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1. Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.

Author

Casanova, Jean-Laurent, Tree, Timothy, Oram, Richard, Johnson, Matthew, Ogishi, Masato, Domingo-Vila, Clara, De Franco, Elisa, Wakeling, Matthew, Imane, Zineb, Resnick, Brittany, Williams, Evangelia, Galão, Rui, Caswell, Richard, Russ-Silsby, James, Seeleuthner, Yoann, Rinchai, Darawan, Fagniez, Iris, Benson, Basilin, Dufort, Matthew, Speake, Cate, Smithmyer, Megan, Hudson, Michelle, Dobbs, Rebecca, Hattersley, Andrew, Zhang, Peng, Boisson-Dupuis, Stephanie, Anderson, Mark, and Quandt, Zoe

Subjects
Infant, Newborn, Humans, Child, Preschool, Child, B7-H1 Antigen, Diabetes Mellitus, Type 1, Programmed Cell Death 1 Receptor, Autoimmunity, Homozygote
Abstract

We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.

Published
2024

2. Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

Author

Tatovic, Danijela, Marwaha, Ashish, Taylor, Peter, Hanna, Stephanie J., Carter, Kym, Cheung, W. Y., Luzio, Steve, Dunseath, Gareth, Hutchings, Hayley A., Holland, Gail, Hiles, Steve, Fegan, Greg, Williams, Evangelia, Yang, Jennie H. M., Domingo-Vila, Clara, Pollock, Emily, Wadud, Muntaha, Ward-Hartstonge, Kirsten, Marques-Jones, Susie, Bowen-Morris, Jane, Stenson, Rachel, Levings, Megan K., Gregory, John W., Tree, Timothy I. M., and Dayan, Colin

Published
2024
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3. Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling

Author

Ogishi, Masato, Kitaoka, Koji, Good-Jacobson, Kim L., Rinchai, Darawan, Zhang, Baihao, Wang, Jun, Gies, Vincent, Rao, Geetha, Nguyen, Tina, Avery, Danielle T., Khan, Taushif, Smithmyer, Megan E., Mackie, Joseph, Yang, Rui, Arias, Andrés Augusto, Asano, Takaki, Ponsin, Khoren, Chaldebas, Matthieu, Zhang, Peng, Peel, Jessica N., Bohlen, Jonathan, Lévy, Romain, Pelham, Simon J., Lei, Wei-Te, Han, Ji Eun, Fagniez, Iris, Chrabieh, Maya, Laine, Candice, Langlais, David, Gruber, Conor, Al Ali, Fatima, Rahman, Mahbuba, Aytekin, Caner, Benson, Basilin, Dufort, Matthew J., Domingo-Vila, Clara, Moriya, Kunihiko, Shlomchik, Mark, Uzel, Gulbu, Gray, Paul E., Suan, Daniel, Preece, Kahn, Chua, Ignatius, Okada, Satoshi, Chikuma, Shunsuke, Kiyonari, Hiroshi, Tree, Timothy I., Bogunovic, Dusan, Gros, Philippe, Marr, Nico, Speake, Cate, Oram, Richard A., Béziat, Vivien, Bustamante, Jacinta, Abel, Laurent, Boisson, Bertrand, Korganow, Anne-Sophie, Ma, Cindy S., Johnson, Matthew B., Chamoto, Kenji, Boisson-Dupuis, Stéphanie, Honjo, Tasuku, Casanova, Jean-Laurent, and Tangye, Stuart G.

Published
2024
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4. A set of circulating microRNAs belonging to the 14q32 chromosome locus identifies two subgroups of individuals with recent-onset type 1 diabetes

Author

Sebastiani, Guido, Grieco, Giuseppina Emanuela, Bruttini, Marco, Auddino, Stefano, Mori, Alessia, Toniolli, Mattia, Fignani, Daniela, Licata, Giada, Aiello, Elena, Nigi, Laura, Formichi, Caterina, Fernandez-Tajes, Juan, Pugliese, Alberto, Evans-Molina, Carmella, Overbergh, Lut, Tree, Timothy, Peakman, Mark, Mathieu, Chantal, and Dotta, Francesco

Published
2024
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5. Gene expression signature predicts rate of type 1 diabetes progression

