7 results on '"Scharfmann, Raphael"'
Search Results
2. Fostering improved human islet research: a European perspective
- Author
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Marchetti, Piero, primary, Schulte, Anke M., additional, Marselli, Lorella, additional, Schoniger, Eyke, additional, Bugliani, Marco, additional, Kramer, Werner, additional, Overbergh, Lut, additional, Ullrich, Susanne, additional, Gloyn, Anna L., additional, Ibberson, Mark, additional, Rutter, Guy, additional, Froguel, Philippe, additional, Groop, Leif, additional, McCarthy, Mark I., additional, Dotta, Francesco, additional, Scharfmann, Raphael, additional, Magnan, Christophe, additional, Eizirik, Decio L., additional, Mathieu, Chantal, additional, Cnop, Miriam, additional, Thorens, Bernard, additional, and Solimena, Michele, additional
- Published
- 2019
- Full Text
- View/download PDF
3. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes
- Author
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Solimena, Michele, primary, Schulte, Anke M., additional, Marselli, Lorella, additional, Ehehalt, Florian, additional, Richter, Daniela, additional, Kleeberg, Manuela, additional, Mziaut, Hassan, additional, Knoch, Klaus-Peter, additional, Parnis, Julia, additional, Bugliani, Marco, additional, Siddiq, Afshan, additional, Jörns, Anne, additional, Burdet, Frédéric, additional, Liechti, Robin, additional, Suleiman, Mara, additional, Margerie, Daniel, additional, Syed, Farooq, additional, Distler, Marius, additional, Grützmann, Robert, additional, Petretto, Enrico, additional, Moreno-Moral, Aida, additional, Wegbrod, Carolin, additional, Sönmez, Anke, additional, Pfriem, Katja, additional, Friedrich, Anne, additional, Meinel, Jörn, additional, Wollheim, Claes B., additional, Baretton, Gustavo B., additional, Scharfmann, Raphael, additional, Nogoceke, Everson, additional, Bonifacio, Ezio, additional, Sturm, Dorothée, additional, Meyer-Puttlitz, Birgit, additional, Boggi, Ugo, additional, Saeger, Hans-Detlev, additional, Filipponi, Franco, additional, Lesche, Mathias, additional, Meda, Paolo, additional, Dahl, Andreas, additional, Wigger, Leonore, additional, Xenarios, Ioannis, additional, Falchi, Mario, additional, Thorens, Bernard, additional, Weitz, Jürgen, additional, Bokvist, Krister, additional, Lenzen, Sigurd, additional, Rutter, Guy A., additional, Froguel, Philippe, additional, von Bülow, Manon, additional, Ibberson, Mark, additional, and Marchetti, Piero, additional
- Published
- 2017
- Full Text
- View/download PDF
4. Innate and adaptive immunity to human beta cell lines: implications for beta cell therapy
- Author
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van der Torren, Cornelis R., primary, Zaldumbide, Arnaud, additional, Roelen, Dave L., additional, Duinkerken, Gaby, additional, Brand-Schaaf, Simone H., additional, Peakman, Mark, additional, Czernichow, Paul, additional, Ravassard, Philippe, additional, Scharfmann, Raphael, additional, and Roep, Bart O., additional
- Published
- 2015
- Full Text
- View/download PDF
5. Innate and adaptive immunity to human beta cell lines: implications for beta cell therapy.
- Author
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Torren, Cornelis, Zaldumbide, Arnaud, Roelen, Dave, Duinkerken, Gaby, Brand-Schaaf, Simone, Peakman, Mark, Czernichow, Paul, Ravassard, Philippe, Scharfmann, Raphael, and Roep, Bart
- Abstract
Aims/hypothesis: Genetically engineered human beta cell lines provide a novel source of human beta cells to study metabolism, pharmacology and beta cell replacement therapy. Since the immune system is essentially involved in beta cell destruction in type 1 diabetes and after beta cell transplantation, we investigated the interaction of human beta cell lines with the immune system to resolve their potential for immune intervention protocol studies. Methods: Human pancreatic beta cell lines (EndoC-βH1 and ECi50) generated by targeted oncogenesis in fetal pancreas were assessed for viability after innate and adaptive immune challenges. Beta cell lines were pre-conditioned with T helper type 1 (Th1) cytokines or high glucose to mimic inflammatory and hyperglycaemia-stressed conditions. Beta cells were then co-cultured with auto- and alloreactive cytotoxic T cells (CTL), natural killer (NK) cells, supernatant fraction from activated autoreactive Th1 cells, or alloantibodies in the presence of complement or effector cells. Results: Low HLA expression protected human beta cell lines from adaptive immune destruction, but it was associated with direct killing by activated NK cells. Autoreactive Th1 cell inflammation, rather than glucose stress, induced increased beta cell apoptosis and upregulation of HLA, increasing beta cell vulnerability to killing by auto- and alloreactive CTL and alloreactive antibodies. Conclusions/interpretation: We demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
6. Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes.
