddine, Institut Jacques Monod (IJM (UMR_7592)), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Placenta ,medicine.medical_treatment ,Uterus ,lcsh:Medicine ,NK cells ,Monocytes ,Leukocyte Count ,Mice ,Pregnancy ,Cellular types ,Leukocytes ,Conceptus ,lcsh:Science ,Maternal-Fetal Exchange ,education.field_of_study ,Multidisciplinary ,Animal Models ,3. Good health ,Phenotype ,medicine.anatomical_structure ,Cytokine ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,White blood cells ,Cytokines ,Female ,Research Article ,Cell biology ,Blood cells ,Immune Cells ,Immunology ,Population ,T cells ,Antigen-Presenting Cells ,Mouse Models ,Biology ,Research and Analysis Methods ,Immune Suppression ,Immunophenotyping ,Immunomodulation ,Model Organisms ,medicine ,Animals ,Interleukin 9 ,education ,B cells ,Fetus ,Biology and life sciences ,lcsh:R ,Immunity ,Interleukin-9 ,Immunoregulation ,Reproductive Immunology ,medicine.disease ,Animal cells ,Clinical Immunology ,lcsh:Q - Abstract
International audience; Despite much interest in the mechanisms regulating fetal-maternal interactions, information on leukocyte populations and major cytokines present in uterus and placenta remains fragmentary. This report presents a detailed and quantitative study of leukocyte populations at the mouse fetal-maternal interface, including a comparison between pregnancies from syngeneic and allogeneic crosses. Our results provide evidence for drastic differences not only in the composition of leukocyte populations in the uterus during pregnancy, but also between uterine and placental tissues. Interestingly, we have observed a significant decrease in the number of myeloid Gr1+ cells including monocytes, and myeloid CD11c+ cells including DCs in placenta from an allogeneic pregnancy. In addition, we have compared the expression levels of a panel of cytokines in non-pregnant (NP) or pregnant mouse uterus, in placenta, or in their isolated resident leukocytes. Qualitative and quantitative differences have emerged between NP, pregnant uterus and placenta. Unexpectedly, IL-9 was the major cytokine in NP uterus, and was maintained at high levels during pregnancy both in uterus and placenta. Moreover, we have found that pregnancy is associated with an increase in uterine IL-1a and a significant decrease in uterine G-CSF and GM-CSF. Comparing allogeneic versus syngeneic pregnancy, less allogeneic placental pro-inflammatory cytokines CCL2 (MCP-1), CXCL10 (IP-10) and more IL1-α in whole uterus was reproducibly observed. To our knowledge, this is the first report showing a detailed overview of the leukocyte and cytokine repertoire in the uterus of virgin females and at the fetal-maternal interface, including a comparison between syngeneic and allogeneic pregnancy. This is also the first evidence for the presence of IL-9 in NP uterus and at the maternal-fetal interface, suggesting a major role in the regulation of local inflammatory or immune responses potentially detrimental to the conceptus.
- Published
- 2014
33. PS1-05 Loss of P2X7 receptor expression on dn regulatory T-cell subsets through T-cell activation
- Author
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Sylvain Le Gall, Pierre Bobé, Michael G. Tovey, and Julie Legrand
- Subjects
medicine.anatomical_structure ,Regulatory T cell ,Chemistry ,T cell ,Immunology ,medicine ,Immunology and Allergy ,Hematology ,Molecular Biology ,Biochemistry ,P2x7 receptor ,Cell biology - Published
- 2010
34. Upregulation of B220 expression correlates with sensitivity to arsenic trioxide (As2O3)-induced cell death in different leukemic T-cell lines (132.11)
- Author
-
Pierre Bobé and Mohcine Benbijja
- Subjects
Immunology ,Immunology and Allergy - Abstract
As2O3 kills a variety of leukemia cells, but with different efficacy. Although cellular redox status is considered essential for As2O3 sensitivity, we show here that murine and human leukemic T-cell lines display dramatic differences in As2O3 sensitivity independently of their GSH content and O2− production. Unexpectedly, As2O3 differently upregulated expression of phosphatase B220 on these T cells in dose-dependent manner. Since we previously reported that As2O3 selectively eliminates pathogenic B220+ T cells in autoimmune MRL/lpr mice (Bobé et al, BLOOD, 2006, 108:30967), we have studied the possible correlation between B220 expression and As2O3-induced T-cell death in leukemic T-cell lines. In the presence of As2O3, we found low (HPB-ALL), intermediate (Jurkat) and high (EL-4, BW5147) levels of both B220 expression and cell death. Ca2+ ionophore A23187 also upregulated B220 expression and cell death, but with opposite efficiencies in the T-cell lines compared to As2O3. A23187 only upregulated the T-cell activation marker CD69 before B220 expression and cell death, suggesting that it kills by an activation-induced cell death mechanism. In L1210 cells, we found constitutive B220 expression. L1210 cells were the most resistant to cell death among As2O3-treated T-cell lines whereas they were the most sensitive to A23187. As2O3 and A23187 probably trigger different signaling pathways through B220 leading to T-cell death, suggesting a checkpoint role for B220 in death pathways.
