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Lymphocytes, Tumor-Infiltrating --- Neoplams --- Mannans

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Le TGF-P est une cytokine aux effets immunosuppresseurs puissants. Le TGF-P inhibe notamment la prolifération des lymphocytes T. Chez les patients cancéreux, l'effet cytostatique du TGF-P sur les lymphocytes T pourrait contribuer à l'inhibition des réponses immunes anti-tumorales et empêcher le rejet des tumeurs.La voie canonique de transduction du signal par le TGF-P passe par les facteurs de transcription SMADs. Le TGF-P régule l'expression d'un grand nombre de gènes, grâce à l'association des SMADs à d'autres facteurs de transcription dont la nature dépend du contexte cellulaire. Les mécanismes conduisant à l'effet cytostatique du TGF-P ont été bien décrits dans les cellules épithéliales. Cependant, des analyses préliminaires réalisées au laboratoire semblent indiquer que les mécanismes opérants dans les lymphocytes T sont différents de ceux opérant dans les cellules épithéliales. L'objectif de mon travail est d'identifier les cofacteurs qui s'associent aux SMADs et qui participent à l'effet cytostatique du TGF-P dans les lymphocytes T.Dans un premier temps, nous avons utilisé le programme TfactS afin d'identifier des facteurs de transcription dont l'activité est régulée par le TGF-P dans les lymphocytes T. Nous avons obtenu une liste de 37 candidats. Nous avons tenté de vérifier expérimentalement si nos candidats interagissaient avec les SMADs par deux techniques indépendantes : d'une part, par co-immunoprécipitation , et d'autre part, par Proximity Ligation Assay (PLA). Nous avons tout d'abord validé ces deux approches dans les lymphocytes T à l'aide d'un contrôle positif, à savoir l'interaction entre SMAD2/3 et SMAD4 induite par un signal TGF-p. Nous avons ensuite appliqué ces deux techniques à une série de candidats que nous avions sélectionnés dans notre liste de 37 cofacteurs. Après une première série d'analyses, deux candidats semblent montrer une interaction avec SMAD2/3 : il s'agit des facteurs de transcription c-Rel et FoxO1.Enfin, nous avons voulu déterminer à l'aide d'un test de prolifération le rôle de ces deux facteurs de transcription dans l'effet cytostatique du TGF-p. Pour ce faire, nous avons électroporé un clone de lymphocyte T CD4+ avec des ARN interférants ciblant soit le gène REL, soit le gène FOXO 1. Cependant, les ARN interférants utilisés n'étaient pas assez efficaces et nous n'avons pas pu observer de diminution de l'effet cytostatique du TGF-P dans ces cellules. De nouvelles expériences utilisant des ARN interférants plus efficaces seront donc nécessaires afin de conclure au rôle de ces 2 facteurs de transcription dans l'effet cytostatique du TGF-P dans les lymphocytes T. Identification of the transcription factors interacting with the SMADs in human T lymphocytesTGF-P is a cytokine with patent immunosuppressive effects. Notably, TGF-P inhibits the proliferation of T cells. In cancer patients, the cytostatic effect of TGF-P on T cells could contribute to the inhibition of anti-tumor immune responses and prevent tumor rejection.Signal transduction upon TGF-P stimulation involves the SMAD transcription factors. SMADs associate to other transcription factors, whose identity depends on cell type and context. As a consequence, which genes are regulated in response to TGF-P signais is also dependent on cell type and context. SMAD cofactors and TGF-P target genes responsible for the cytostatic effect of TGF-P have been well characterized in epithelial cells. However, preliminary analyses in our laboratory suggest that the mechanisms at play in T cells are different from the ones operating in epithelial cells. The aim of my work is to identify cofactors that associate with SMADs and participate to the cytostatic effect of TGF-P in human T cells.We used the TfactS program to identify transcription factors whose activity appears to be regulated in response to TGF-P in human T cells. We obtained a list of 37 candidates.We tried to verify experimentally if some of the candidates interact with SMADs, using two independent techniques, namely co-immunoprecipitation and Proximity Ligation Assay. We validated these two approaches in human T cells using the known interaction between SMAD2/3 and SMAD4 as a positive contrai. We then applied these techniques to 6 of the 37 candidates. Our results indicate that two candidates, namely c-Rel and Foxü l, interact with SMAD2/3.Finally, we attempted to test if these two transcription factors play a role in the cytostatic effect of TGF-P on human T cells. We electroporated a human CD4+ T cell clone with siRNAs targeting the REL or the FOXOJ gene. Unfortunately, the siRNAs did not efficiently decrease REL and FOXOJ mRNA levels, and we observed no decrease in the cytostatic effect of TGF-P in these cells. Further experiments, using for example more patent siRNAs, are required to conclude about the role of these two transcription factors in the cytostatic effect of TGF- p in human T cells.