Author

Mathieu, Chantal, Gillard, Pieter, Casteels, Kristina, Overbergh, Lutgart, Dunger, David, Wallace, Chris, Evans, Mark, Thankamony, Ajay, Hendriks, Emile, Bruggraber, Sylvaine, Marcoveccchio, Loredana, Peakman, Mark, Tree, Timothy, Morgan, Noel G., Richardson, Sarah, Todd, John A., Wicker, Linda, Mander, Adrian, Dayan, Colin, Alhadj Ali, Mohammad, Pieber, Thomas, Eizirik, Decio L., Cnop, Myriam, Brunak, Søren, Pociot, Flemming, Johannesen, Jesper, Rossing, Peter, Quigley, Cristina Legido, Mallone, Roberto, Scharfmann, Raphael, Boitard, Christian, Knip, Mikael, Otonkoski, Timo, Veijola, Riitta, Lahesmaa, Riitta, Oresic, Matej, Toppari, Jorma, Danne, Thomas, Ziegler, Anette G., Achenbach, Peter, Rodriguez-Calvo, Teresa, Solimena, Michele, Bonifacio, Ezio E., Speier, Stephan, Holl, Reinhard, Dotta, Francesco, Chiarelli, Francesco, Marchetti, Piero, Bosi, Emanuele, Cianfarani, Stefano, Ciampalini, Paolo, De Beaufort, Carine, Dahl-Jørgensen, Knut, Skrivarhaug, Torild, Joner, Geir, Krogvold, Lars, Jarosz-Chobot, Przemka, Battelino, Tadej, Thorens, Bernard, Gotthardt, Martin, Roep, Bart O., Nikolic, Tanja, Zaldumbide, Arnaud, Lernmark, Ake, Lundgren, Marcus, Costacalde, Guillaume, Strube, Thorsten, Schulte, Anke M., Nitsche, Almut, Vela, Jose, Von Herrath, Matthias, Wesley, Johnna, Napolitano-Rosen, Antonella, Thomas, Melissa, Schloot, Nanette, Goldfine, Allison, Waldron-Lynch, Frank, Kompa, Jill, Vedala, Aruna, Hartmann, Nicole, Nicolas, Gwenaelle, van Rampelbergh, Jean, Bovy, Nicolas, Dutta, Sanjoy, Soderberg, Jeannette, Ahmed, Simi, Martin, Frank, Latres, Esther, Agiostratidou, Gina, Koralova, Anne, Willemsen, Ruben, Smith, Anne, Anand, Binu, Datta, Vipan, Puthi, Vijith, Zac-Varghese, Sagen, Dias, Renuka, Sundaram, Premkumar, Vaidya, Bijay, Patterson, Catherine, Owen, Katharine, Piel, Barbara, Heller, Simon, Randell, Tabitha, Gazis, Tasso, Reismen, Elise Bismuth, Carel, Jean-Claude, Riveline, Jean-Pierre, Gautier, Jean-Francoise, Andreelli, Fabrizion, Travert, Florence, Cosson, Emmanuel, Penfornis, Alfred, Petit, Catherine, Feve, Bruno, Lucidarme, Nadine, Beressi, Jean-Paul, Ajzenman, Catherina, Radu, Alina, Greteau-Hamoumou, Stephanie, Bibal, Cecile, Meissner, Thomas, Heidtmann, Bettina, Toni, Sonia, Rami-Merhar, Birgit, Eeckhout, Bart, Peene, Bernard, Vantongerloo, N., Maes, Toon, Gommers, Leen, Suomi, Tomi, Starskaia, Inna, Kalim, Ubaid Ullah, Rasool, Omid, Jaakkola, Maria K., Grönroos, Toni, Välikangas, Tommi, Brorsson, Caroline, Mazzoni, Gianluca, Overbergh, Lut, Chmura, Piotr, and Elo, Laura L.