- Published
- 2010
35. Loss of P2X7 receptor membrane expression in B220+ double-negative T lymphocytes of autoimmune MRL/lpr mice (143.32)
- Author
-
Pierre Bobé, Sylvain Le Gall, Julie Legrand, Mohcine Benbijja, Karim Benihoud, and Jean Kanellopoulos
- Subjects
Immunology ,Immunology and Allergy - Abstract
Lupus is an autoimmune disease influenced by multiple genetic loci. Fas-deficient MRL/lpr mice exhibit lupus and lymphoproliferative syndromes with massive accumulation of B220+CD4-CD8- (DN) T lymphocytes. Pathogenic B220+ DN T lymphocytes are derived from normal activated T lymphocytes which have not undergone activation-induced cell death due to inactivation of Fas. Normal activated peripheral T lymphocytes up-regulate the membrane phosphatase B220 before undergoing apoptosis. In Fas-deficient mice, activated T cells down-regulate CD4 or CD8 molecules but retain the expression of B220. P2X7R is an extracellular ATP-gated cell membrane receptor involved in the release of inflammatory cytokines and cell death. We show herein that MRL/lpr mice carry a P2X7R allele, which confers a high sensitivity to ATP. However, during aging, the MRL/lpr T-cell population exhibits a drastically reduced sensitivity to ATP-mediated stimulation of P2X7R. This decrease in P2X7R activity parallels the increase in B220+ DN T-cell numbers in lymphoid organs. The rare B220+ T cells observed in normal mice are also resistant to ATP treatment. Moreover, B cells, which express B220 as a developmental marker, are also dramatically less sensitive to ATP treatment. Using rabbit anti-P2X7R sera, we found a strong reduction in P2X7R levels on B220+ cells. Our results prompt the conclusion that B220 expression strongly correlates with the negative regulation of ATP/P2X7R pathway on both T and B cells.
- Published
- 2010
36. Spontaneous autocytotoxicity against an unexpected H-2 d haplotype in MRL/lpr (H-2 k) autoimmune disease-prone mice
- Author
-
Nicole Kiger, Pierre Bobé, and Gabriel Gachelin
- Subjects
Cytotoxicity, Immunologic ,medicine.drug_class ,Lymphocyte ,Immunology ,Biology ,urologic and male genital diseases ,Monoclonal antibody ,medicine.disease_cause ,Autoantigens ,Autoimmune Diseases ,Autoimmunity ,Mice ,Inbred strain ,Antigen ,immune system diseases ,Genetics ,medicine ,Animals ,Lupus Erythematosus, Systemic ,Cytotoxic T cell ,skin and connective tissue diseases ,Autoimmune disease ,H-2 Antigens ,Antibodies, Monoclonal ,medicine.disease ,Mice, Mutant Strains ,CTL ,medicine.anatomical_structure ,Haplotypes ,T-Lymphocytes, Cytotoxic - Abstract
The MRL/lpr (H-2k) inbred strain, a model for the autoimmune disease systemic lupus erythematosus, differs from the healthy inbred strain MRL +/+ (H-2k) by only 0.1% of its genome. Southern blot analysis using class I and class II probes confirmed the H-2k genotype of both strains. Among the Iak-positive peritoneal cells, cells with an unexpected expression of Iad specificities were detected in a radioimmunoassay using several monoclonal antibodies and one conventional antiserum. This was only found in aged (6- to 9-month-old) mice both in the MRL/lpr strain (32% Iad-positive mice) and in the MRL +/+ strain (42% Iad-positive mice). Furthermore, 24% of aged MRL/lpr mice exhibited strong spontaneous cytotoxic T lymphocyte (CTL) activities against P815 (H-2d) target cells, and 57% had a weaker but still detectable level of cytotoxicity. In contrast, such a CTL activity has never been found in the MRL +/+ strain. These results suggest that the anti-H-2d CTL plays a role in the onset of the autoimmune process in MRL/lpr mice.
