33 results on '"Yang, Jennie H."'
Search Results
2. Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes
- Author
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Zhang, Jia-Yuan, Hamey, Fiona, Trzupek, Dominik, Mickunas, Marius, Lee, Mercede, Godfrey, Leila, Yang, Jennie H. M., Pekalski, Marcin L., Kennet, Jane, Waldron-Lynch, Frank, Evans, Mark L., Tree, Timothy I. M., Wicker, Linda S., Todd, John A., and Ferreira, Ricardo C.
- Published
- 2022
- Full Text
- View/download PDF
3. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans
- Author
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Hanna, Stephanie J., primary, Thayer, Terri C., additional, Robinson, Emma J. S., additional, Vinh, Ngoc-Nga, additional, Williams, Nigel, additional, Landry, Laurie G., additional, Andrews, Robert, additional, Siah, Qi Zhuang, additional, Leete, Pia, additional, Wyatt, Rebecca, additional, McAteer, Martina A., additional, Nakayama, Maki, additional, Wong, F. Susan, additional, Yang, Jennie H. M., additional, Tree, Timothy I. M., additional, Ludvigsson, Johnny, additional, Dayan, Colin M., additional, and Tatovic, Danijela, additional
- Published
- 2023
- Full Text
- View/download PDF
4. IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors
- Author
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Whitehouse, Gavin, Gray, Elizabeth, Mastoridis, Sotiris, Merritt, Elliot, Kodela, Elisavet, Yang, Jennie H. M., Danger, Richard, Mairal, Marta, Christakoudi, Sofia, Lozano, Juan J., Macdougall, Iain C., Tree, Timothy I. M., Sanchez-Fueyo, Alberto, and Martinez-Llordella, Marc
- Published
- 2017
5. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans
- Author
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Hanna, Stephanie J., Thayer, Terri C., Robinson, Emma J. S., Vinh, Ngoc-Nga, Williams, Nigel, Landry, Laurie G., Andrews, Robert, Siah, Qi Zhuang, Leete, Pia, Wyatt, Rebecca, Mcateer, Martina A., Nakayama, Maki, Wong, F. Susan, Yang, Jennie H. M., Tree, Timothy I. M., Ludvigsson, Johnny, Dayan, Colin M., Tatovic, Danijela, Hanna, Stephanie J., Thayer, Terri C., Robinson, Emma J. S., Vinh, Ngoc-Nga, Williams, Nigel, Landry, Laurie G., Andrews, Robert, Siah, Qi Zhuang, Leete, Pia, Wyatt, Rebecca, Mcateer, Martina A., Nakayama, Maki, Wong, F. Susan, Yang, Jennie H. M., Tree, Timothy I. M., Ludvigsson, Johnny, Dayan, Colin M., and Tatovic, Danijela
- Abstract
Gold nanoparticles (GNPs) have been used in the development of novel therapies as a way of delivery of both stimulatory and tolerogenic peptide cargoes. Here we report that intradermal injection of GNPs loaded with the proinsulin peptide C19-A3, in patients with type 1 diabetes, results in recruitment and retention of immune cells in the skin. These include large numbers of clonally expanded T-cells sharing the same paired T-cell receptors (TCRs) with activated phenotypes, half of which, when the TCRs were re-expressed in a cell-based system, were confirmed to be specific for either GNP or proinsulin. All the identified gold-specific clones were CD8+, whilst proinsulin-specific clones were both CD8+ and CD4+. Proinsulin-specific CD8+ clones had a distinctive cytotoxic phenotype with overexpression of granulysin (GNLY) and KIR receptors. Clonally expanded antigen-specific T cells remained in situ for months to years, with a spectrum of tissue resident memory and effector memory phenotypes. As the T-cell response is divided between targeting the gold core and the antigenic cargo, this offers a route to improving resident memory T-cells formation in response to vaccines. In addition, our scRNAseq data indicate that focusing on clonally expanded skin infiltrating T-cells recruited to intradermally injected antigen is a highly efficient method to enrich and identify antigen-specific cells. This approach has the potential to be used to monitor the intradermal delivery of antigens and nanoparticles for immune modulation in humans., Funding Agencies|European Commission under the Health Cooperation Work Programme of the 7th Framework Programme [305305]
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- 2023
- Full Text
- View/download PDF
6. Guidelines for standardizing T-cell cytometry assays to link biomarkers, mechanisms, and disease outcomes in type 1 diabetes
- Author
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Yang, Jennie H. M., Ward‐Hartstonge, Kirsten A., Perry, Daniel J., Blanchfield, J. Lori, Posgai, Amanda L., Wiedeman, Alice E., Diggins, Kirsten, Rahman, Adeeb, Tree, Timothy I. M., Brusko, Todd M., Levings, Megan K., James, Eddie A., Kent, Sally C., Speake, Cate, Homann, Dirk, and Long, S. Alice
- Subjects
Diabetes Mellitus, Type 1 ,T-Lymphocytes ,Immunology ,Immunology and Allergy ,Humans ,Flow Cytometry ,Biomarkers ,Article ,Immunophenotyping - Abstract
Cytometric immunophenotyping is a powerful tool to discover and implement T-cell biomarkers of type 1 diabetes (T1D) progression and response to clinical therapy. Although many discovery-based T-cell biomarkers have been described, to date, no such markers have been widely adopted in standard practice. The heterogeneous nature of T1D and lack of standardized assays and experimental design across studies is a major barrier to the broader adoption of T-cell immunophenotyping assays. There is an unmet need to harmonize the design of immunophenotyping assays, including those that measure antigen-agnostic cell populations, such that data collected from different clinical trial sites and T1D cohorts are comparable, yet account for cohort-specific features and different drug mechanisms of action. In these Guidelines, we aim to provide expert advice on how to unify aspects of study design and practice. We provide recommendations for defining cohorts, method implementation, as well as tools for data analysis and reporting by highlighting and building on selected successes. Harmonization of cytometry-based T-cell assays will allow researchers to better integrate findings across trials, ultimately enabling the identification and validation of biomarkers of disease progression and treatment response in T1D.
- Published
- 2021
7. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
- Author
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Cossarizza, Andrea, primary, Chang, Hyun‐Dong, additional, Radbruch, Andreas, additional, Abrignani, Sergio, additional, Addo, Richard, additional, Akdis, Mübeccel, additional, Andrä, Immanuel, additional, Andreata, Francesco, additional, Annunziato, Francesco, additional, Arranz, Eduardo, additional, Bacher, Petra, additional, Bari, Sudipto, additional, Barnaba, Vincenzo, additional, Barros‐Martins, Joana, additional, Baumjohann, Dirk, additional, Beccaria, Cristian G., additional, Bernardo, David, additional, Boardman, Dominic A., additional, Borger, Jessica, additional, Böttcher, Chotima, additional, Brockmann, Leonie, additional, Burns, Marie, additional, Busch, Dirk H., additional, Cameron, Garth, additional, Cammarata, Ilenia, additional, Cassotta, Antonino, additional, Chang, Yinshui, additional, Chirdo, Fernando Gabriel, additional, Christakou, Eleni, additional, Čičin‐Šain, Luka, additional, Cook, Laura, additional, Corbett, Alexandra J., additional, Cornelis, Rebecca, additional, Cosmi, Lorenzo, additional, Davey, Martin S., additional, De Biasi, Sara, additional, De Simone, Gabriele, additional, del Zotto, Genny, additional, Delacher, Michael, additional, Di Rosa, Francesca, additional, Di Santo, James, additional, Diefenbach, Andreas, additional, Dong, Jun, additional, Dörner, Thomas, additional, Dress, Regine J., additional, Dutertre, Charles‐Antoine, additional, Eckle, Sidonia B. G., additional, Eede, Pascale, additional, Evrard, Maximilien, additional, Falk, Christine S., additional, Feuerer, Markus, additional, Fillatreau, Simon, additional, Fiz‐Lopez, Aida, additional, Follo, Marie, additional, Foulds, Gemma A., additional, Fröbel, Julia, additional, Gagliani, Nicola, additional, Galletti, Giovanni, additional, Gangaev, Anastasia, additional, Garbi, Natalio, additional, Garrote, José Antonio, additional, Geginat, Jens, additional, Gherardin, Nicholas A., additional, Gibellini, Lara, additional, Ginhoux, Florent, additional, Godfrey, Dale I., additional, Gruarin, Paola, additional, Haftmann, Claudia, additional, Hansmann, Leo, additional, Harpur, Christopher M., additional, Hayday, Adrian C., additional, Heine, Guido, additional, Hernández, Daniela Carolina, additional, Herrmann, Martin, additional, Hoelsken, Oliver, additional, Huang, Qing, additional, Huber, Samuel, additional, Huber, Johanna E., additional, Huehn, Jochen, additional, Hundemer, Michael, additional, Hwang, William Y. K., additional, Iannacone, Matteo, additional, Ivison, Sabine M., additional, Jäck, Hans‐Martin, additional, Jani, Peter K., additional, Keller, Baerbel, additional, Kessler, Nina, additional, Ketelaars, Steven, additional, Knop, Laura, additional, Knopf, Jasmin, additional, Koay, Hui‐Fern, additional, Kobow, Katja, additional, Kriegsmann, Katharina, additional, Kristyanto, H., additional, Krueger, Andreas, additional, Kuehne, Jenny F., additional, Kunze‐Schumacher, Heike, additional, Kvistborg, Pia, additional, Kwok, Immanuel, additional, Latorre, Daniela, additional, Lenz, Daniel, additional, Levings, Megan K., additional, Lino, Andreia C., additional, Liotta, Francesco, additional, Long, Heather M., additional, Lugli, Enrico, additional, MacDonald, Katherine N., additional, Maggi, Laura, additional, Maini, Mala K., additional, Mair, Florian, additional, Manta, Calin, additional, Manz, Rudolf Armin, additional, Mashreghi, Mir‐Farzin, additional, Mazzoni, Alessio, additional, McCluskey, James, additional, Mei, Henrik E., additional, Melchers, Fritz, additional, Melzer, Susanne, additional, Mielenz, Dirk, additional, Monin, Leticia, additional, Moretta, Lorenzo, additional, Multhoff, Gabriele, additional, Muñoz, Luis Enrique, additional, Muñoz‐Ruiz, Miguel, additional, Muscate, Franziska, additional, Natalini, Ambra, additional, Neumann, Katrin, additional, Ng, Lai Guan, additional, Niedobitek, Antonia, additional, Niemz, Jana, additional, Almeida, Larissa