Published
2023
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7. Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study

Author

Mahil, Satveer K, Bechman, Katie, Raharja, Antony, Domingo-Vila, Clara, Baudry, David, Brown, Matthew A, Cope, Andrew P, Dasandi, Tejus, Graham, Carl, Khan, Hataf, Lechmere, Thomas, Malim, Michael H, Meynell, Freya, Pollock, Emily, Sychowska, Kamila, Barker, Jonathan N, Norton, Sam, Galloway, James B, Doores, Katie J, Tree, Timothy, and Smith, Catherine H

Published
2022
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10. Pharmacometabolomics applied to low‐dose interleukin‐2 treatment in amyotrophic lateral sclerosis

Author

Alarcan, Hugo, primary, Bruno, Clément, additional, Emond, Patrick, additional, Raoul, Cédric, additional, Vourc'h, Patrick, additional, Corcia, Philippe, additional, Camu, William, additional, Veyrune, Jean‐Luc, additional, Garlanda, Cecilia, additional, Locati, Massimo, additional, Juntas‐Morales, Raúl, additional, Saker, Safaa, additional, Suehs, Carey, additional, Masseguin, Christophe, additional, Kirby, Janine, additional, Shaw, Pamela, additional, Malaspina, Andrea, additional, De Vos, John, additional, Al‐Chalabi, Ammar, additional, Leigh, P. Nigel, additional, Tree, Timothy, additional, Bensimon, Gilbert, additional, and Blasco, Hélène, additional

Published
2024
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13. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study

Author

Mahil, Satveer K, Bechman, Katie, Raharja, Antony, Domingo-Vila, Clara, Baudry, David, Brown, Matthew A, Cope, Andrew P, Dasandi, Tejus, Graham, Carl, Lechmere, Thomas, Malim, Michael H, Meynell, Freya, Pollock, Emily, Seow, Jeffery, Sychowska, Kamila, Barker, Jonathan N, Norton, Sam, Galloway, James B, Doores, Katie J, Tree, Timothy I M, and Smith, Catherine H

Published
2021
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14. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study

Author

Monin, Leticia, Laing, Adam G, Muñoz-Ruiz, Miguel, McKenzie, Duncan R, del Molino del Barrio, Irene, Alaguthurai, Thanussuyah, Domingo-Vila, Clara, Hayday, Thomas S, Graham, Carl, Seow, Jeffrey, Abdul-Jawad, Sultan, Kamdar, Shraddha, Harvey-Jones, Elizabeth, Graham, Rosalind, Cooper, Jack, Khan, Muhammad, Vidler, Jennifer, Kakkassery, Helen, Sinha, Shubhankar, Davis, Richard, Dupont, Liane, Francos Quijorna, Isaac, O'Brien-Gore, Charlotte, Lee, Puay Ling, Eum, Josephine, Conde Poole, Maria, Joseph, Magdalene, Davies, Daniel, Wu, Yin, Swampillai, Angela, North, Bernard V, Montes, Ana, Harries, Mark, Rigg, Anne, Spicer, James, Malim, Michael H, Fields, Paul, Patten, Piers, Di Rosa, Francesca, Papa, Sophie, Tree, Timothy, Doores, Katie J, Hayday, Adrian C, and Irshad, Sheeba

Published
2021
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15. Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function

Author

Sabbah, Shereen, Liew, Aaron, Brooks, Augustin M., Kundu, Rhiannon, Reading, James L., Flatt, Anneliese, Counter, Claire, Choudhary, Pratik, Forbes, Shareen, Rosenthal, Miranda J., Rutter, Martin K., Cairns, Stephanie, Johnson, Paul, Casey, John, Peakman, Mark, Shaw, James A., and Tree, Timothy I.M.

Published
2021
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16. Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial

Author

Camu, William, Mickunas, Marius, Veyrune, Jean-Luc, Payan, Christine, Garlanda, Cecilia, Locati, Massimo, Juntas-Morales, Raul, Pageot, Nicolas, Malaspina, Andrea, Andreasson, Ulf, Kirby, Janine, Suehs, Carey, Saker, Safa, Masseguin, Christophe, De Vos, John, Zetterberg, Henrik, Shaw, Pamela J, Al-Chalabi, Ammar, Leigh, P Nigel, Tree, Timothy, and Bensimon, Gilbert

Published
2020
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17. Single-cell transcriptomics reveals markers of regulatory T cell dysfunction in Gestational Diabetes Mellitus

Author

Shangaris, Panicos, primary, Mensah, Nana, additional, Efthimiou, Athina, additional, Mureanu, Nicoleta, additional, Vaikkinen, Heli, additional, Kannambath, Shichina, additional, Bowman, Amanda, additional, Menon, Athul, additional, Tree, Timothy, additional, Lombardi, Giovanna, additional, Dhami, Pawan, additional, Nicolaides, Kypros, additional, and Scottá, Cristiano, additional