- Published
- 1987
37. Immunogenetic studies of spontaneous abortion in mice
- Author
-
Marc Stanislawski, Gérard Chaouat, Nicole Kiger, and Pierre Bobé
- Subjects
Fetus ,medicine.medical_specialty ,Ratón ,Immunology ,Spleen ,Immunogenetics ,Biology ,Immune tolerance ,law.invention ,Endocrinology ,medicine.anatomical_structure ,Inbred strain ,law ,Internal medicine ,medicine ,biology.protein ,Recombinant DNA ,Antibody - Abstract
CBA/J females (H-2k) mated with DBA2/J males (H-2d) exhibit a high rate of fetal resorption. Fetal survival has been improved by pretreatment of CBA/J females with spleen cells from BALB/c J (H-2d) (but not from CBA/J or DBA/2/J) males. Similarly, three out of nine recombinant inbred strains (recombining BALB/c and DBA2 genomes at the homozygous state) possess antiabortive effects like the BALB/c parent. Previous studies showed that BALB/c pretreatment triggers the appearance of suppressor cells in the spleen and of IgG1 anti-H-2d antibodies in the serum of CBA/J females. Studies of these two immunological parameters after CBA/J preimmunization by the different recombinant strains suggest that local intrauterine immunoregulation is the determinant of success or failure of allopregnancy.
- Published
- 1986
38. Deviation of humoral and cellular alloimmune reactions by placental extracts
- Author
-
Aline Massé, H.T. Duc, R. Kinsky, Guy A. Voisin, and Pierre Bobé
- Subjects
Cellular immunity ,Isoantigens ,Lymphocyte ,Placenta ,Immunology ,Spleen ,Mice, Inbred Strains ,Biology ,In Vitro Techniques ,Mice ,Immune system ,In vivo ,Pregnancy ,medicine ,Immune Tolerance ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Transplantation, Homologous ,Immunity, Cellular ,Graft Survival ,Obstetrics and Gynecology ,medicine.anatomical_structure ,Reproductive Medicine ,Humoral immunity ,Antibody Formation ,biology.protein ,Female ,Immunization ,Antibody - Abstract
Modifications of the alloimmune response at both the humoral and the cellular levels by placental extracts (PE) syngeneic to the recipient were studied in the mouse using two different H-2 strain combinations, CBA (II-2 k ) or C57BL/Ks (H-2 d ), immunized with A/J (H-2 a ) spleen cells. The tests included in vivo tumor allograft evolution (accelerated rejection or enhancement reactions), and in vitro analysis of the involved immune agents, both cellular and humoral, using mixed lymphocyte reactions (MLR) and biological activity studies of serum samples. Animals from the recipient strains exhibited a delayed rejection of A/J tumor Sa 1 allografts if preimmunization was carried out with 10 6 A/J spleen cells combined with PE syngeneic to the recipients, as compared to controls immunized with A/J cells only or supplemented with isogeneic liver extracts (LE). The serological analysis revealed that PE treatment did not modify the overal hemagglutinating antibody production but resulted simultaneously in both a decreased production of cytotoxic complement fixing antibodies and an increase of specific anaphylactic mast cell degranulating antibodies, as compared to controls. The sera from PE-treated donors also demonstrated enhancing activity following passive transfer to isogeneic recipients. MLR regulatory activity was exhibited by spleen cells from PE- and immunogen-treated mice although the same or stronger activity was obtained from mice immunized without the addition of PE. However, in vivo transfer of these cells to syngeneic recipients showed that PE treatment erased the accelerated rejection caused by allogeneic immunization in the absence of PE and could even cause some degree of allografted tumor enhancement. The cells responsible for this inhibitory effect were mainly IJ + lymphocytes, since their elimination with a relevant anti-IJ serum and complement restored a secondary type rejection pattern. These results show that PE present during the onset of immunization can promote the activation of regulatory agents such as enhancing antibodies and suppressor cells favoring allograft survival.