Nogueira, additional, Notarbartolo, Samuele, additional, Ostendorf, Lennard, additional, Pallett, Laura J., additional, Patel, Amit A., additional, Percin, Gulce Itir, additional, Peruzzi, Giovanna, additional, Pinti, Marcello, additional, Pockley, A. Graham, additional, Pracht, Katharina, additional, Prinz, Immo, additional, Pujol‐Autonell, Irma, additional, Pulvirenti, Nadia, additional, Quatrini, Linda, additional, Quinn, Kylie M., additional, Radbruch, Helena, additional, Rhys, Hefin, additional, Rodrigo, Maria B., additional, Romagnani, Chiara, additional, Saggau, Carina, additional, Sakaguchi, Shimon, additional, Sallusto, Federica, additional, Sanderink, Lieke, additional, Sandrock, Inga, additional, Schauer, Christine, additional, Scheffold, Alexander, additional, Scherer, Hans U., additional, Schiemann, Matthias, additional, Schildberg, Frank A., additional, Schober, Kilian, additional, Schoen, Janina, additional, Schuh, Wolfgang, additional, Schüler, Thomas, additional, Schulz, Axel R., additional, Schulz, Sebastian, additional, Schulze, Julia, additional, Simonetti, Sonia, additional, Singh, Jeeshan, additional, Sitnik, Katarzyna M., additional, Stark, Regina, additional, Starossom, Sarah, additional, Stehle, Christina, additional, Szelinski, Franziska, additional, Tan, Leonard, additional, Tarnok, Attila, additional, Tornack, Julia, additional, Tree, Timothy I. M., additional, van Beek, Jasper J. P., additional, van de Veen, Willem, additional, van Gisbergen, Klaas, additional, Vasco, Chiara, additional, Verheyden, Nikita A., additional, von Borstel, Anouk, additional, Ward‐Hartstonge, Kirsten A., additional, Warnatz, Klaus, additional, Waskow, Claudia, additional, Wiedemann, Annika, additional, Wilharm, Anneke, additional, Wing, James, additional, Wirz, Oliver, additional, Wittner, Jens, additional, Yang, Jennie H. M., additional, and Yang, Juhao, additional
- Published
- 2021
- Full Text
- View/download PDF
8. A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes
- Author
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Marwaha, Ashish K, primary, Chow, Samuel, additional, Pesenacker, Anne M, additional, Cook, Laura, additional, Sun, Annika, additional, Long, S Alice, additional, Yang, Jennie H M, additional, Ward-Hartstonge, Kirsten A, additional, Williams, Evangelia, additional, Domingo-Vila, Clara, additional, Halani, Khalif, additional, Harris, Kristina M, additional, Tree, Timothy I M, additional, Levings, Megan K, additional, Elliott, Thomas, additional, Tan, Rusung, additional, and Dutz, Jan P, additional
- Published
- 2021
- Full Text
- View/download PDF
9. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
- Author
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Rolf M. Schwiete Foundation, Associazione Italiana per la Ricerca sul Cancro, German Research Foundation, National Institutes of Health (US), European Commission, Cossarizza, Andrea, Chang, Hyun‐Dong, Radbruch, Andreas, Abrignani, Sergio, Addo, Richard, Akdis, Mübeccel, Andrä, Immanuel, Andreata, Francesco, Annunziato, Francesco, Arranz, Eduardo, Bacher, Petra, Knop, Laura, Knopf, Jasmin, Koay, Hui-Fern, Kobow, Katja, Kriegsmann, Katharina, Kristyanto, H., Krueger, Andreas, Kuehne, Jenny F., Kunze-Schumacher, Heike, Maini, Mala K., Verheyden, Nikita A., Kvistborg, Pia, Kwok, Immanuel, Latorre, Daniela, Mair, Florian, Bari, Sudipto, Manta, Calin, Armin Manz, Rudolf, Mashreghi, Mir-Farzin, Mazzoni, Alessio, McCluskey, James, Borstel, Anouk von, Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Monin, Leticia, Barnaba, Vincenzo, Moretta, Lorenzo, Multhoff, Gabriele, Muñoz, Luis Enrique, Muñoz-Ruiz, Miguel, Ward-Hartstonge, Kirsten A., Muscate, Franziska, Natalini, Ambra, Neumann, Katrin, Guan N., Lai, Niedobitek, Antonia, Niemz, Jana, Barros-Martins, Joana, Nogueira Almeida, Larissa, Notarbartolo, Samuele, Ostendorf, Lennard, Warnatz, Klaus, Pallett, Laura J., Patel, Amit A., Itir Percin, Gulce, Peruzzi, Giovanna, Pinti, Marcello, Pockley, A. Graham, Pracht, Katharina, Baumjohann, Dirk, Prinz, Immo, Pujol-Autonell, Irma, Waskow, Claudia, Pulvirenti, Nadia, Quatrini, Linda, Quinn, Kylie M., Radbruch, Helena, Rhys, Hefin, Rodrigo, Maria B., Romagnani, Chiara, Saggau, Carina, Beccaria, Cristian G., Sakaguchi, Shimon, Wiedemann, Annika, Sallusto, Federica, Sanderink, Lieke, Sandrock, Inga, Schauer, Christine, Scheffold, Alexander, Scherer, Hans U., Schiemann, Matthias, Schildberg, Frank A., Schober, Kilian, Bernardo, David, Wilharm, Anneke, Schoen, Janina, Schuh, Wolfgang, Schüler, Thomas, Schulz, Axel R., Schulz, Sebastian, Schulze, Julia, Simonetti, Sonia, Singh, Jeeshan, Sitnik, Katarzyna M., Stark, Regina, Wing, James, Boardman, Dominic A., Starossom, Sarah, Stehle, Christina, Szelinski, Franziska, Tan, Leonard, Tarnok, Attila, Tornack, Julia, Tree, Timothy I. M., Van Beek, Jasper J. P., Veen, Willem van de, Wirz, Oliver, Gisbergen, Klaas van, Borger, Jessica, Vasco, Chiara, Böttcher, Chotima, Lenz, Daniel, Wittner, Jens, Yang, Jennie H. M., Yang, Juhao, Brockmann, Leonie, Burns, Marie, Busch, Dirk H., Cameron, Garth, Cammarata, Ilenia, Cassotta, Antonino, Chang, Yinshui, Levings, Megan K., Chirdo, Fernando G., Christakou, Eleni, Cicin-Sain, Luka, Cook, Laura, Corbett, Alexandra J., Cornelis, Rebecca, Cosmi, Lorenzo, Davey, Martin S., Biasi, Sara De, Simone, Gabriele De, Lino, Andreia C., Zotto, Genny del, Delacher, Michael, Rosa, Francesca Di, Santo, James Di, Diefenbach, Andreas, Dong, Jun, Dörner, Thomas, Dress, Regine J., Dutertre, Charles-Antoine, Eckle, Sidonia B. G., Liotta, Francesco, Eede, Pascale, Evrard, Maximilien, Falk, Christine S., Feuerer, Markus, Fillatreau, Simon, Fiz-López, Aida, Follo, Marie, Foulds, Gemma A., Fröbel, Julia, Gagliani, Nicola, Long, Heather M., Galletti, Giovanni, Gangaev, Anastasia, Garbi, Natalio, Garrote, José Antonio, Geginat, Jens, Gherardin, Nicholas A., Gibellini, Lara, Ginhoux, Florent, Godfrey, Dale I., Gruarin, Paola, Lugli, Enrico, Haftmann, Claudia, Hansmann, Leo, Harpur, Christopher M., Hayday, Adrian C., Heine, Guido, Hernández, Daniela Carolina, Herrmann, Martin, Hoelsken, Oliver, Huang, Qing, Huber, Samuel, MacDonald, Katherine N., Huber, Johanna E., Huehn, Jochen, Hundemer, Michael, Hwang, William Y. K., Iannacone, Matteo, Ivison, Sabine M., Jäck, Hans-Martin, Jani, Peter K., Keller, Baerbel, Kessler, Nina, Maggi, Laura, Ketelaars, Steven, Rolf M. Schwiete Foundation, Associazione Italiana per la Ricerca sul Cancro, German Research Foundation, National Institutes of Health (US), European Commission, Cossarizza, Andrea, Chang, Hyun‐Dong, Radbruch, Andreas, Abrignani, Sergio, Addo, Richard, Akdis, Mübeccel, Andrä, Immanuel, Andreata, Francesco, Annunziato, Francesco, Arranz, Eduardo, Bacher, Petra, Knop, Laura, Knopf, Jasmin, Koay, Hui-Fern, Kobow, Katja, Kriegsmann, Katharina, Kristyanto, H., Krueger, Andreas, Kuehne, Jenny F., Kunze-Schumacher, Heike, Maini, Mala K., Verheyden, Nikita A., Kvistborg, Pia, Kwok, Immanuel, Latorre, Daniela, Mair, Florian, Bari, Sudipto, Manta, Calin, Armin Manz, Rudolf, Mashreghi, Mir-Farzin, Mazzoni, Alessio, McCluskey, James, Borstel, Anouk von, Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Monin, Leticia, Barnaba, Vincenzo, Moretta, Lorenzo, Multhoff, Gabriele, Muñoz, Luis Enrique, Muñoz-Ruiz, Miguel, Ward-Hartstonge, Kirsten A., Muscate, Franziska, Natalini, Ambra, Neumann, Katrin, Guan N., Lai, Niedobitek, Antonia, Niemz, Jana, Barros-Martins, Joana, Nogueira Almeida, Larissa, Notarbartolo, Samuele, Ostendorf, Lennard, Warnatz, Klaus, Pallett, Laura J., Patel, Amit A., Itir Percin, Gulce, Peruzzi, Giovanna, Pinti, Marcello, Pockley, A. Graham, Pracht, Katharina, Baumjohann, Dirk, Prinz, Immo, Pujol-Autonell, Irma, Waskow, Claudia, Pulvirenti, Nadia, Quatrini, Linda, Quinn, Kylie M., Radbruch, Helena, Rhys, Hefin, Rodrigo, Maria B., Romagnani, Chiara, Saggau, Carina, Beccaria, Cristian G., Sakaguchi, Shimon, Wiedemann, Annika, Sallusto, Federica, Sanderink, Lieke, Sandrock, Inga, Schauer, Christine, Scheffold, Alexander, Scherer, Hans U., Schiemann, Matthias, Schildberg, Frank A., Schober, Kilian, Bernardo, David, Wilharm, Anneke, Schoen, Janina, Schuh, Wolfgang, Schüler, Thomas, Schulz, Axel R., Schulz, Sebastian, Schulze, Julia, Simonetti, Sonia, Singh, Jeeshan, Sitnik, Katarzyna M., Stark, Regina, Wing, James, Boardman, Dominic A., Starossom, Sarah, Stehle, Christina, Szelinski, Franziska, Tan, Leonard, Tarnok, Attila, Tornack, Julia, Tree, Timothy I. M., Van Beek, Jasper J. P., Veen, Willem van de, Wirz, Oliver, Gisbergen, Klaas van, Borger, Jessica, Vasco, Chiara, Böttcher, Chotima, Lenz, Daniel, Wittner, Jens, Yang, Jennie H. M., Yang, Juhao, Brockmann, Leonie, Burns, Marie, Busch, Dirk H., Cameron, Garth, Cammarata, Ilenia, Cassotta, Antonino, Chang, Yinshui, Levings, Megan K., Chirdo, Fernando G., Christakou, Eleni, Cicin-Sain, Luka, Cook, Laura, Corbett, Alexandra J., Cornelis, Rebecca, Cosmi, Lorenzo, Davey, Martin S., Biasi, Sara De, Simone, Gabriele De, Lino, Andreia C., Zotto, Genny del, Delacher, Michael, Rosa, Francesca Di, Santo, James Di, Diefenbach, Andreas, Dong, Jun, Dörner, Thomas, Dress, Regine J., Dutertre, Charles-Antoine, Eckle, Sidonia B. G., Liotta, Francesco, Eede, Pascale, Evrard, Maximilien, Falk, Christine S., Feuerer, Markus, Fillatreau, Simon, Fiz-López, Aida, Follo, Marie, Foulds, Gemma A., Fröbel, Julia, Gagliani, Nicola, Long, Heather M., Galletti, Giovanni, Gangaev, Anastasia, Garbi, Natalio, Garrote, José Antonio, Geginat, Jens, Gherardin, Nicholas A., Gibellini, Lara, Ginhoux, Florent, Godfrey, Dale I., Gruarin, Paola, Lugli, Enrico, Haftmann, Claudia, Hansmann, Leo, Harpur, Christopher M., Hayday, Adrian C., Heine, Guido, Hernández, Daniela Carolina, Herrmann, Martin, Hoelsken, Oliver, Huang, Qing, Huber, Samuel, MacDonald, Katherine N., Huber, Johanna E., Huehn, Jochen, Hundemer, Michael, Hwang, William Y. K., Iannacone, Matteo, Ivison, Sabine M., Jäck, Hans-Martin, Jani, Peter K., Keller, Baerbel, Kessler, Nina, Maggi, Laura, and Ketelaars, Steven
- Abstract
The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.