Published
2024
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20. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans

Author

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
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24. Gene expression signature predicts rate of type 1 diabetes progression

Author

Suomi, Tomi, primary, Starskaia, Inna, additional, Kalim, Ubaid Ullah, additional, Rasool, Omid, additional, Jaakkola, Maria K., additional, Grönroos, Toni, additional, Välikangas, Tommi, additional, Brorsson, Caroline, additional, Mazzoni, Gianluca, additional, Bruggraber, Sylvaine, additional, Overbergh, Lut, additional, Dunger, David, additional, Peakman, Mark, additional, Chmura, Piotr, additional, Brunak, Søren, additional, Schulte, Anke M., additional, Mathieu, Chantal, additional, Knip, Mikael, additional, Lahesmaa, Riitta, additional, Elo, Laura L., additional, Gillard, Pieter, additional, Casteels, Kristina, additional, Overbergh, Lutgart, additional, Wallace, Chris, additional, Evans, Mark, additional, Thankamony, Ajay, additional, Hendriks, Emile, additional, Marcoveccchio, Loredana, additional, Tree, Timothy, additional, Morgan, Noel G., additional, Richardson, Sarah, additional, Todd, John A., additional, Wicker, Linda, additional, Mander, Adrian, additional, Dayan, Colin, additional, Alhadj Ali, Mohammad, additional, Pieber, Thomas, additional, Eizirik, Decio L., additional, Cnop, Myriam, additional, Pociot, Flemming, additional, Johannesen, Jesper, additional, Rossing, Peter, additional, Quigley, Cristina Legido, additional, Mallone, Roberto, additional, Scharfmann, Raphael, additional, Boitard, Christian, additional, Otonkoski, Timo, additional, Veijola, Riitta, additional, Oresic, Matej, additional, Toppari, Jorma, additional, Danne, Thomas, additional, Ziegler, Anette G., additional, Achenbach, Peter, additional, Rodriguez-Calvo, Teresa, additional, Solimena, Michele, additional, Bonifacio, Ezio E., additional, Speier, Stephan, additional, Holl, Reinhard, additional, Dotta, Francesco, additional, Chiarelli, Francesco, additional, Marchetti, Piero, additional, Bosi, Emanuele, additional, Cianfarani, Stefano, additional, Ciampalini, Paolo, additional, De Beaufort, Carine, additional, Dahl-Jørgensen, Knut, additional, Skrivarhaug, Torild, additional, Joner, Geir, additional, Krogvold, Lars, additional, Jarosz-Chobot, Przemka, additional, Battelino, Tadej, additional, Thorens, Bernard, additional, Gotthardt, Martin, additional, Roep, Bart O., additional, Nikolic, Tanja, additional, Zaldumbide, Arnaud, additional, Lernmark, Ake, additional, Lundgren, Marcus, additional, Costacalde, Guillaume, additional, Strube, Thorsten, additional, Nitsche, Almut, additional, Vela, Jose, additional, Von Herrath, Matthias, additional, Wesley, Johnna, additional, Napolitano-Rosen, Antonella, additional, Thomas, Melissa, additional, Schloot, Nanette, additional, Goldfine, Allison, additional, Waldron-Lynch, Frank, additional, Kompa, Jill, additional, Vedala, Aruna, additional, Hartmann, Nicole, additional, Nicolas, Gwenaelle, additional, van Rampelbergh, Jean, additional, Bovy, Nicolas, additional, Dutta, Sanjoy, additional, Soderberg, Jeannette, additional, Ahmed, Simi, additional, Martin, Frank, additional, Latres, Esther, additional, Agiostratidou, Gina, additional, Koralova, Anne, additional, Willemsen, Ruben, additional, Smith, Anne, additional, Anand, Binu, additional, Datta, Vipan, additional, Puthi, Vijith, additional, Zac-Varghese, Sagen, additional, Dias, Renuka, additional, Sundaram, Premkumar, additional, Vaidya, Bijay, additional, Patterson, Catherine, additional, Owen, Katharine, additional, Piel, Barbara, additional, Heller, Simon, additional, Randell, Tabitha, additional, Gazis, Tasso, additional, Reismen, Elise Bismuth, additional, Carel, Jean-Claude, additional, Riveline, Jean-Pierre, additional, Gautier, Jean-Francoise, additional, Andreelli, Fabrizion, additional, Travert, Florence, additional, Cosson, Emmanuel, additional, Penfornis, Alfred, additional, Petit, Catherine, additional, Feve, Bruno, additional, Lucidarme, Nadine, additional, Beressi, Jean-Paul, additional, Ajzenman, Catherina, additional, Radu, Alina, additional, Greteau-Hamoumou, Stephanie, additional, Bibal, Cecile, additional, Meissner, Thomas, additional, Heidtmann, Bettina, additional, Toni, Sonia, additional, Rami-Merhar, Birgit, additional, Eeckhout, Bart, additional, Peene, Bernard, additional, Vantongerloo, N., additional, Maes, Toon, additional, and Gommers, Leen, additional