- Published
- 1985
39. Modulation of mouse anti-SRBC antibody response by placental extracts
- Author
-
Miljenko Dorić, Pierre Bobé, Guy A. Voisin, and R. Kinsky
- Subjects
medicine.medical_specialty ,Erythrocytes ,Ratón ,Placenta ,Immunology ,Immunoglobulins ,chemical and pharmacologic phenomena ,Stimulation ,Spleen ,Immunoglobulin G ,Mice ,Immune system ,Pregnancy ,Internal medicine ,Placental Extracts ,medicine ,Animals ,Humans ,liver extract ,placental extract ,placental fraction ,plaque forming cells ,sheep red blood cells ,Immunosuppression Therapy ,Sheep ,biology ,Tissue Extracts ,Endocrinology ,medicine.anatomical_structure ,Humoral immunity ,Antibody Formation ,biology.protein ,Chromatography, Gel ,Mice, Inbred CBA ,Female ,Antibody - Abstract
Mouse placental extracts (PE) and corresponding Sephadex G-200 fractions were administered to isogeneic CBA mice along with an optimal immunizing dose of SRBC. Spleen cells were harvested 8 days later and transferred to CBA recipients, subsequently immunized with SRBC. The immunoregulatory activity of spleen cells from PE-treated donors was compared to cells from liver extract (LE)-treated controls or from mice immunized with SRBC only, using Cunningham's PFC direct and indirect tests. Within the dose range used, selective modulatory activities were obtained with cells from PE, but not from LE, treated mice, the latter being comparable to cell transfer effects from donors immunized with SRBC only. Spleen cells from animals injected with low doses of PE (0.25 to 4 mg per mouse) added to immunizing SRBC had a suppressive effect on the primary IgM response of recipients immunized against SRBC. In contrast, when SRBC were given to donor animals with higher doses of PE (8 to 13 mg), transferred spleen cells potentiated the IgM response of the recipients. These opposite suppressive and potentiating activities were found in distinct Sephadex G-200 fractions of 40 and 60 kDa, respectively. When the effect of PE treatment was tested within the same animal, the indirect secondary PFC response following a challenge with SRBC was significantly modified. We observed an overall suppression of the different isotypes after treatment with lower doses of PE or with its 40-kDa fraction. PE doses of 0.5 to 2 mg resulted in a stronger inhibition of IgM than IgG1 production. This phenomenon was also obtained with the 40 KDa fraction. IgG2 responses were significantly reduced by all doses of this fraction. In contrast, all doses of the 60-kDa fraction gave a strong stimulation of IgG2 and IgM responses and a constant suppression of the IgG1 response. This shows a clear dissociation between IgG1 and C'-fixing (IgM, IgG2) antibody classes as far as the influence of placental substances is concerned in their regulation. These data emphasize the relevance of isogeneic placental products as a useful physiological material capable of modulating xenogeneic immune responses (as well as allogeneic systems).
- Published
- 1984
40. In vivo and in vitro study of regulatory effects caused by placental extracts
- Author
-
Aline Massé, Guy A. Voisin, R. Kinsky, Pierre Bobé, and H.T. Duc
- Subjects
Reproductive Medicine ,In vivo ,Immunology ,Placental Extracts ,Obstetrics and Gynecology ,Immunology and Allergy ,In vitro study ,Biology ,Pharmacology - Published
- 1983
41. Rôle des récepteurs purinergiques P2X7 et d'apoptose Fas dans l'homéostasie des lymphocytes T et le développement des maladies auto-immunes
- Author
-
Mellouk, Amine, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), Pierre Bobé, and STAR, ABES
- Subjects
Lymphocytes T ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Fas receptor ,Homéostasie ,T lymphocytes ,Récepteur Fas ,Autoimmunity ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Récepteur P2X7 ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,immune system diseases ,P2X7 receptor ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Homeostasis ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Autoimmunité ,skin and connective tissue diseases - Abstract