- Published
- 2021
10. Guidelines for standardizing T‐cell cytometry assays to link biomarkers, mechanisms, and disease outcomes in type 1 diabetes.
- Author
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Yang, Jennie H. M., Ward‐Hartstonge, Kirsten A., Perry, Daniel J., Blanchfield, J. Lori, Posgai, Amanda L., Wiedeman, Alice E., Diggins, Kirsten, Rahman, Adeeb, Tree, Timothy I. M., Brusko, Todd M., Levings, Megan K., James, Eddie A., Kent, Sally C., Speake, Cate, Homann, Dirk, and Long, S. Alice
- Subjects
TYPE 1 diabetes ,T cells ,CYTOMETRY ,BIOMARKERS ,CELL populations - Abstract
Cytometric immunophenotyping is a powerful tool to discover and implement T‐cell biomarkers of type 1 diabetes (T1D) progression and response to clinical therapy. Although many discovery‐based T‐cell biomarkers have been described, to date, no such markers have been widely adopted in standard practice. The heterogeneous nature of T1D and lack of standardized assays and experimental design across studies is a major barrier to the broader adoption of T‐cell immunophenotyping assays. There is an unmet need to harmonize the design of immunophenotyping assays, including those that measure antigen‐agnostic cell populations, such that data collected from different clinical trial sites and T1D cohorts are comparable, yet account for cohort‐specific features and different drug mechanisms of action. In these Guidelines, we aim to provide expert advice on how to unify aspects of study design and practice. We provide recommendations for defining cohorts, method implementation, as well as tools for data analysis and reporting by highlighting and building on selected successes. Harmonization of cytometry‐based T‐cell assays will allow researchers to better integrate findings across trials, ultimately enabling the identification and validation of biomarkers of disease progression and treatment response in T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
11. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial
- Author
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Todd, John A., Evangelou, Marina, Cutler, Antony J., Pekalski, Marcin L., Walker, Neil M., Stevens, Helen E., Porter, Linsey, Smyth, Deborah J., Rainbow, Daniel B., Ferreira, Ricardo C., Esposito, Laura, Hunter, Kara M. D., Loudon, Kevin, Irons, Kathryn, Yang, Jennie H., Bell, Charles J. M., Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L., Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I., Evans, Mark, Mander, Adrian P., Bond, Simon, Wicker, Linda S., and Waldron-Lynch, Frank
- Subjects
Immunotherapy -- Analysis -- Health aspects -- Research ,Interleukin-2 -- Physiological aspects -- Genetic aspects -- Research ,Type 1 diabetes -- Analysis -- Health aspects -- Genetic aspects -- Care and treatment -- Research ,T cells -- Analysis -- Health aspects -- Physiological aspects -- Genetic aspects -- Research ,Biological sciences - Abstract
Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4.sup.+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4.sup.+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3.sup.+ CD4.sup.+ CD25.sup.high CD127.sup.low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 x 10.sup.6 to 1.5 x 10.sup.6 IU/m.sup.2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 x 10.sup.6 IU/m.sup.2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 x 10.sup.6 IU/m.sup.2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 x 10.sup.6 and 0.045 x 10.sup.6 IU/m.sup.2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the [beta] chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735, Author(s): John A. Todd 1,*, Marina Evangelou 2, Antony J. Cutler 1, Marcin L. Pekalski 1, Neil M. Walker 1, Helen E. Stevens 1, Linsey Porter 1, Deborah J. Smyth [...]
- Published
- 2016
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12. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
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Cossarizza, Andrea, Chang, Hyun-Dong, Radbruch, Andreas, Acs, Andreas, Adam, Dieter, Adam-Klages, Sabine, Agace, William W., Aghaeepour, Nima, Akdis, Muebeccel, Allez, Matthieu, Almeida, Larissa Nogueira, Alvisi, Giorgia, Anderson, Graham, Andrae, Immanuel, Annunziato, Francesco, Anselmo, Achille, Bacher, Petra, Baldari, Cosima T., Bari, Sudipto, Barnaba, Vincenzo, Barros-Martins, Joana, Battistini, Luca, Bauer, Wolfgang, Baumgart, Sabine, Baumgarth, Nicole, Baumjohann, Dirk, Baying, Bianka, Bebawy, Mary, Becher, Burkhard, Beisker, Wolfgang, Benes, Vladimir, Beyaert, Rudi, Blanco, Alfonso, Boardman, Dominic A., Bogdan, Christian, Borger, Jessica G., Borsellino, Giovanna, Boulais, Philip E., Bradford, Jolene A., Brenner, Dirk, Brinkman, Ryan R., Brooks, Anna E. S., Busch, Dirk H., Buescher, Martin, Bushnell, Timothy P., Calzetti, Federica, Cameron, Garth, Cammarata, Ilenia, Cao, Xuetao, Cardell, Susanna L., Casola, Stefano, Cassatella, Marco A., Cavani, Andrea, Celada, Antonio, Chatenoud, Lucienne, Chattopadhyay, Pratip K., Chow, Sue, Christakou, Eleni, Cicin-Sain, Luka, Clerici, Mario, Colombo, Federico S., Cook, Laura, Cooke, Anne, Cooper, Andrea M., Corbett, Alexandra J., Cosma, Antonio, Cosmi, Lorenzo, Coulie, Pierre G., Cumano, Ana, Cvetkovic, Ljiljana, Dang, Van Duc, Dang-Heine, Chantip, Davey, Martin S., Davies, Derek, De Biasi, Sara, Del Zotto, Genny, Dela Cruz, Gelo Victoriano, Delacher, Michael, Della Bella, Silvia, Dellabona, Paolo, Deniz, Guennur, Dessing, Mark, Di Santo, James P., Diefenbach, Andreas, Dieli, Francesco, Dolf, Andreas, Doerner, Thomas, Dress, Regine J., Dudziak, Diana, Dustin, Michael, Dutertre, Charles-Antoine, Ebner, Friederike, Eckle, Sidonia B. G., Edinger, Matthias, Eede, Pascale, Ehrhardt, Goetz R. A., Eich, Marcus, Engel, Pablo, Engelhardt, Britta, Erdei, Anna, Esser, Charlotte, Everts, Bart, Evrard, Maximilien, Falk, Christine S., Fehniger, Todd A., Felipo-Benavent, Mar, Ferry, Helen, Feuerer, Markus, Filby, Andrew, Filkor, Kata, Fillatreau, Simon, Follo, Marie, Foerster, Irmgard, Foster, John, Foulds, Gemma A., Frehse, Britta, Frenette, Paul S., Frischbutter, Stefan, Fritzsche, Wolfgang, Galbraith, David W., Gangaev, Anastasia, Garbi, Natalio, Gaudilliere, Brice, Gazzinelli, Ricardo T., Geginat, Jens, Gerner, Wilhelm, Gherardin, Nicholas A., Ghoreschi, Kamran, Gibellini, Lara, Ginhoux, Florent, Goda, Keisuke, Godfrey, Dale I., Goettlinger, Christoph, Gonzalez-Navajas, Jose M., Goodyear, Carl S., Gori, Andrea, Grogan, Jane L., Grummitt, Daryl, Gruetzkau, Andreas, Haftmann, Claudia, Hahn, Jonas, Hammad, Hamida, Haemmerling, Guenter, Hansmann, Leo, Hansson, Goran, Harpur, Christopher M., Hartmann, Susanne, Hauser, Andrea, Hauser, Anja E., Haviland, David L., Hedley, David, Hernandez, Daniela C., Herrera, Guadalupe, Herrmann, Martin, Hess, Christoph, Hoefer, Thomas, Hoffmann, Petra, Hogquist, Kristin, Holland, Tristan, Hollt, Thomas, Holmdahl, Rikard, Hombrink, Pleun, Houston, Jessica P., Hoyer, Bimba F., Huang, Bo, Huang, Fang-Ping, Huber, Johanna E., Huehn, Jochen, Hundemer, Michael, Hunter, Christopher A., Hwang, William Y. K., Iannone, Anna, Ingelfinger, Florian, Ivison, Sabine M., Jaeck, Hans-Martin, Jani, Peter K., Javega, Beatriz, Jonjic, Stipan, Kaiser, Toralf, Kalina, Tomas, Kamradt, Thomas, Kaufmann, Stefan H. E., Keller, Baerbel, Ketelaars, Steven L. C., Khalilnezhad, Ahad, Khan, Srijit, Kisielow, Jan, Klenerman, Paul, Knopf, Jasmin, Koay, Hui-Fern, Kobow, Katja, Kolls, Jay K., Kong, Wan Ting, Kopf, Manfred, Korn, Thomas, Kriegsmann, Katharina, Kristyanto, Hendy, Kroneis, Thomas, Krueger, Andreas, Kuehne, Jenny, Kukat, Christian, Kunkel, Desiree, Kunze-Schumacher, Heike, Kurosaki, Tomohiro, Kurts, Christian, Kvistborg, Pia, Kwok, Immanuel, Landry, Jonathan, Lantz, Olivier, Lanuti, Paola, LaRosa, Francesca, Lehuen, Agnes, LeibundGut-Landmann, Salome, Leipold, Michael D., Leung, Leslie Y. T., Levings, Megan K., Lino, Andreia C., Liotta, Francesco, Litwin, Virginia, Liu, Yanling, Ljunggren, Hans-Gustaf, Lohoff, Michael, Lombardi, Giovanna, Lopez, Lilly, Lopez-Botet, Miguel, Lovett-Racke, Amy E., Lubberts, Erik, Luche, Herve, Ludewig, Burkhard, Lugli, Enrico, Lunemann, Sebastian, Maecker, Holden T., Maggi, Laura, Maguire, Orla, Mair, Florian, Mair, Kerstin H., Mantovani, Alberto, Manz, Rudolf A., Marshall, Aaron J., Martinez-Romero, Alicia, Martrus, Gloria, Marventano, Ivana, Maslinski, Wlodzimierz, Matarese, Giuseppe, Mattioli, Anna Vittoria, Maueroder, Christian, Mazzoni, Alessio, McCluskey, James, McGrath, Mairi, McGuire, Helen M., McInnes, Iain B., Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Miller, Stephen D., Mills, Kingston H. G., Minderman, Hans, Mjosberg, Jenny, Moore, Jonni, Moran, Barry, Moretta, Lorenzo, Mosmann, Tim R., Mueller, Susann, Multhoff, Gabriele, Munoz, Luis Enrique, Munz, Christian, Nakayama, Toshinori, Nasi, Milena, Neumann, Katrin, Ng, Lai Guan, Niedobitek, Antonia, Nourshargh, Sussan, Nunez, Gabriel, O'Connor, Jose-Enrique, Ochel, Aaron, Oja, Anna, Ordonez, Diana, Orfao, Alberto, Orlowski-Oliver, Eva, Ouyang, Wenjun, Oxenius, Annette, Palankar, Raghavendra, Panse, Isabel, Pattanapanyasat, Kovit, Paulsen, Malte, Pavlinic, Dinko, Penter, Livius, Peterson, Paert, Peth, Christian, Petriz, Jordi, Piancone, Federica, Pickl, Winfried