Published
2023
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26. Data from Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer

Author

McKenzie, Duncan R., primary, Graham, Rosalind, primary, Lechmere, Thomas, primary, Domingo-Vila, Clara, primary, Alaguthurai, Thanussuyah, primary, Arman, Celeste, primary, Pollock, Emily, primary, Gousis, Charalampos, primary, Kakkassery, Helen, primary, Carpenter, Esme, primary, Kurshan, Ashwini, primary, Vidler, Jennifer, primary, Kulasekararaj, Austin, primary, Patten, Piers, primary, North, Bernard V., primary, Tree, Timothy, primary, Doores, Katie J., primary, Hayday, Adrian C., primary, and Irshad, Sheeba, primary

Published
2023
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27. Supplementary Data SD1 from Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer

Author

McKenzie, Duncan R., primary, Graham, Rosalind, primary, Lechmere, Thomas, primary, Domingo-Vila, Clara, primary, Alaguthurai, Thanussuyah, primary, Arman, Celeste, primary, Pollock, Emily, primary, Gousis, Charalampos, primary, Kakkassery, Helen, primary, Carpenter, Esme, primary, Kurshan, Ashwini, primary, Vidler, Jennifer, primary, Kulasekararaj, Austin, primary, Patten, Piers, primary, North, Bernard V., primary, Tree, Timothy, primary, Doores, Katie J., primary, Hayday, Adrian C., primary, and Irshad, Sheeba, primary

Published
2023
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28. Figure S1 from Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer

Author

McKenzie, Duncan R., primary, Graham, Rosalind, primary, Lechmere, Thomas, primary, Domingo-Vila, Clara, primary, Alaguthurai, Thanussuyah, primary, Arman, Celeste, primary, Pollock, Emily, primary, Gousis, Charalampos, primary, Kakkassery, Helen, primary, Carpenter, Esme, primary, Kurshan, Ashwini, primary, Vidler, Jennifer, primary, Kulasekararaj, Austin, primary, Patten, Piers, primary, North, Bernard V., primary, Tree, Timothy, primary, Doores, Katie J., primary, Hayday, Adrian C., primary, and Irshad, Sheeba, primary

Published
2023
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29. Single-cell RNAseq identifies clonally expanded antigen-specific T-cells following intradermal injection of gold nanoparticles loaded with diabetes autoantigen in humans

Author

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]

Published
2023
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33. Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer

Author

McKenzie, Duncan R., primary, Graham, Rosalind, additional, Lechmere, Thomas, additional, Domingo-Vila, Clara, additional, Alaguthurai, Thanussuyah, additional, Arman, Celeste, additional, Pollock, Emily, additional, Gousis, Charalampos, additional, Kakkassery, Helen, additional, Carpenter, Esme, additional, Kurshan, Ashwini, additional, Vidler, Jennifer, additional, Kulasekararaj, Austin, additional, Patten, Piers, additional, North, Bernard V., additional, Tree, Timothy, additional, Doores, Katie J., additional, Hayday, Adrian C., additional, and Irshad, Sheeba, additional

Published
2022
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35. Concordance of B‐ and T‐cell responses to SARS‐CoV‐2 infection, irrespective of symptoms suggestive of COVID‐19