My project aims to determine the role of the purinergic receptor P2X7 (P2X7R) in the pathophysiological processes involved in the development of autoimmune lupus-like syndrome. MRL/lpr mice, deficient for the cell death receptor Fas (lpr mutation), spontaneously develop this pathology following the accumulation of pathogenic B220+CD4−CD8− (DN) T lymphocytes in secondary lymphoid organs. We have observed that these lymphocytes are also deficient in P2X7R cell surface expression. This led us to hypothesize that P2X7R could play a key role in T cell homeostasis and lupus development. To test our hypothesis, we produced B6 mice deficient for both Fas (lpr) and P2X7R (P2X7KO). These mice, but not single mutant B6 mice (lpr or P2X7KO), develop a massive accumulation of DN B220+ T lymphocytes and high levels of autoantibodies and proinflammatory cytokines, confirming for the first time the involvement of P2X7R in T-cell homeostasis. I have found that the pathogenic DN T lymphocytes are predominantly derived from the CD8+ T lymphocyte subpopulation. Chronic inflammation in B6/lpr P2X7KO mice induces the activation of the whole CD4+ and CD8+ naïve T lymphocyte subpopulations leading to the accumulation of Effector/Memory and exhausted T lymphocytes. Accumulated T-cells lose the ability to be reactivated. To confirm these results, I compared the adaptive immune response against adenovirus between mice deficient for Fas (lpr mutation), P2X7R-deficient mice or both receptors. The cellular and the humoral responses were lower in the B6/lpr-P2X7KO mouse strain compared to B6, B6-P2X7KO and B6/lpr mouse strains. The antiviral immune response in the B6/lpr mice was lower than in B6 and B6-P2X7KO mice. These results reinforce our hypothesis about the synergistic role of both receptors in the maintaining of T cell homeostasis. Ours results suggest that Fas and P2X7R play their synergistic role in T-cell homeostasis. In collaboration with a team from the University of Taiwan, we sequenced the mRNAs expressed in the spleen and lymph nodes of MRL/lpr mice before and after the onset of the diseases as well as in the B6, B6/lpr, B6 P2X7KO and B6/lpr P2X7KO mouse strains in order to better understand the mechanism triggering the disease and to identify the role of each receptor on the expression of the susceptibility loci., Mon étude a porté sur le rôle du récepteur purinergique P2X7 (P2X7R) dans les processus physiopathologiques impliqués dans le développement des maladies auto-immunes de type lupique. Les souris MRL/lpr, déficientes en récepteurs d’apoptose Fas (mutation lpr), développent spontanément ces pathologies suite à l’accumulation lymphocytes T pathogéniques CD4−CD8− (DN) B220+ dans les organes lymphoïdes secondaires. Nous avons observé que ces lymphocytes ont également un déficit d’expression en P2X7R à leur surface. Cela nous a amené à postuler que P2X7R pourrait jouer un rôle clé dans l’homéostasie des lymphocytes T et le développement du lupus. Afin de vérifier notre hypothèse, nous avons produit des souris C57BL/6J (B6) déficientes simultanément pour Fas (lpr) et P2X7R (P2X7KO). Ces souris présentent une accumulation massive de lymphocytes T DN B220+ et des titres très élevés en auto-anticorps et en cytokines proinflammatoires ce qui n’est pas le cas pour les souris B6 simples mutantes lpr ou P2X7KO confirmant pour la première fois l’implication de P2X7R dans l’homéostasie des lymphocytes T, en synergie avec le récepteur Fas. Les lymphocytes T DN pathogéniques responsables de la lymphoaccumulation sont issues majoritairement de la sous populations des lymphocytes T CD8+. L’inflammation chronique présente chez les souris B6/lpr P2X7KO induit l’activation de l’ensemble des populations lymphocytaires T CD4+ et CD8+ naïves conduisant à l’accumulation de lymphocytes T Effecteurs/Mémoires : EM et CM et atteignent parfois le stade exhausted PD1+TIM3+. Ces cellules accumulées CD4+, CD8+ et DN B220+ ont une capacité de réactivation réduite. Ce biais fonctionnel et phénotypique a été confirmé en comparant la réponse immunitaire adaptative anti-adénovirus entre des souris déficientes en Fas et/ou P2X7R. Les réponses cellulaires et humorales sont moins importantes dans les souris B6/lpr P2X7KO que B6, B6-P2X7KO. Ces réponses antivirales sont intermédiaires dans les souris B6/lpr. L’ensemble de ces résultats renforcent notre hypothèse sur le rôle synergique des récepteurs Fas et P2X7R dans l’homéostasie des lymphocytes T. Le taux d’apoptose induit par l’activation des récepteurs Fas ou P2X7R séparément est moins important dans les lymphocytes T CD8+ par rapport au lymphocytes T CD4+. La synergie Fas-P2X7R serait donc nécessaire pour l’homéostasie des lymphocytes T CD8+. Afin de préciser les mécanismes à l’origine de la maladie et d’identifier l’influence de chaque récepteur sur l’expression des loci de susceptibilité, nous avons séquencé les ARNm exprimés dans la rate et les ganglions lymphatiques des souris MRL/lpr avant et après le développement de l’auto-immunité ainsi que chez les souris B6, B6/lpr, B6 P2X7KO et B6/lpr P2X7KO.