F., Piconese, Silvia, Pinti, Marcello, Pockley, A. Graham, Podolska, Malgorzata Justyna, Poon, Zhiyong, Pracht, Katharina, Prinz, Immo, Pucillo, Carlo E. M., Quataert, Sally A., Quatrini, Linda, Quinn, Kylie M., Radbruch, Helena, Radstake, Tim R. D. J., Rahmig, Susann, Rahn, Hans-Peter, Rajwa, Bartek, Ravichandran, Gevitha, Raz, Yotam, Rebhahn, Jonathan A., Recktenwald, Diether, Reimer, Dorothea, Reis e Sousa, Caetano, Remmerswaal, Ester B. M., Richter, Lisa, Rico, Laura G., Riddell, Andy, Rieger, Aja M., Robinson, J. Paul, Romagnani, Chiara, Rubartelli, Anna, Ruland, Juergen, Saalmueller, Armin, Saeys, Yvan, Saito, Takashi, Sakaguchi, Shimon, Sala-de-Oyanguren, Francisco, Samstag, Yvonne, Sanderson, Sharon, Sandrock, Inga, Santoni, Angela, Sanz, Ramon Bellmas, Saresella, Marina, Sautes-Fridman, Catherine, Sawitzki, Birgit, Schadt, Linda, Scheffold, Alexander, Scherer, Hans U., Schiemann, Matthias, Schildberg, Frank A., Schimisky, Esther, Schlitzer, Andreas, Schlosser, Josephine, Schmid, Stephan, Schmitt, Steffen, Schober, Kilian, Schraivogel, Daniel, Schuh, Wolfgang, Schueler, Thomas, Schulte, Reiner, Schulz, Axel Ronald, Schulz, Sebastian R., Scotta, Cristiano, Scott-Algara, Daniel, Sester, David P., Shankey, T. Vincent, Silva-Santos, Bruno, Simon, Anna Katharina, Sitnik, Katarzyna M., Sozzani, Silvano, Speiser, Daniel E., Spidlen, Josef, Stahlberg, Anders, Stall, Alan M., Stanley, Natalie, Stark, Regina, Stehle, Christina, Steinmetz, Tobit, Stockinger, Hannes, Takahama, Yousuke, Takeda, Kiyoshi, Tan, Leonard, Tarnok, Attila, Tiegs, Gisa, Toldi, Gergely, Tornack, Julia, Traggiai, Elisabetta, Trebak, Mohamed, Tree, Timothy I. M., Trotter, Joe, Trowsdale, John, Tsoumakidou, Maria, Ulrich, Henning, Urbanczyk, Sophia, van de Veen, Willem, van den Broek, Maries, van der Pol, Edwin, Van Gassen, Sofie, Van Isterdael, Gert, van Lier, Rene A. W., Veldhoen, Marc, Vento-Asturias, Salvador, Vieira, Paulo, Voehringer, David, Volk, Hans-Dieter, von Borstel, Anouk, von Volkmann, Konrad, Waisman, Ari, Walker, Rachael V., Wallace, Paul K., Wang, Sa A., Wang, Xin M., Ward, Michael D., Ward-Hartstonge, Kirsten A., Warnatz, Klaus, Warnes, Gary, Warth, Sarah, Waskow, Claudia, Watson, James V., Watzl, Carsten, Wegener, Leonie, Weisenburger, Thomas, Wiedemann, Annika, Wienands, Juergen, Wilharm, Anneke, Wilkinson, Robert John, Willimsky, Gerald, Wing, James B., Winkelmann, Rieke, Winkler, Thomas H., Wirz, Oliver F., Wong, Alicia, Wurst, Peter, Yang, Jennie H. M., Yang, Juhao, Yazdanbakhsh, Maria, Yu, Liping, Yue, Alice, Zhang, Hanlin, Zhao, Yi, Ziegler, Susanne Maria, Zielinski, Christina, Zimmermann, Jakob, Zychlinsky, Arturo, Cossarizza, Andrea, Chang, Hyun-Dong, Radbruch, Andreas, Acs, Andreas, Adam, Dieter, Adam-Klages, Sabine, Agace, William W., Aghaeepour, Nima, Akdis, Muebeccel, Allez, Matthieu, Almeida, Larissa Nogueira, Alvisi, Giorgia, Anderson, Graham, Andrae, Immanuel, Annunziato, Francesco, Anselmo, Achille, Bacher, Petra, Baldari, Cosima T., Bari, Sudipto, Barnaba, Vincenzo, Barros-Martins, Joana, Battistini, Luca, Bauer, Wolfgang, Baumgart, Sabine, Baumgarth, Nicole, Baumjohann, Dirk, Baying, Bianka, Bebawy, Mary, Becher, Burkhard, Beisker, Wolfgang, Benes, Vladimir, Beyaert, Rudi, Blanco, Alfonso, Boardman, Dominic A., Bogdan, Christian, Borger, Jessica G., Borsellino, Giovanna, Boulais, Philip E., Bradford, Jolene A., Brenner, Dirk, Brinkman, Ryan R., Brooks, Anna E. S., Busch, Dirk H., Buescher, Martin, Bushnell, Timothy P., Calzetti, Federica, Cameron, Garth, Cammarata, Ilenia, Cao, Xuetao, Cardell, Susanna L., Casola, Stefano, Cassatella, Marco A., Cavani, Andrea, Celada, Antonio, Chatenoud, Lucienne, Chattopadhyay, Pratip K., Chow, Sue, Christakou, Eleni, Cicin-Sain, Luka, Clerici, Mario, Colombo, Federico S., Cook, Laura, Cooke, Anne, Cooper, Andrea M., Corbett, Alexandra J., Cosma, Antonio, Cosmi, Lorenzo, Coulie, Pierre G., Cumano, Ana, Cvetkovic, Ljiljana, Dang, Van Duc, Dang-Heine, Chantip, Davey, Martin S., Davies, Derek, De Biasi, Sara, Del Zotto, Genny, Dela Cruz, Gelo Victoriano, Delacher, Michael, Della Bella, Silvia, Dellabona, Paolo, Deniz, Guennur, Dessing, Mark, Di Santo, James P., Diefenbach, Andreas, Dieli, Francesco, Dolf, Andreas, Doerner, Thomas, Dress, Regine J., Dudziak, Diana, Dustin, Michael, Dutertre, Charles-Antoine, Ebner, Friederike, Eckle, Sidonia B. G., Edinger, Matthias, Eede, Pascale, Ehrhardt, Goetz R. A., Eich, Marcus, Engel, Pablo, Engelhardt, Britta, Erdei, Anna, Esser, Charlotte, Everts, Bart, Evrard, Maximilien, Falk, Christine S., Fehniger, Todd A., Felipo-Benavent, Mar, Ferry, Helen, Feuerer, Markus, Filby, Andrew, Filkor, Kata, Fillatreau, Simon, Follo, Marie, Foerster, Irmgard, Foster, John, Foulds, Gemma A., Frehse, Britta, Frenette, Paul S., Frischbutter, Stefan, Fritzsche, Wolfgang, Galbraith, David W., Gangaev, Anastasia, Garbi, Natalio, Gaudilliere, Brice, Gazzinelli, Ricardo T., Geginat, Jens, Gerner, Wilhelm, Gherardin, Nicholas A., Ghoreschi, Kamran, Gibellini, Lara, Ginhoux, Florent, Goda, Keisuke, Godfrey, Dale I., Goettlinger, Christoph, Gonzalez-Navajas, Jose M., Goodyear, Carl S., Gori, Andrea, Grogan, Jane L., Grummitt, Daryl, Gruetzkau, Andreas, Haftmann, Claudia, Hahn, Jonas, Hammad, Hamida, Haemmerling, Guenter, Hansmann, Leo, Hansson, Goran, Harpur, Christopher M., Hartmann, Susanne, Hauser, Andrea, Hauser, Anja E., Haviland, David L., Hedley, David, Hernandez, Daniela C., Herrera, Guadalupe, Herrmann, Martin, Hess, Christoph, Hoefer, Thomas, Hoffmann, Petra, Hogquist, Kristin, Holland, Tristan, Hollt, Thomas, Holmdahl, Rikard, Hombrink, Pleun, Houston, Jessica P., Hoyer, Bimba F., Huang, Bo, Huang, Fang-Ping, Huber, Johanna E., Huehn, Jochen, Hundemer, Michael, Hunter, Christopher A., Hwang, William Y. K., Iannone, Anna, Ingelfinger, Florian, Ivison, Sabine M., Jaeck, Hans-Martin, Jani, Peter K., Javega, Beatriz, Jonjic, Stipan, Kaiser, Toralf, Kalina, Tomas, Kamradt, Thomas, Kaufmann, Stefan H. E., Keller, Baerbel, Ketelaars, Steven L. C., Khalilnezhad, Ahad, Khan, Srijit, Kisielow, Jan, Klenerman, Paul, Knopf, Jasmin, Koay, Hui-Fern, Kobow, Katja, Kolls, Jay K., Kong, Wan Ting, Kopf, Manfred, Korn, Thomas, Kriegsmann, Katharina, Kristyanto, Hendy, Kroneis, Thomas, Krueger, Andreas, Kuehne, Jenny, Kukat, Christian, Kunkel, Desiree, Kunze-Schumacher, Heike, Kurosaki, Tomohiro, Kurts, Christian, Kvistborg, Pia, Kwok, Immanuel, Landry, Jonathan, Lantz, Olivier, Lanuti, Paola, LaRosa, Francesca, Lehuen, Agnes, LeibundGut-Landmann, Salome, Leipold, Michael D., Leung, Leslie Y. T., Levings, Megan K., Lino, Andreia C., Liotta, Francesco, Litwin, Virginia, Liu, Yanling, Ljunggren, Hans-Gustaf, Lohoff, Michael, Lombardi, Giovanna, Lopez, Lilly, Lopez-Botet, Miguel, Lovett-Racke, Amy E., Lubberts, Erik, Luche, Herve, Ludewig, Burkhard, Lugli, Enrico, Lunemann, Sebastian, Maecker, Holden T., Maggi, Laura, Maguire, Orla, Mair, Florian, Mair, Kerstin H., Mantovani, Alberto, Manz, Rudolf A., Marshall, Aaron J., Martinez-Romero, Alicia, Martrus, Gloria, Marventano, Ivana, Maslinski, Wlodzimierz, Matarese, Giuseppe, Mattioli, Anna Vittoria, Maueroder, Christian, Mazzoni, Alessio, McCluskey, James, McGrath, Mairi, McGuire, Helen M., McInnes, Iain B., Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Miller, Stephen D., Mills, Kingston H. G., Minderman, Hans, Mjosberg, Jenny, Moore, Jonni, Moran, Barry, Moretta, Lorenzo, Mosmann, Tim R., Mueller, Susann, Multhoff, Gabriele, Munoz, Luis Enrique, Munz, Christian, Nakayama, Toshinori, Nasi, Milena, Neumann, Katrin, Ng, Lai Guan, Niedobitek, Antonia, Nourshargh, Sussan, Nunez, Gabriel, O'Connor, Jose-Enrique, Ochel, Aaron, Oja, Anna, Ordonez, Diana, Orfao, Alberto, Orlowski-Oliver, Eva, Ouyang, Wenjun, Oxenius, Annette, Palankar, Raghavendra, Panse, Isabel, Pattanapanyasat, Kovit, Paulsen, Malte, Pavlinic, Dinko, Penter, Livius, Peterson, Paert, Peth, Christian, Petriz, Jordi, Piancone, Federica, Pickl, Winfried F., Piconese, Silvia, Pinti, Marcello, Pockley, A. Graham, Podolska, Malgorzata Justyna, Poon, Zhiyong, Pracht, Katharina, Prinz, Immo, Pucillo, Carlo E. M., Quataert, Sally A., Quatrini, Linda, Quinn, Kylie M., Radbruch, Helena, Radstake, Tim R. D. J., Rahmig, Susann, Rahn, Hans-Peter, Rajwa, Bartek, Ravichandran, Gevitha, Raz, Yotam, Rebhahn, Jonathan A., Recktenwald, Diether, Reimer, Dorothea, Reis e Sousa, Caetano, Remmerswaal, Ester B. M., Richter, Lisa, Rico, Laura G., Riddell, Andy, Rieger, Aja M., Robinson, J. Paul, Romagnani, Chiara, Rubartelli, Anna, Ruland, Juergen, Saalmueller, Armin, Saeys, Yvan, Saito, Takashi, Sakaguchi, Shimon, Sala-de-Oyanguren, Francisco, Samstag, Yvonne, Sanderson, Sharon, Sandrock, Inga, Santoni, Angela, Sanz, Ramon Bellmas, Saresella, Marina, Sautes-Fridman, Catherine, Sawitzki, Birgit, Schadt, Linda, Scheffold, Alexander, Scherer, Hans U., Schiemann, Matthias, Schildberg, Frank