Author

Österdahl, Marc F., primary, Christakou, Eleni, additional, Hart, Deborah, additional, Harris, Ffion, additional, Shahrabi, Yasaman, additional, Pollock, Emily, additional, Wadud, Muntaha, additional, Spector, Tim D., additional, Brown, Matthew A., additional, Seow, Jeffrey, additional, Malim, Michael H., additional, Steves, Claire J., additional, Doores, Katie J., additional, Duncan, Emma L., additional, and Tree, Timothy, additional

Published
2022
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36. Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote transplantation tolerance in humans

Author

Lim, Tiong Yeng, primary, Perpinan, Elena, additional, Londoño, Maria Carlota, additional, Miquel, Rosa, additional, Ruiz, Paula, additional, Kurt, Ada, additional, Codela, Elisavet, additional, Cross, Amy, additional, Berlin, Claudia, additional, Hester, Joanna, additional, Issa, Fadi, additional, Douiri, Abdel, additional, Volmer, Felix, additional, Taubert, Richard, additional, Williams, Evangelia, additional, Demetris, Jake, additional, Lesniak, Andrew, additional, Bensimon, Gilbert, additional, Lozano, Juanjo, additional, Martinez-Llordella, Marc, additional, Tree, Timothy, additional, and Sanchez-Fueyo, Alberto, additional

Published
2022
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37. INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Author

Dunger, David, Bruggraber, Sylvaine FA, Mander, Adrian P, Marcovecchio, Loredana, Tree, Timothy, Chmura, Piotr Jaroslaw, Knip, Mikael, Schulte, Anke M, Mathieu, Chantal, INNODIA Consortium, Marcovecchio, M Loredana [0000-0002-4415-316X], Apollo - University of Cambridge Repository, Dunger, David [0000-0002-2566-9304], and Marcovecchio, Loredana [0000-0002-4415-316X]

Subjects
Trials, Adult, Adolescent, SARS-CoV-2, Prevention, Beta-cell function, COVID-19, Phase 2, Study Protocol, Type 1 diabetes, Diabetes Mellitus, Type 1, Treatment Outcome, Master protocol, Humans, C-peptide, Child, Biomarkers
Abstract

BACKGROUND: The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. METHODS: In this context, we have developed a Master Protocol, based on the "backbone" of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. DISCUSSION: The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

Published
2022
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38. INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Author

Marcovecchio, M Loredana, Dunger, David, Bruggraber, Sylvaine, Mander, Adrian, Tree, Timothy, Schulte, Anke, Mathieu, Chantal, Kinp, Mikael, Chmura, Piotr, Marcovecchio, Loredana [0000-0002-4415-316X], and Apollo - University of Cambridge Repository

Abstract

Background: The INNODIA consortium has established a pan-European infrastructure using validated centres to evaluate prospectively clinical data from individuals with newly diagnosed Type 1 diabetes combined with centralized collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of Phase 2 clinical trials. Methods: In this context we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of Phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed Type 1 diabetes. Although many IMPs have demonstrated potential efficacy in Phase 2 studies, few subsequent Phase 3 studies have confirmed these benefits. Currently Phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion: The Master Protocol provides: 1) standardized assessment of efficacy and safety; 2) comparable collection of mechanistic data; 3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies; 4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

Published
2022

39. INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Author

Dunger, David B, Bruggraber, Sylvaine F A, Mander, Adrian P, Marcovecchio, M Loredana, Tree, Timothy, Chmura, Piotr Jaroslaw, Knip, Mikael, Schulte, Anke M, Mathieu, Chantal, Dunger, David B, Bruggraber, Sylvaine F A, Mander, Adrian P, Marcovecchio, M Loredana, Tree, Timothy, Chmura, Piotr Jaroslaw, Knip, Mikael, Schulte, Anke M, and Mathieu, Chantal

Abstract

BACKGROUND: The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials.METHODS: In this context, we have developed a Master Protocol, based on the "backbone" of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow.DISCUSSION: The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

Published
2022

40. Low-dose IL-2 reduces IL-21+T cells and induces a long-lived anti-inflammatory gene expression signature inversely modulated in COVID-19 patients