- Published
- 2018
42. Role of Purinergic P2X7 and Apoptosis Fas Receptors in T Lymphocyte Homeostasis and Autoimmune Desease Developpement
- Author
-
Mellouk, Amine, Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Saclay (COmUE), and Pierre Bobé
- Subjects
Lymphocytes T ,Fas receptor ,Homéostasie ,T lymphocytes ,Récepteur Fas ,Autoimmunity ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Récepteur P2X7 ,immune system diseases ,P2X7 receptor ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Homeostasis ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Autoimmunité ,skin and connective tissue diseases - Abstract
My project aims to determine the role of the purinergic receptor P2X7 (P2X7R) in the pathophysiological processes involved in the development of autoimmune lupus-like syndrome. MRL/lpr mice, deficient for the cell death receptor Fas (lpr mutation), spontaneously develop this pathology following the accumulation of pathogenic B220+CD4−CD8− (DN) T lymphocytes in secondary lymphoid organs. We have observed that these lymphocytes are also deficient in P2X7R cell surface expression. This led us to hypothesize that P2X7R could play a key role in T cell homeostasis and lupus development. To test our hypothesis, we produced B6 mice deficient for both Fas (lpr) and P2X7R (P2X7KO). These mice, but not single mutant B6 mice (lpr or P2X7KO), develop a massive accumulation of DN B220+ T lymphocytes and high levels of autoantibodies and proinflammatory cytokines, confirming for the first time the involvement of P2X7R in T-cell homeostasis. I have found that the pathogenic DN T lymphocytes are predominantly derived from the CD8+ T lymphocyte subpopulation. Chronic inflammation in B6/lpr P2X7KO mice induces the activation of the whole CD4+ and CD8+ naïve T lymphocyte subpopulations leading to the accumulation of Effector/Memory and exhausted T lymphocytes. Accumulated T-cells lose the ability to be reactivated. To confirm these results, I compared the adaptive immune response against adenovirus between mice deficient for Fas (lpr mutation), P2X7R-deficient mice or both receptors. The cellular and the humoral responses were lower in the B6/lpr-P2X7KO mouse strain compared to B6, B6-P2X7KO and B6/lpr mouse strains. The antiviral immune response in the B6/lpr mice was lower than in B6 and B6-P2X7KO mice. These results reinforce our hypothesis about the synergistic role of both receptors in the maintaining of T cell homeostasis. Ours results suggest that Fas and P2X7R play their synergistic role in T-cell homeostasis. In collaboration with a team from the University of Taiwan, we sequenced the mRNAs expressed in the spleen and lymph nodes of MRL/lpr mice before and after the onset of the diseases as well as in the B6, B6/lpr, B6 P2X7KO and B6/lpr P2X7KO mouse strains in order to better understand the mechanism triggering the disease and to identify the role of each receptor on the expression of the susceptibility loci.; Mon étude a porté sur le rôle du récepteur purinergique P2X7 (P2X7R) dans les processus physiopathologiques impliqués dans le développement des maladies auto-immunes de type lupique. Les souris MRL/lpr, déficientes en récepteurs d’apoptose Fas (mutation lpr), développent spontanément ces pathologies suite à l’accumulation lymphocytes T pathogéniques CD4−CD8− (DN) B220+ dans les organes lymphoïdes secondaires. Nous avons observé que ces lymphocytes ont également un déficit d’expression en P2X7R à leur surface. Cela nous a amené à postuler que P2X7R pourrait jouer un rôle clé dans l’homéostasie des lymphocytes T et le développement du lupus. Afin de vérifier notre hypothèse, nous avons produit des souris C57BL/6J (B6) déficientes simultanément pour Fas (lpr) et P2X7R (P2X7KO). Ces souris présentent une accumulation massive de lymphocytes T DN B220+ et des titres très élevés en auto-anticorps et en cytokines proinflammatoires ce qui n’est pas le cas pour les souris B6 simples mutantes lpr ou P2X7KO confirmant pour la première fois l’implication de P2X7R dans l’homéostasie des lymphocytes T, en synergie avec le récepteur Fas. Les lymphocytes T DN pathogéniques responsables de la lymphoaccumulation sont issues majoritairement de la sous populations des lymphocytes T CD8+. L’inflammation chronique présente chez les souris B6/lpr P2X7KO induit l’activation de l’ensemble des populations lymphocytaires T CD4+ et CD8+ naïves conduisant à l’accumulation de lymphocytes T Effecteurs/Mémoires : EM et CM et atteignent parfois le stade exhausted PD1+TIM3+. Ces cellules accumulées CD4+, CD8+ et DN B220+ ont une capacité de réactivation réduite. Ce biais fonctionnel et phénotypique a été confirmé en comparant la réponse immunitaire adaptative