- Author
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Solimena M, Schulte AM, Marselli L, Ehehalt F, Richter D, Kleeberg M, Mziaut H, Knoch KP, Parnis J, Bugliani M, Siddiq A, Jörns A, Burdet F, Liechti R, Suleiman M, Margerie D, Syed F, Distler M, Grützmann R, Petretto E, Moreno-Moral A, Wegbrod C, Sönmez A, Pfriem K, Friedrich A, Meinel J, Wollheim CB, Baretton GB, Scharfmann R, Nogoceke E, Bonifacio E, Sturm D, Meyer-Puttlitz B, Boggi U, Saeger HD, Filipponi F, Lesche M, Meda P, Dahl A, Wigger L, Xenarios I, Falchi M, Thorens B, Weitz J, Bokvist K, Lenzen S, Rutter GA, Froguel P, von Bülow M, Ibberson M, and Marchetti P
- Subjects
- Aged, Aged, 80 and over, Computational Biology, Female, Humans, Male, Pancreatectomy, Biological Specimen Banks, Diabetes Mellitus, Type 2 metabolism, Systems Biology methods, Tissue Donors, Transcriptome genetics
- Abstract
Aims/hypothesis: Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium ( www.imidia.org ) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP)., Methods: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells., Results: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca
2+ -influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes., Conclusions/interpretation: These studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.- Published
- 2018
- Full Text
- View/download PDF
7. Innate and adaptive immunity to human beta cell lines: implications for beta cell therapy.
- Author
-
van der Torren CR, Zaldumbide A, Roelen DL, Duinkerken G, Brand-Schaaf SH, Peakman M, Czernichow P, Ravassard P, Scharfmann R, and Roep BO
- Subjects
- Antibodies immunology, Cell Line, Cell Transplantation methods, Complement System Proteins immunology, Cytokines metabolism, Diabetes Mellitus, Type 1 immunology, Genetic Engineering methods, Genotype, HLA Antigens immunology, HeLa Cells, Humans, Hyperglycemia metabolism, Immune System, Inflammation, Insulin-Secreting Cells cytology, Killer Cells, Natural cytology, Leukocytes, Mononuclear cytology, T-Lymphocytes, Cytotoxic cytology, Th1 Cells cytology, Adaptive Immunity, Immunity, Innate, Insulin-Secreting Cells immunology
- Abstract
Aims/hypothesis: Genetically engineered human beta cell lines provide a novel source of human beta cells to study metabolism, pharmacology and beta cell replacement therapy. Since the immune system is essentially involved in beta cell destruction in type 1 diabetes and after beta cell transplantation, we investigated the interaction of human beta cell lineswith the immune system to resolve their potential for immune intervention protocol studies., Methods: Human pancreatic beta cell lines (EndoC-βH1 and ECi50) generated by targeted oncogenesis in fetal pancreas were assessed for viability after innate and adaptive immune challenges. Beta cell lines were pre-conditioned with T helper type 1 (Th1) cytokines or high glucose to mimic inflammatory and hyperglycaemia-stressed conditions. Beta cells were then co-cultured with auto- and alloreactive cytotoxic T cells (CTL), natural killer (NK) cells, supernatant fraction from activated autoreactive Th1 cells, or alloantibodies in the presence of complement or effector cells., Results: Low HLA expression protected human beta cell lines from adaptive immune destruction, but it was associated with direct killing by activated NK cells. Autoreactive Th1 cell inflammation, rather than glucose stress, induced increased beta cell apoptosis and upregulation of HLA, increasing beta cell vulnerability to killing by auto- and alloreactive CTL and alloreactive antibodies., Conclusions/interpretation: We demonstrate that genetically engineered human beta cell lines can be used in vitro to assess diverse immune responses that may be involved in the pathogenesis of type 1 diabetes in humans and beta cell transplantation, enabling preclinical evaluation of novel immune intervention strategies protecting beta cells from immune destruction.
- Published
- 2016
- Full Text
- View/download PDF
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