Author

Zhang, Jia-Yuan, primary, Hamey, Fiona, additional, Trzupek, Dominik, additional, Mickunas, Marius, additional, Lee, Mercede, additional, Godfrey, Leila, additional, Yang, Jennie H.M., additional, Pekalski, Marcin L, additional, Kennet, Jane, additional, Waldron-Lynch, Frank, additional, Evans, Mark L., additional, Tree, Timothy I. M., additional, Wicker, Linda S., additional, Todd, John A., additional, and Ferreira, Ricardo C., additional

Published
2022
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42. Immune and Metabolic Effects of Antigen-Specific Immunotherapy Using Multiple β-Cell Peptides in Type 1 Diabetes

Author

Liu, Yuk-Fun, primary, Powrie, Jake, primary, Arif, Sefina, primary, Yang, Jennie H.M., primary, Williams, Evangelia, primary, Khatri, Leena, primary, Joshi, Mamta, primary, Lhuillier, Loic, primary, Fountoulakis, Nikolaos, primary, Smith, Emma, primary, Beam, Craig, primary, Lorenc, Anna, primary, Peakman, Mark, primary, and Tree, Timothy, primary

Published
2022
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43. Guidelines for standardizing T-cell cytometry assays to link biomarkers, mechanisms, and disease outcomes in type 1 diabetes

Author

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

44. IL-2-based approaches to Treg enhancement.

Author

Harris, Ffion, Berdugo, Yoana Arroyo, and Tree, Timothy

Subjects
REGULATORY T cells, AUTOIMMUNE diseases, T cells, DISEASE susceptibility, GENETIC polymorphisms
Abstract

Summary: Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients. [ABSTRACT FROM AUTHOR]

Published
2023
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45. Humoral and cellular immunity to delayed second dose of SARS-CoV-2 BNT162b2 mRNA vaccination in patients with cancer

Author

McKenzie, Duncan R., Muñoz-Ruiz, Miguel, Monin, Leticia, Alaguthurai, Thanussuyah, Lechmere, Thomas, Abdul-Jawad, Sultan, Graham, Carl, Pollock, Emily, Graham, Rosalind, Sychowska, Kamila, Seow, Jeffrey, Tremain, Catherine, Gousis, Charalampos, Domingo-Vila, Clara, Cooper, Jack, Vidler, Jennifer, Owczarczyk, Kasia, Swampillai, Angela, Kristeleit, Hartmut, Malim, Michael H., Fields, Paul, Patten, Piers E.M., Papa, Sophie, North, Bernard V., Tree, Timothy, Doores, Katie J., Hayday, Adrian C., and Irshad, Sheeba

Published
2021
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46. Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes

Author

Wilhelm-Benartzi, Charlotte S, primary, Miller, Sarah E, additional, Bruggraber, Sylvaine, additional, Picton, Diane, additional, Wilson, Mark, additional, Gatley, Katrina, additional, Chhabra, Anita, additional, Marcovecchio, M Loredana, additional, Hendriks, A Emile J, additional, Morobé, Hilde, additional, Chmura, Piotr Jaroslaw, additional, Bond, Simon, additional, Aschemeier-Fuchs, Bärbel, additional, Knip, Mikael, additional, Tree, Timothy, additional, Overbergh, Lut, additional, Pall, Jaivier, additional, Arnaud, Olivier, additional, Haller, Michael J, additional, Nitsche, Almut, additional, Schulte, Anke M, additional, Mathieu, Chantal, additional, Mander, Adrian, additional, and Dunger, David, additional

Published
2021
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47. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Author

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
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48. A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes

Author

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
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49. Phase II multicentre, double-blind, randomised trial of ustekinumab in adolescents with new-onset type 1 diabetes (USTEK1D): trial protocol

Author

Gregory, John W, primary, Carter, Kymberley, additional, Cheung, Wai Yee, additional, Holland, Gail, additional, Bowen-Morris, Jane, additional, Luzio, Stephen, additional, Dunseath, Gareth, additional, Tree, Timothy, additional, Yang, Jennie Hsiu Mien, additional, Marwaha, Ashish, additional, Ali, Mohammad Alhadj, additional, Bashir, Nadim, additional, Hutchings, Hayley Anne, additional, Fegan, Greg W, additional, Stenson, Rachel, additional, Hiles, Stephen, additional, Marques-Jones, Susie, additional, Brown, Amy, additional, Tatovic, Danijela, additional, and Dayan, Colin, additional

Published
2021
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