Smad Proteins, receptor-Regulated --- Lymphocytes, Tumor-Infiltrating --- T-Lymphocytes, Cytotoxic

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Modern cell biology has brought improvements in therapy for advanced malignant diseases through immunomodulation, hematopoietic stem cell transplantation, and other advanced techniques. Collected here are selected papers from the Fifth International Symposium of Keio University for Life Sciences and Medicine on Cell Therapy. All chapters include innovative basic research for clinical application: immunotherapy, cancer vaccination, molecular biology of hematopoietic stem cells, stem cell processing, and gene therapy. The book is divided into three parts: Immunotherapy for malignant diseases; Hematopoietic stem cell biology and clinical application; and International collaboration in hematopoietic stem cell transplantation. Included in the third part is information on bone marrow registries from around the world. The book thus presents up-to-date information on biological and clinical aspects of treatment, with insight into the future of cell therapy.

Hematopoietic Stem Cell Transplantation. --- Hematopoietic Stem Cells --- Immunotherapy, Adoptive. --- Neoplasms --- Cellular therapy --- Cell therapy --- Cells --- Therapy, Cellular --- Organotherapy --- Therapeutics, Physiological --- Transplantation of organs, tissues, etc. --- Cell transplantation --- Adoptive Immunotherapy --- Cellular Immunotherapy, Adoptive --- Immunotherapy, Adoptive Cellular --- Adoptive Cellular Immunotherapy --- Adoptive Cellular Immunotherapies --- Adoptive Immunotherapies --- Cellular Immunotherapies, Adoptive --- Immunotherapies, Adoptive --- Immunotherapies, Adoptive Cellular --- Killer Cells, Lymphokine-Activated --- Cytapheresis --- Lymphocytes, Tumor-Infiltrating --- Monocytes, Activated Killer --- Transplantation, Hematopoietic Stem Cell --- Stem Cell Transplantation, Hematopoietic --- Bone Marrow Transplantation --- Bone Marrow Purging --- Hematopoietic Stem Cell Mobilization --- physiology. --- therapy. --- Therapeutic use --- transplantation --- Hematopoietic Stem Cell Transplantation --- Immunotherapy, Adoptive --- physiology --- therapy --- Physiology --- Therapy --- CAR T-Cell Therapy --- Chimeric Antigen Receptor Therapy --- CAR T Cell Therapy --- CAR T-Cell Therapies --- T-Cell Therapies, CAR --- T-Cell Therapy, CAR --- Therapies, CAR T-Cell --- Therapy, CAR T-Cell --- Receptors, Chimeric Antigen --- Cell biology. --- Molecular biology. --- Oncology  . --- Cell Biology. --- Molecular Medicine. --- Oncology. --- Tumors --- Molecular biochemistry --- Molecular biophysics --- Biochemistry --- Biophysics --- Biomolecules --- Systems biology --- Cell biology --- Cellular biology --- Biology