A., Schimisky, Esther, Schlitzer, Andreas, Schlosser, Josephine, Schmid, Stephan, Schmitt, Steffen, Schober, Kilian, Schraivogel, Daniel, Schuh, Wolfgang, Schueler, Thomas, Schulte, Reiner, Schulz, Axel Ronald, Schulz, Sebastian R., Scotta, Cristiano, Scott-Algara, Daniel, Sester, David P., Shankey, T. Vincent, Silva-Santos, Bruno, Simon, Anna Katharina, Sitnik, Katarzyna M., Sozzani, Silvano, Speiser, Daniel E., Spidlen, Josef, Stahlberg, Anders, Stall, Alan M., Stanley, Natalie, Stark, Regina, Stehle, Christina, Steinmetz, Tobit, Stockinger, Hannes, Takahama, Yousuke, Takeda, Kiyoshi, Tan, Leonard, Tarnok, Attila, Tiegs, Gisa, Toldi, Gergely, Tornack, Julia, Traggiai, Elisabetta, Trebak, Mohamed, Tree, Timothy I. M., Trotter, Joe, Trowsdale, John, Tsoumakidou, Maria, Ulrich, Henning, Urbanczyk, Sophia, van de Veen, Willem, van den Broek, Maries, van der Pol, Edwin, Van Gassen, Sofie, Van Isterdael, Gert, van Lier, Rene A. W., Veldhoen, Marc, Vento-Asturias, Salvador, Vieira, Paulo, Voehringer, David, Volk, Hans-Dieter, von Borstel, Anouk, von Volkmann, Konrad, Waisman, Ari, Walker, Rachael V., Wallace, Paul K., Wang, Sa A., Wang, Xin M., Ward, Michael D., Ward-Hartstonge, Kirsten A., Warnatz, Klaus, Warnes, Gary, Warth, Sarah, Waskow, Claudia, Watson, James V., Watzl, Carsten, Wegener, Leonie, Weisenburger, Thomas, Wiedemann, Annika, Wienands, Juergen, Wilharm, Anneke, Wilkinson, Robert John, Willimsky, Gerald, Wing, James B., Winkelmann, Rieke, Winkler, Thomas H., Wirz, Oliver F., Wong, Alicia, Wurst, Peter, Yang, Jennie H. M., Yang, Juhao, Yazdanbakhsh, Maria, Yu, Liping, Yue, Alice, Zhang, Hanlin, Zhao, Yi, Ziegler, Susanne Maria, Zielinski, Christina, Zimmermann, Jakob, and Zychlinsky, Arturo
- Abstract
These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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- 2019
13. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression
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Ferreira, Ricardo C., primary, Castro Dopico, Xaquin, additional, Oliveira, João J., additional, Rainbow, Daniel B., additional, Yang, Jennie H., additional, Trzupek, Dominik, additional, Todd, Sarah A., additional, McNeill, Mhairi, additional, Steri, Maristella, additional, Orrù, Valeria, additional, Fiorillo, Edoardo, additional, Crouch, Daniel J. M., additional, Pekalski, Marcin L., additional, Cucca, Francesco, additional, Tree, Tim I., additional, Vyse, Tim J., additional, Wicker, Linda S., additional, and Todd, John A., additional
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- 2019
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14. Phenotypic Analysis of Human Lymph Nodes in Subjects With New-Onset Type 1 Diabetes and Healthy Individuals by Flow Cytometry
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Yang, Jennie H. M., primary, Khatri, Leena, additional, Mickunas, Marius, additional, Williams, Evangelia, additional, Tatovic, Danijela, additional, Alhadj Ali, Mohammad, additional, Young, Philippa, additional, Moyle, Penelope, additional, Sahni, Vishal, additional, Wang, Ryan, additional, Kaur, Rejbinder, additional, Tannahill, Gillian M., additional, Beaton, Andrew R., additional, Gerlag, Danielle M., additional, Savage, Caroline O. S., additional, Napolitano Rosen, Antonella, additional, Waldron-Lynch, Frank, additional, Dayan, Colin M., additional, and Tree, Timothy I. M., additional
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- 2019
- Full Text
- View/download PDF
15. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
- Author
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Cossarizza, Andrea, primary, Chang, Hyun‐Dong, additional, Radbruch, Andreas, additional, Acs, Andreas, additional, Adam, Dieter, additional, Adam‐Klages, Sabine, additional, Agace, William W., additional, Aghaeepour, Nima, additional, Akdis, Mübeccel, additional, Allez, Matthieu, additional, Almeida, Larissa Nogueira, additional, Alvisi, Giorgia, additional, Anderson, Graham, additional, Andrä, Immanuel, additional, Annunziato, Francesco, additional, Anselmo, Achille, additional, Bacher, Petra, additional, Baldari, Cosima T., additional, Bari, Sudipto, additional, Barnaba, Vincenzo, additional, Barros‐Martins, Joana, additional, Battistini, Luca, additional, Bauer, Wolfgang, additional, Baumgart, Sabine, additional, Baumgarth, Nicole, additional, Baumjohann, Dirk, additional, Baying, Bianka, additional, Bebawy, Mary, additional, Becher, Burkhard, additional, Beisker, Wolfgang, additional, Benes, Vladimir, additional, Beyaert, Rudi, additional, Blanco, Alfonso, additional, Boardman, Dominic A., additional, Bogdan, Christian, additional, Borger, Jessica G., additional, Borsellino, Giovanna, additional, Boulais, Philip E., additional, Bradford, Jolene A., additional, Brenner, Dirk, additional, Brinkman, Ryan R., additional, Brooks, Anna E. S., additional, Busch, Dirk H., additional, Büscher, Martin, additional, Bushnell, Timothy P., additional, Calzetti, Federica, additional, Cameron, Garth, additional, Cammarata, Ilenia, additional, Cao, Xuetao, additional, Cardell, Susanna L., additional, Casola, Stefano, additional, Cassatella, Marco A., additional, Cavani, Andrea, additional, Celada, Antonio, additional, Chatenoud, Lucienne, additional, Chattopadhyay, Pratip K., additional, Chow, Sue, additional, Christakou, Eleni, additional, Čičin‐Šain, Luka, additional, Clerici, Mario, additional, Colombo, Federico S., additional, Cook, Laura, additional, Cooke, Anne, additional, Cooper, Andrea M., additional, Corbett, Alexandra J., additional, Cosma, Antonio, additional, Cosmi, Lorenzo, additional, Coulie, Pierre G., additional, Cumano, Ana, additional, Cvetkovic, Ljiljana, additional, Dang, Van Duc, additional, Dang‐Heine, Chantip, additional, Davey, Martin S., additional, Davies, Derek, additional, De Biasi, Sara, additional, Del Zotto, Genny, additional, Dela Cruz, Gelo Victoriano, additional, Delacher, Michael, additional, Della Bella, Silvia, additional, Dellabona, Paolo, additional, Deniz, Günnur, additional, Dessing, Mark, additional, Di Santo, James P., additional, Diefenbach, Andreas, additional, Dieli, Francesco, additional, Dolf, Andreas, additional, Dörner, Thomas, additional, Dress, Regine J., additional, Dudziak, Diana, additional, Dustin, Michael, additional, Dutertre, Charles‐Antoine, additional, Ebner, Friederike, additional, Eckle, Sidonia B. G., additional, Edinger, Matthias, additional, Eede, Pascale, additional, Ehrhardt, Götz R.A., additional, Eich, Marcus, additional, Engel, Pablo, additional, Engelhardt, Britta, additional, Erdei, Anna, additional, Esser, Charlotte, additional, Everts, Bart, additional, Evrard, Maximilien, additional, Falk, Christine S., additional, Fehniger, Todd A., additional, Felipo‐Benavent, Mar, additional, Ferry, Helen, additional, Feuerer, Markus, additional, Filby, Andrew, additional, Filkor, Kata, additional, Fillatreau, Simon, additional, Follo, Marie, additional, Förster, Irmgard, additional, Foster, John, additional, Foulds, Gemma A., additional, Frehse, Britta, additional, Frenette, Paul S., additional, Frischbutter, Stefan, additional, Fritzsche, Wolfgang, additional, Galbraith, David W., additional, Gangaev, Anastasia, additional, Garbi, Natalio, additional, Gaudilliere, Brice, additional, Gazzinelli, Ricardo T., additional, Geginat, Jens, additional, Gerner, Wilhelm, additional, Gherardin, Nicholas A., additional, Ghoreschi, Kamran, additional, Gibellini, Lara, additional, Ginhoux, Florent, additional, Goda, Keisuke, additional, Godfrey, Dale I., additional, Goettlinger, Christoph, additional, González‐Navajas, Jose M., additional, Goodyear, Carl S., additional, Gori, Andrea, additional, Grogan, Jane L., additional, Grummitt, Daryl, additional, Grützkau, Andreas, additional, Haftmann, Claudia, additional, Hahn, Jonas, additional, Hammad, Hamida, additional, Hämmerling, Günter, additional, Hansmann, Leo, additional, Hansson, Goran, additional, Harpur, Christopher M., additional, Hartmann, Susanne, additional, Hauser, Andrea, additional, Hauser, Anja E., additional, Haviland, David L., additional, Hedley, David, additional, Hernández, Daniela C., additional, Herrera, Guadalupe, additional, Herrmann, Martin, additional, Hess, Christoph, additional, Höfer, Thomas, additional, Hoffmann, Petra, additional, Hogquist, Kristin, additional, Holland, Tristan, additional, Höllt, Thomas, additional, Holmdahl, Rikard, additional, Hombrink, Pleun, additional, Houston, Jessica P., additional, Hoyer, Bimba F., additional, Huang, Bo, additional, Huang, Fang‐Ping, additional, Huber, Johanna E., additional, Huehn, Jochen, additional, Hundemer, Michael, additional, Hunter, Christopher A., additional, Hwang, William Y. K., additional, Iannone, Anna, additional, Ingelfinger, Florian, additional, Ivison, Sabine M, additional, Jäck, Hans‐Martin, additional, Jani, Peter K., additional, Jávega, Beatriz, additional, Jonjic, Stipan, additional, Kaiser, Toralf, additional, Kalina, Tomas, additional, Kamradt, Thomas, additional, Kaufmann, Stefan H. E., additional, Keller, Baerbel, additional, Ketelaars, Steven