anti-adénovirus entre des souris déficientes en Fas et/ou P2X7R. Les réponses cellulaires et humorales sont moins importantes dans les souris B6/lpr P2X7KO que B6, B6-P2X7KO. Ces réponses antivirales sont intermédiaires dans les souris B6/lpr. L’ensemble de ces résultats renforcent notre hypothèse sur le rôle synergique des récepteurs Fas et P2X7R dans l’homéostasie des lymphocytes T. Le taux d’apoptose induit par l’activation des récepteurs Fas ou P2X7R séparément est moins important dans les lymphocytes T CD8+ par rapport au lymphocytes T CD4+. La synergie Fas-P2X7R serait donc nécessaire pour l’homéostasie des lymphocytes T CD8+. Afin de préciser les mécanismes à l’origine de la maladie et d’identifier l’influence de chaque récepteur sur l’expression des loci de susceptibilité, nous avons séquencé les ARNm exprimés dans la rate et les ganglions lymphatiques des souris MRL/lpr avant et après le développement de l’auto-immunité ainsi que chez les souris B6, B6/lpr, B6 P2X7KO et B6/lpr P2X7KO.
- Published
- 2018
43. Modulation of purinergic receptor P2X7-dependant activities during T lymphocyte activation
- Author
-
Safya, Hanaa, Signalisation calcique et interactions cellulaires dans le foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Sud - Paris XI, and Pierre Bobé
- Subjects
ATP ,Lymphocyte T ,Signalisation ,T Lymphocyte ,Activation ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,P2X7 - Abstract
Extracellular ATP through the receptor P2X7 (P2X7R) plays a key role in innate immunity as a danger signal that causes the activation of the inflammasome, enhancement of immune cell migration and cell death. Although the role of the ATP/P2X7R pathway in adaptative immunity remains underestimated, it has been reported that P2X7R regulates signaling events involved in T-cell activation, proliferation, and differentiation into effector lineages. Moreover, we have previously shown that effector T lymphocytes (either CD4+ or CD8+) that express the B220 isoform of CD45 at the plasma membrane at the end of the secondary immune response are totally resistant to ATP stimulation due to loss of P2X7R membrane expression. In the present study, we compared the sensitivity of T lymphocytes to cellular activities trigerred by P2X7R according to their stage of activation. Interestingly, our results showed that P2X7-dependent cellular activities are dissociated. T lymphocytes at effector/memory stage are less sensitive to CD62L shedding than naïve or recently activated T lymphocyte during primary immune response. Naive T lymphocytes recently activated during primary immune response are the most sensitive to pore formation. Furthermore, recently activated T lymphocytes at both primary and secondary immune responses are the most sensitive to PS externalization. Finally, pore formation, PS externalization but not CD62L shedding, are dependent on calcium signaling.; L’ATP extracellulaire, à travers l’activation du récepteur P2X7, joue un rôle important dans l’immunité inné comme signal de danger responsable de l’assemblage de l’inflammasome, de la migration des cellules immunitaires et de la mort cellulaire. Bien que le rôle de la voie ATP/P2X7 dans l’immunité adaptative reste sous-estimé, il a été rapporté que le récepteur P2X7 participe aux mécanismes de signalisation impliqués dans l’activation des lymphocytes T, leur prolifération et leur différentiation. Notre laboratoire a récemment montré que les lymphocytes T effecteurs (CD4+ ou CD8+) en fin de réponse immunitaire secondaire, exprimant à la membrane la tyrosine phosphatase de membrane B220, sont totalement résistant à l’activation du récepteur P2X7 à cause d’une perte d’adressage de ce récepteur à la membrane. Le but de ce travail de thèse est d’étudier la sensibilité des lymphocytes T, à différents stades d’activation, aux activités cellulaires induites par l’ATP, notamment le clivage de la molécule de homing CD62L ou L-sélectine, l’ouverture du canal ionique, la formation du pore et l’externalisation de la PS. Mes principaux résultats montrent que les activités cellulaires dépendantes du récepteur P2X7 sont dissociées. Les lymphocytes T au stade effecteur/mémoire sont moins sensibles au clivage de la molécule CD62L que les lymphocytes T au stade naïf et récemment activé. Les lymphocytes naïfs T récemment activé en réponse immunitaire primaire sont les plus sensibles à la formation du pore. De plus, les lymphocytes T récemment activés, aussi bien en réponse immunitaire primaire que secondaire, sont les plus sensibles à l’externalisation de la PS. Enfin, dans les lymphocytes T récemment activé, les activités de pore et d’externalisation de PS, mais pas le clivage de CD62L, sont dépendantes du taux de calcium.