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Hematopoietic stem cells --- Cellular therapy --- Hematopoietic stem cell disorders --- Cellular therapy. --- Hematopoietic Stem Cell Transplantation. --- Immunotherapy, Adoptive. --- Transplantation --- Treatment. --- Transplantation. --- Adoptive Immunotherapy --- CAR T-Cell Therapy --- Cellular Immunotherapy, Adoptive --- Chimeric Antigen Receptor Therapy --- Immunotherapy, Adoptive Cellular --- Adoptive Cellular Immunotherapy --- Adoptive Cellular Immunotherapies --- Adoptive Immunotherapies --- CAR T Cell Therapy --- CAR T-Cell Therapies --- Cellular Immunotherapies, Adoptive --- Immunotherapies, Adoptive --- Immunotherapies, Adoptive Cellular --- T-Cell Therapies, CAR --- T-Cell Therapy, CAR --- Therapies, CAR T-Cell --- Therapy, CAR T-Cell --- Receptors, Chimeric Antigen --- Killer Cells, Lymphokine-Activated --- Cytapheresis --- Lymphocytes, Tumor-Infiltrating --- Monocytes, Activated Killer --- Transplantation, Hematopoietic Stem Cell --- Stem Cell Transplantation, Hematopoietic --- Hematopoietic Stem Cells --- Bone Marrow Transplantation --- Bone Marrow Purging --- Hematopoietic Stem Cell Mobilization --- HSCs (Hematopoietic stem cells) --- Blood cells --- Bone marrow cells --- Hematopoietic system --- Multipotent stem cells --- Cell therapy --- Cells --- Therapy, Cellular --- Organotherapy --- Therapeutics, Physiological --- Transplantation of organs, tissues, etc. --- Cell transplantation --- Hematopoietic stem cell diseases --- Blood --- transplantation --- Therapeutic use --- Diseases

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Genetic transformation --- Gene therapy --- Cellular therapy --- Gene Transfer Techniques. --- Genetic Therapy. --- Thérapie génique --- Thérapie cellulaire --- Cellular therapy. --- Gene therapy. --- Genetic transformation. --- Gene Transfer --- Gene Therapy --- Therapy, Gene --- Gene transfer --- Transformation (Genetics) --- DNA Therapy --- Gene Therapy, Somatic --- Genetic Therapy, Gametic --- Genetic Therapy, Somatic --- Therapy, DNA --- Therapy, Somatic Gene --- Somatic Gene Therapy --- Gametic Genetic Therapies --- Gametic Genetic Therapy --- Genetic Therapies --- Genetic Therapies, Gametic --- Genetic Therapies, Somatic --- Somatic Genetic Therapies --- Somatic Genetic Therapy --- Therapies, Gametic Genetic --- Therapies, Genetic --- Therapies, Somatic Genetic --- Therapy, Gametic Genetic --- Therapy, Genetic --- Therapy, Somatic Genetic --- Cell therapy --- Cells --- Therapy, Cellular --- Therapeutic use --- Genetic engineering --- Therapeutics --- Genetic recombination --- Microbial genetics --- Nucleic acids --- Transfection --- Gene Transfer Techniques --- Genetic Services --- Genes, Transgenic, Suicide --- Organotherapy --- Therapeutics, Physiological --- Transplantation of organs, tissues, etc. --- Cell transplantation --- Gene Transfer. --- Gene Delivery Systems --- Gene Transfer Technique --- Transgenesis --- Delivery System, Gene --- Delivery Systems, Gene --- Gene Delivery System --- Technique, Gene Transfer --- Techniques, Gene Transfer --- Transfer Technique, Gene --- Transfer Techniques, Gene --- Genetic Therapy --- Transgenes --- Genetics --- Gene Therapy. --- Gene Therap. --- Gene Transfer, Horizontal --- Genetic Structures --- Genetic Phenomena --- Recombination, Interspecific --- Gene Transfer, Lateral --- Horizontal Gene Transfer --- Lateral Gene Transfer --- Recombination, Interspecies --- Gene Transfers, Lateral --- Interspecies Recombination --- Interspecific Recombination --- Lateral Gene Transfers --- Thérapie génique. --- Transformation, Genetic. --- Genetic Transformation --- Genetic Transformations --- Transformations, Genetic --- Crosses, Genetic --- Transduction, Genetic --- Immunotherapy, Adoptive --- Adoptive Immunotherapy --- CAR T-Cell Therapy --- Cellular Immunotherapy, Adoptive --- Chimeric Antigen Receptor Therapy --- Immunotherapy, Adoptive Cellular --- Adoptive Cellular Immunotherapy --- Adoptive Cellular Immunotherapies --- Adoptive Immunotherapies --- CAR T Cell Therapy --- CAR T-Cell Therapies --- Cellular Immunotherapies, Adoptive --- Immunotherapies, Adoptive --- Immunotherapies, Adoptive Cellular --- T-Cell Therapies, CAR --- T-Cell Therapy, CAR --- Therapies, CAR T-Cell --- Therapy, CAR T-Cell --- Receptors, Chimeric Antigen --- Killer Cells, Lymphokine-Activated --- Cytapheresis --- Lymphocytes, Tumor-Infiltrating --- Monocytes, Activated Killer