L. C., additional, Khalilnezhad, Ahad, additional, Khan, Srijit, additional, Kisielow, Jan, additional, Klenerman, Paul, additional, Knopf, Jasmin, additional, Koay, Hui‐Fern, additional, Kobow, Katja, additional, Kolls, Jay K., additional, Kong, Wan Ting, additional, Kopf, Manfred, additional, Korn, Thomas, additional, Kriegsmann, Katharina, additional, Kristyanto, Hendy, additional, Kroneis, Thomas, additional, Krueger, Andreas, additional, Kühne, Jenny, additional, Kukat, Christian, additional, Kunkel, Désirée, additional, Kunze‐Schumacher, Heike, additional, Kurosaki, Tomohiro, additional, Kurts, Christian, additional, Kvistborg, Pia, additional, Kwok, Immanuel, additional, Landry, Jonathan, additional, Lantz, Olivier, additional, Lanuti, Paola, additional, LaRosa, Francesca, additional, Lehuen, Agnès, additional, LeibundGut‐Landmann, Salomé, additional, Leipold, Michael D., additional, Leung, Leslie Y.T., additional, Levings, Megan K., additional, Lino, Andreia C., additional, Liotta, Francesco, additional, Litwin, Virginia, additional, Liu, Yanling, additional, Ljunggren, Hans‐Gustaf, additional, Lohoff, Michael, additional, Lombardi, Giovanna, additional, Lopez, Lilly, additional, López‐Botet, Miguel, additional, Lovett‐Racke, Amy E., additional, Lubberts, Erik, additional, Luche, Herve, additional, Ludewig, Burkhard, additional, Lugli, Enrico, additional, Lunemann, Sebastian, additional, Maecker, Holden T., additional, Maggi, Laura, additional, Maguire, Orla, additional, Mair, Florian, additional, Mair, Kerstin H., additional, Mantovani, Alberto, additional, Manz, Rudolf A., additional, Marshall, Aaron J., additional, Martínez‐Romero, Alicia, additional, Martrus, Glòria, additional, Marventano, Ivana, additional, Maslinski, Wlodzimierz, additional, Matarese, Giuseppe, additional, Mattioli, Anna Vittoria, additional, Maueröder, Christian, additional, Mazzoni, Alessio, additional, McCluskey, James, additional, McGrath, Mairi, additional, McGuire, Helen M., additional, McInnes, Iain B., additional, Mei, Henrik E., additional, Melchers, Fritz, additional, Melzer, Susanne, additional, Mielenz, Dirk, additional, Miller, Stephen D., additional, Mills, Kingston H.G., additional, Minderman, Hans, additional, Mjösberg, Jenny, additional, Moore, Jonni, additional, Moran, Barry, additional, Moretta, Lorenzo, additional, Mosmann, Tim R., additional, Müller, Susann, additional, Multhoff, Gabriele, additional, Muñoz, Luis Enrique, additional, Münz, Christian, additional, Nakayama, Toshinori, additional, Nasi, Milena, additional, Neumann, Katrin, additional, Ng, Lai Guan, additional, Niedobitek, Antonia, additional, Nourshargh, Sussan, additional, Núñez, Gabriel, additional, O'Connor, José‐Enrique, additional, Ochel, Aaron, additional, Oja, Anna, additional, Ordonez, Diana, additional, Orfao, Alberto, additional, Orlowski‐Oliver, Eva, additional, Ouyang, Wenjun, additional, Oxenius, Annette, additional, Palankar, Raghavendra, additional, Panse, Isabel, additional, Pattanapanyasat, Kovit, additional, Paulsen, Malte, additional, Pavlinic, Dinko, additional, Penter, Livius, additional, Peterson, Pärt, additional, Peth, Christian, additional, Petriz, Jordi, additional, Piancone, Federica, additional, Pickl, Winfried F., additional, Piconese, Silvia, additional, Pinti, Marcello, additional, Pockley, A. Graham, additional, Podolska, Malgorzata Justyna, additional, Poon, Zhiyong, additional, Pracht, Katharina, additional, Prinz, Immo, additional, Pucillo, Carlo E. M., additional, Quataert, Sally A., additional, Quatrini, Linda, additional, Quinn, Kylie M., additional, Radbruch, Helena, additional, Radstake, Tim R. D. J., additional, Rahmig, Susann, additional, Rahn, Hans‐Peter, additional, Rajwa, Bartek, additional, Ravichandran, Gevitha, additional, Raz, Yotam, additional, Rebhahn, Jonathan A., additional, Recktenwald, Diether, additional, Reimer, Dorothea, additional, Reis e Sousa, Caetano, additional, Remmerswaal, Ester B.M., additional, Richter, Lisa, additional, Rico, Laura G., additional, Riddell, Andy, additional, Rieger, Aja M., additional, Robinson, J. Paul, additional, Romagnani, Chiara, additional, Rubartelli, Anna, additional, Ruland, Jürgen, additional, Saalmüller, Armin, additional, Saeys, Yvan, additional, Saito, Takashi, additional, Sakaguchi, Shimon, additional, Sala‐de‐Oyanguren, Francisco, additional, Samstag, Yvonne, additional, Sanderson, Sharon, additional, Sandrock, Inga, additional, Santoni, Angela, additional, Sanz, Ramon Bellmàs, additional, Saresella, Marina, additional, Sautes‐Fridman, Catherine, additional, Sawitzki, Birgit, additional, Schadt, Linda, additional, Scheffold, Alexander, additional, Scherer, Hans U., additional, Schiemann, Matthias, additional, Schildberg, Frank A., additional, Schimisky, Esther, additional, Schlitzer, Andreas, additional, Schlosser, Josephine, additional, Schmid, Stephan, additional, Schmitt, Steffen, additional, Schober, Kilian, additional, Schraivogel, Daniel, additional, Schuh, Wolfgang, additional, Schüler, Thomas, additional, Schulte, Reiner, additional, Schulz, Axel Ronald, additional, Schulz, Sebastian R., additional, Scottá, Cristiano, additional, Scott‐Algara, Daniel, additional, Sester, David P., additional, Shankey, T. Vincent, additional, Silva‐Santos, Bruno, additional, Simon, Anna Katharina, additional, Sitnik, Katarzyna M., additional, Sozzani, Silvano, additional, Speiser, Daniel E., additional, Spidlen, Josef, additional, Stahlberg, Anders, additional, Stall, Alan M., additional, Stanley, Natalie, additional, Stark, Regina, additional, Stehle, Christina, additional, Steinmetz, Tobit, additional, Stockinger, Hannes, additional, Takahama, Yousuke, additional, Takeda, Kiyoshi, additional, Tan, Leonard, additional, Tárnok, Attila, additional, Tiegs, Gisa, additional, Toldi, Gergely, additional, Tornack, Julia, additional, Traggiai, Elisabetta, additional, Trebak, Mohamed, additional, Tree, Timothy I.M., additional, Trotter, Joe, additional, Trowsdale, John, additional, Tsoumakidou, Maria, additional, Ulrich, Henning, additional, Urbanczyk, Sophia, additional, van de Veen, Willem, additional, van den Broek, Maries, additional, van der Pol, Edwin, additional, Van Gassen, Sofie, additional, Van Isterdael, Gert, additional, van Lier, René A.W., additional, Veldhoen, Marc, additional, Vento‐Asturias, Salvador, additional, Vieira, Paulo, additional, Voehringer, David, additional, Volk, Hans‐Dieter, additional, von Borstel, Anouk, additional, von Volkmann, Konrad, additional, Waisman, Ari, additional, Walker, Rachael V., additional, Wallace, Paul K., additional, Wang, Sa A., additional, Wang, Xin M., additional, Ward, Michael D., additional, Ward‐Hartstonge, Kirsten A, additional, Warnatz, Klaus, additional, Warnes, Gary, additional, Warth, Sarah, additional, Waskow, Claudia, additional, Watson, James V., additional, Watzl, Carsten, additional, Wegener, Leonie, additional, Weisenburger, Thomas, additional, Wiedemann, Annika, additional, Wienands, Jürgen, additional, Wilharm, Anneke, additional, Wilkinson, Robert John, additional, Willimsky, Gerald, additional, Wing, James B., additional, Winkelmann, Rieke, additional, Winkler, Thomas H., additional, Wirz, Oliver F., additional, Wong, Alicia, additional, Wurst, Peter, additional, Yang, Jennie H. M., additional, Yang, Juhao, additional, Yazdanbakhsh, Maria, additional, Yu, Liping, additional, Yue, Alice, additional, Zhang, Hanlin, additional, Zhao, Yi, additional, Ziegler, Susanne Maria, additional, Zielinski, Christina, additional, Zimmermann, Jakob, additional, and Zychlinsky, Arturo, additional
- Published
- 2019
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16. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes
- Author
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Alhadj Ali, Mohammad, primary, Liu, Yuk-Fun, additional, Arif, Sefina, additional, Tatovic, Danijela, additional, Shariff, Hina, additional, Gibson, Vivienne B., additional, Yusuf, Norkhairin, additional, Baptista, Roman, additional, Eichmann, Martin, additional, Petrov, Nedyalko, additional, Heck, Susanne, additional, Yang, Jennie H. M., additional, Tree, Timothy I. M., additional, Pujol-Autonell, Irma, additional, Yeo, Lorraine, additional, Baumard, Lucas, additional, Stenson, Rachel, additional, Howell, Alex, additional, Clark, Alison, additional, Boult, Zoe, additional, Powrie, Jake, additional, Adams, Laura, additional, Wong, Florence S., additional, Luzio, Stephen, additional, Dunseath, Gareth, additional, Green, Kate, additional, O’Keefe, Alison, additional, Bayly, Graham, additional, Thorogood, Natasha, additional, Andrews, Robert, additional, Leech, Nicola, additional, Joseph, Frank, additional, Nair, Sunil, additional, Seal, Susan, additional, Cheung, HoYee, additional, Beam, Craig, additional, Hills, Robert, additional, Peakman, Mark, additional, and Dayan, Colin M., additional
- Published
- 2017
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17. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression.