- Published
- 2014
44. Modulation des activités du récepteur purinergique P2X7 au cours de l’activation des lymphocytes T
- Author
-
Safya, Hanaa, STAR, ABES, Signalisation calcique et interactions cellulaires dans le foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Sud - Paris XI, and Pierre Bobé
- Subjects
ATP ,Lymphocyte T ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Signalisation ,T Lymphocyte ,Activation ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,P2X7 - Abstract
Extracellular ATP through the receptor P2X7 (P2X7R) plays a key role in innate immunity as a danger signal that causes the activation of the inflammasome, enhancement of immune cell migration and cell death. Although the role of the ATP/P2X7R pathway in adaptative immunity remains underestimated, it has been reported that P2X7R regulates signaling events involved in T-cell activation, proliferation, and differentiation into effector lineages. Moreover, we have previously shown that effector T lymphocytes (either CD4+ or CD8+) that express the B220 isoform of CD45 at the plasma membrane at the end of the secondary immune response are totally resistant to ATP stimulation due to loss of P2X7R membrane expression. In the present study, we compared the sensitivity of T lymphocytes to cellular activities trigerred by P2X7R according to their stage of activation. Interestingly, our results showed that P2X7-dependent cellular activities are dissociated. T lymphocytes at effector/memory stage are less sensitive to CD62L shedding than naïve or recently activated T lymphocyte during primary immune response. Naive T lymphocytes recently activated during primary immune response are the most sensitive to pore formation. Furthermore, recently activated T lymphocytes at both primary and secondary immune responses are the most sensitive to PS externalization. Finally, pore formation, PS externalization but not CD62L shedding, are dependent on calcium signaling., L’ATP extracellulaire, à travers l’activation du récepteur P2X7, joue un rôle important dans l’immunité inné comme signal de danger responsable de l’assemblage de l’inflammasome, de la migration des cellules immunitaires et de la mort cellulaire. Bien que le rôle de la voie ATP/P2X7 dans l’immunité adaptative reste sous-estimé, il a été rapporté que le récepteur P2X7 participe aux mécanismes de signalisation impliqués dans l’activation des lymphocytes T, leur prolifération et leur différentiation. Notre laboratoire a récemment montré que les lymphocytes T effecteurs (CD4+ ou CD8+) en fin de réponse immunitaire secondaire, exprimant à la membrane la tyrosine phosphatase de membrane B220, sont totalement résistant à l’activation du récepteur P2X7 à cause d’une perte d’adressage de ce récepteur à la membrane. Le but de ce travail de thèse est d’étudier la sensibilité des lymphocytes T, à différents stades d’activation, aux activités cellulaires induites par l’ATP, notamment le clivage de la molécule de homing CD62L ou L-sélectine, l’ouverture du canal ionique, la formation du pore et l’externalisation de la PS. Mes principaux résultats montrent que les activités cellulaires dépendantes du récepteur P2X7 sont dissociées. Les lymphocytes T au stade effecteur/mémoire sont moins sensibles au clivage de la molécule CD62L que les lymphocytes T au stade naïf et récemment activé. Les lymphocytes naïfs T récemment activé en réponse immunitaire primaire sont les plus sensibles à la formation du pore. De plus, les lymphocytes T récemment activés, aussi bien en réponse immunitaire primaire que secondaire, sont les plus sensibles à l’externalisation de la PS. Enfin, dans les lymphocytes T récemment activé, les activités de pore et d’externalisation de PS, mais pas le clivage de CD62L, sont dépendantes du taux de calcium.
- Published
- 2014
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