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Ferreira, Ricardo C., Castro Dopico, Xaquin, Oliveira, João J., Rainbow, Daniel B., Yang, Jennie H., Trzupek, Dominik, Todd, Sarah A., McNeill, Mhairi, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Crouch, Daniel J. M., Pekalski, Marcin L., Cucca, Francesco, Tree, Tim I., Vyse, Tim J., Wicker, Linda S., and Todd, John A.
- Subjects
SUPPRESSOR cells ,SYSTEMIC lupus erythematosus ,TYPE I interferons ,T cells ,IMMUNOLOGIC diseases - Abstract
In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4
+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+ FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+ HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders. [ABSTRACT FROM AUTHOR]- Published
- 2019
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18. Clinical-Grade Multipotent Adult Progenitor Cells Durably Control Pathogenic T Cell Responses in Human Models of Transplantation and Autoimmunity
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Reading, James L., primary, Yang, Jennie H. M., additional, Sabbah, Shereen, additional, Skowera, Ania, additional, Knight, Robin R., additional, Pinxteren, Jef, additional, Vaes, Bart, additional, Allsopp, Timothy, additional, Ting, Anthony E., additional, Busch, Sarah, additional, Raber, Amy, additional, Deans, Robert, additional, and Tree, Timothy I. M., additional
- Published
- 2013
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19. Type 1 Diabetes-Associated IL2RA Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function
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Garg, Garima, primary, Tyler, Jennifer R., additional, Yang, Jennie H. M., additional, Cutler, Antony J., additional, Downes, Kate, additional, Pekalski, Marcin, additional, Bell, Gwynneth L., additional, Nutland, Sarah, additional, Peakman, Mark, additional, Todd, John A., additional, Wicker, Linda S., additional, and Tree, Timothy I. M., additional
- Published
- 2012
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20. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource
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Dendrou, Calliope A, primary, Plagnol, Vincent, additional, Fung, Erik, additional, Yang, Jennie H M, additional, Downes, Kate, additional, Cooper, Jason D, additional, Nutland, Sarah, additional, Coleman, Gillian, additional, Himsworth, Matthew, additional, Hardy, Matthew, additional, Burren, Oliver, additional, Healy, Barry, additional, Walker, Neil M, additional, Koch, Kerstin, additional, Ouwehand, Willem H, additional, Bradley, John R, additional, Wareham, Nicholas J, additional, Todd, John A, additional, and Wicker, Linda S, additional
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- 2009
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21. Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.
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Yang, Jennie H. M., Cutler, Antony J., Ferreira, Ricardo C., Reading, James L., Cooper, Nicholas J., Wallace, Chris, Clarke, Pamela, Smyth, Deborah J., Boyce, Christopher S., Guo-Jian Gao, Todd, John A., Wicker, Linda S., Tree, Timothy I. M., and Gao, Guo-Jian
- Subjects
- *
INTERLEUKIN-2 , *T cells , *TYPE 1 diabetes , *HOMEOSTASIS , *GENETIC polymorphisms , *IMMUNOTHERAPY , *PHOSPHORYLATION , *CELLULAR signal transduction , *ESTERASES , *RESEARCH funding , *GENOTYPES , *PHYSIOLOGY - Abstract
Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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22. Evidence of association with type 1 diabetes in the SLC11A1 gene region.
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Yang, Jennie H. M., Downes, Kate, Howson, Joanna M. M., Nutland, Sarah, Stevens, Helen E., Walker, Neil M., and Todd, John A.
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DIABETES , *LINKAGE (Genetics) , *GENETIC polymorphisms , *AUTOIMMUNE diseases , *MICROSATELLITE repeats - Abstract
Background: Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform. Methods: Nine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C®T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P ≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR). Results: Using the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression. Conclusion: We conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. Association of the Vitamin D Metabolism Gene CYP27B1 With Type 1 Diabetes.
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Bailey, Rebecca, Cooper, Jason D., Zeitels, Lauren, Smyth, Deborah J., Yang, Jennie H. M., Walker, Neil M., Hyppönen, Elina, Dunger, David B., Ramos-Lopez, Elizabeth, Badenhoop, Klaus, Nejentsev, Sergey, and Todd, John A.
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VITAMIN D ,VITAMIN D deficiency ,DIABETES ,GENETICS of disease susceptibility ,METABOLITES ,PANCREATIC beta cells ,GENETIC polymorphisms - Abstract
OBJECTIVE--Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1α25-dihydroxyvitamin D (1α,25(OH)
2 D) could protect from immune destruction of the pancreatic β-cells. 1α,25(OH)2 D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1α-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes. RESEARCH DESIGN AND METHODS--We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms -1260C>A (rs10877012) and +2838T>C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene. RESULTS--We found evidence of association with type 1 diabetes for CYP27B1 -1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 - 1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 x 10-4 ) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 x 10-3 ). The combined P value for an association with type 1 diabetes was 3.8 x 10-6 . For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23). CONCLUSIONS--The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes. Diabetes 56:2616-2621, 2007 [ABSTRACT FROM AUTHOR]- Published
- 2007
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24. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.
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Todd, John A., Walker, Neil M., Cooper, Jason D., Smyth, Deborah J., Downes, Kate, Plagnol, Vincent, Bailey, Rebecca, Nejentsev, Sergey, Field, Sarah F., Payne, Felicity, Lowe, Christopher E., Szeszko, Jeffrey S., Hafler, Jason P., Zeitels, Lauren, Yang, Jennie H. M., Vella, Adrian, Nutland, Sarah, Stevens, Helen E., Schuilenburg, Helen, and Coleman, Gillian
- Subjects
GENOMICS ,DIABETES ,AUTOIMMUNE diseases ,GENETIC polymorphisms ,GENETICS of disease susceptibility ,THYROID diseases ,GRAVES' disease - Abstract
The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 × 10
−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9 ; Poverall ≤ 1.15 × 10−14 ), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8 ) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten. [ABSTRACT FROM AUTHOR]- Published
- 2007
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25. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial
- Author
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Todd, John A, Evangelou, Marina, Cutler, Antony J, Pekalski, Marcin L, Walker, Neil M, Stevens, Helen E, Porter, Linsey, Smyth, Deborah J, Rainbow, Daniel B, Ferreira, Ricardo C, Esposito, Laura, Hunter, Kara MD, Loudon, Kevin, Irons, Kathryn, Yang, Jennie H, Bell, Charles JM, Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah L, Lu, Jia, Greatorex, Jane, Goodfellow, Ian, Wallace, Chris, Tree, Tim I, Evans, Mark, Mander, Adrian P, Bond, Simon, Wicker, Linda S, and Waldron-Lynch, Frank
- Subjects
Adult ,Male ,Adolescent ,Dose-Response Relationship, Drug ,Middle Aged ,T-Lymphocytes, Regulatory ,Recombinant Proteins ,3. Good health ,Immunophenotyping ,Eosinophils ,Killer Cells, Natural ,Young Adult ,Diabetes Mellitus, Type 1 ,Humans ,Interleukin-2 ,Female ,Lymphocyte Count ,Chemokines ,Inflammation Mediators ,Biomarkers - Abstract
BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.
26. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression
- Author
-
Ferreira, Ricardo C, Castro Dopico, Xaquin, Oliveira, João J, Rainbow, Daniel B, Yang, Jennie H, Trzupek, Dominik, Todd, Sarah A, McNeill, Mhairi, Steri, Maristella, Orrù, Valeria, Fiorillo, Edoardo, Crouch, Daniel JM, Pekalski, Marcin L, Cucca, Francesco, Tree, Tim I, Vyse, Tim J, Wicker, Linda S, and Todd, John A
- Subjects
Adult ,Male ,Risk ,FOXP3 ,Programmed Cell Death 1 Receptor ,chemical and pharmacologic phenomena ,PTPN22 Arg620Trp ,T-Lymphocytes, Regulatory ,Young Adult ,PD-1 ,Humans ,Lupus Erythematosus, Systemic ,systemic lupus erythematosus (SLE) ,Alleles ,Aged ,Aged, 80 and over ,autoimmunity ,hemic and immune systems ,Forkhead Transcription Factors ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,Middle Aged ,3. Good health ,regulatory T cells (Tregs) ,type I interferon ,Interleukin-2 ,Female ,immunotherapy - Abstract
In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.
27. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial
- Author
-
Todd, John A, Evangelou, Marina, Cutler, Antony J, Pekalski, Marcin L, Walker, Neil M, Stevens, Helen E, Porter, Linsey, Smyth, Deborah J, Rainbow, Daniel B, Ferreira, Ricardo C, Esposito, Laura, Hunter, Kara MD, Loudon, Kevin, Irons, Kathryn, Yang, Jennie H, Bell, Charles JM, Schuilenburg, Helen, Heywood, James, Challis, Ben, Neupane, Sankalpa, Clarke, Pamela, Coleman, Gillian, Dawson, Sarah, Goymer, Donna, Anselmiova, Katerina, Kennet, Jane, Brown, Judy, Caddy, Sarah, Lu, Jia, Greatorex, Jane, Goodfellow, Ian Gordon, Wallace, Chris, Tree, Tim I, Evans, Mark, Mander, Adrian Paul, Bond, Simon, Wicker, Linda S, and Waldron-Lynch, Frank
- Subjects
lymphocytes ,blood counts ,blood ,memory T cells ,T cells ,eosinophils ,regulatory T cells ,3. Good health ,blood plasma - Abstract
BACKGROUND: Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. METHODS AND FINDINGS: To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. CONCLUSIONS: The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D. TRIAL REGISTRATION: ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735., This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pmed.1002139
28. Type 1 Diabetes-Associated IL2RA Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function.
- Author
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Garg, Garima, Tyler, Jennifer R., Yang, Jennie H. M., Cutler, Antony J., Downes, Kate, Pekalski, Marcin, Bell, Gwynneth L., Nutland, Sarah, Peakman, Mark, Todd, John A., Wicker, Linda S., and Tree, Timothy I. M.
- Subjects
- *
INTERLEUKIN-2 , *T cells , *TYPE 1 diabetes , *AUTOIMMUNE diseases , *GENETIC polymorphisms , *PHOSPHORYLATION - Abstract
Numerous reports have demonstrated that CD4+CD25+ regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1 diabetes, are deficient in their ability to control autologous proinflammatory responses when compared with nondiseased, control individuals. Treg dysfunction could be a primary, causal event or may result from perturbations in the immune system during disease development. Polymorphisms in genes associated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease. Although this suggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphisms and Treg function has not been examined. We addressed this by examining the impact of an IL2RA haplotype associated with type 1 diabetes on Treg fitness and suppressive function. Studies were conducted using healthy human subjects to avoid any confounding effects of disease. We demonstrated that the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2 responsiveness in Ag-experienced CD4+ T cells, as measured by phosphorylation of STAT5a, and is associated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppress proliferation of autologous effector T cells. These data offer a rationale that contributes to the molecular and cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, and consequently upon susceptibility to autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
29. Immune and Metabolic Effects of Antigen-Specific Immunotherapy Using Multiple β-Cell Peptides in Type 1 Diabetes.
- Author
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Liu YF, Powrie J, Arif S, Yang JHM, Williams E, Khatri L, Joshi M, Lhuillier L, Fountoulakis N, Smith E, Beam C, Lorenc A, Peakman M, and Tree T
- Subjects
- Autoantigens, Humans, Immunologic Factors therapeutic use, Immunotherapy, Peptides therapeutic use, T-Lymphocytes, Regulatory, Diabetes Mellitus, Type 1 genetics
- Abstract
Type 1 diabetes is characterized by a loss of tolerance to pancreatic β-cell autoantigens and defects in regulatory T-cell (Treg) function. In preclinical models, immunotherapy with MHC-selective, autoantigenic peptides restores immune tolerance, prevents diabetes, and shows greater potency when multiple peptides are used. To translate this strategy into the clinical setting, we administered a mixture of six HLA-DRB1*0401-selective, β-cell peptides intradermally to patients with recent-onset type 1 diabetes possessing this genotype in a randomized placebo-controlled study at monthly doses of 10, 100, and 500 μg for 24 weeks. Stimulated C-peptide (measuring insulin functional reserve) had declined in all placebo subjects at 24 weeks but was maintained at ≥100% baseline levels in one-half of the treated group. Treatment was accompanied by significant changes in islet-specific immune responses and a dose-dependent increase in Treg expression of the canonical transcription factor FOXP3 and changes in Treg gene expression. In this first-in-human study, multiple-peptide immunotherapy shows promise as a strategy to correct immune regulatory defects fundamental to the pathobiology of autoimmune diabetes., (© 2022 by the American Diabetes Association.)
- Published
- 2022
- Full Text
- View/download PDF
30. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp 620 Risk Allele Drive the Expansion of FOXP3 + Regulatory T Cells and PD-1 Expression.
- Author
-
Ferreira RC, Castro Dopico X, Oliveira JJ, Rainbow DB, Yang JH, Trzupek D, Todd SA, McNeill M, Steri M, Orrù V, Fiorillo E, Crouch DJM, Pekalski ML, Cucca F, Tree TI, Vyse TJ, Wicker LS, and Todd JA
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Autoimmunity, Female, Forkhead Transcription Factors, Humans, Interleukin-2 blood, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic genetics, Male, Middle Aged, Protein Tyrosine Phosphatase, Non-Receptor Type 22 immunology, Risk, Young Adult, Lupus Erythematosus, Systemic immunology, Programmed Cell Death 1 Receptor immunology, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, T-Lymphocytes, Regulatory immunology
- Abstract
In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4
+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+ FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+ HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders., (Copyright © 2019 Ferreira, Castro Dopico, Oliveira, Rainbow, Yang, Trzupek, Todd, McNeill, Steri, Orrù, Fiorillo, Crouch, Pekalski, Cucca, Tree, Vyse, Wicker and Todd.)- Published
- 2019
- Full Text
- View/download PDF
31. Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes.
- Author
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Wallace C, Rotival M, Cooper JD, Rice CM, Yang JH, McNeill M, Smyth DJ, Niblett D, Cambien F, Tiret L, Todd JA, Clayton DG, and Blankenberg S
- Subjects
- Adult, Aged, Algorithms, Female, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Genetic, Quantitative Trait Loci genetics, Risk Factors, Diabetes Mellitus, Type 1 genetics, Genetic Predisposition to Disease genetics, Monocytes metabolism, Polymorphism, Single Nucleotide, Transcriptome
- Abstract
One mechanism by which disease-associated DNA variation can alter disease risk is altering gene expression. However, linkage disequilibrium (LD) between variants, mostly single-nucleotide polymorphisms (SNPs), means it is not sufficient to show that a particular variant associates with both disease and expression, as there could be two distinct causal variants in LD. Here, we describe a formal statistical test of colocalization and apply it to type 1 diabetes (T1D)-associated regions identified mostly through genome-wide association studies and expression quantitative trait loci (eQTLs) discovered in a recently determined large monocyte expression data set from the Gutenberg Health Study (1370 individuals), with confirmation sought in an additional data set from the Cardiogenics Transcriptome Study (558 individuals). We excluded 39 out of 60 overlapping eQTLs in 49 T1D regions from possible colocalization and identified 21 coincident eQTLs, representing 21 genes in 14 distinct T1D regions. Our results reflect the importance of monocyte (and their derivatives, macrophage and dendritic cell) gene expression in human T1D and support the candidacy of several genes as causal factors in autoimmune pancreatic beta-cell destruction, including AFF3, CD226, CLECL1, DEXI, FKRP, PRKD2, RNLS, SMARCE1 and SUOX, in addition to the recently described GPR183 (EBI2) gene.
- Published
- 2012
- Full Text
- View/download PDF
32. Genome-wide analysis of allelic expression imbalance in human primary cells by high-throughput transcriptome resequencing.
- Author
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Heap GA, Yang JH, Downes K, Healy BC, Hunt KA, Bockett N, Franke L, Dubois PC, Mein CA, Dobson RJ, Albert TJ, Rodesch MJ, Clayton DG, Todd JA, van Heel DA, and Plagnol V
- Subjects
- Alleles, Base Pairing genetics, Bias, Cells, Cultured, Computational Biology, Disease genetics, Epigenesis, Genetic, False Positive Reactions, Genetic Loci genetics, Heterozygote, Humans, Polymorphism, Single Nucleotide genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Reproducibility of Results, Allelic Imbalance genetics, Gene Expression Profiling methods, Genome-Wide Association Study, High-Throughput Screening Assays methods, Sequence Analysis, DNA methods
- Abstract
Many disease-associated variants identified by genome-wide association (GWA) studies are expected to regulate gene expression. Allele-specific expression (ASE) quantifies transcription from both haplotypes using individuals heterozygous at tested SNPs. We performed deep human transcriptome-wide resequencing (RNA-seq) for ASE analysis and expression quantitative trait locus discovery. We resequenced double poly(A)-selected RNA from primary CD4(+) T cells (n = 4 individuals, both activated and untreated conditions) and developed tools for paired-end RNA-seq alignment and ASE analysis. We generated an average of 20 million uniquely mapping 45 base reads per sample. We obtained sufficient read depth to test 1371 unique transcripts for ASE. Multiple biases inflate the false discovery rate which we estimate to be approximately 50% for random SNPs. However, after controlling for these biases and considering the subset of SNPs that pass HapMap QC, 4.6% of heterozygous SNP-sample pairs show evidence of imbalance (P < 0.001). We validated four findings by both bacterial cloning and Sanger sequencing assays. We also found convincing evidence for allelic imbalance at multiple reporter exonic SNPs in CD6 for two samples heterozygous at the multiple sclerosis-associated variant rs17824933, linking GWA findings with variation in gene expression. Finally, we show in CD4(+) T cells from a further individual that high-throughput sequencing of genomic DNA and RNA-seq following enrichment for targeted gene sequences by sequence capture methods offers an unbiased means to increase the read depth for transcripts of interest, and therefore a method to investigate the regulatory role of many disease-associated genetic variants.
- Published
- 2010
- Full Text
- View/download PDF
33. Shared and distinct genetic variants in type 1 diabetes and celiac disease.
- Author
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Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, Howson JM, Stevens H, McManus R, Wijmenga C, Heap GA, Dubois PC, Clayton DG, Hunt KA, van Heel DA, and Todd JA
- Subjects
- Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Aged, 80 and over, Antigens, CD genetics, CTLA-4 Antigen, Celiac Disease immunology, Child, Child, Preschool, Cytoskeletal Proteins genetics, Diabetes Mellitus, Type 1 immunology, Female, Genetic Linkage, Genetic Predisposition to Disease, Humans, Infant, Interleukin-12 Subunit p35 genetics, Interleukin-18 Receptor beta Subunit genetics, Interleukin-2 Receptor alpha Subunit genetics, Intracellular Signaling Peptides and Proteins, LIM Domain Proteins, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Proteins genetics, RGS Proteins genetics, Receptors, CCR5 genetics, Young Adult, Autoimmunity genetics, Celiac Disease genetics, Diabetes Mellitus, Type 1 genetics
- Abstract
Background: Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared., Methods: We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects., Results: Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease., Conclusions: A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases., (2008 Massachusetts Medical Society)
- Published
- 2008
- Full Text
- View/download PDF
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