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  1. Article ; Online: Predicting clinical response to costimulation blockade in autoimmunity.

    Edner, Natalie M / Wang, Chun Jing / Petersone, Lina / Walker, Lucy S K

    Immunotherapy advances

    2020  Volume 1, Issue 1, Page(s) ltaa003

    Abstract: Curbing unwanted T cell responses by costimulation blockade has been a recognised immunosuppressive strategy for the last 15 years. However, our understanding of how best to deploy this intervention is still evolving. A key challenge has been the ... ...

    Abstract Curbing unwanted T cell responses by costimulation blockade has been a recognised immunosuppressive strategy for the last 15 years. However, our understanding of how best to deploy this intervention is still evolving. A key challenge has been the heterogeneity in the clinical response to costimulation blockade, and an inability to predict which individuals are likely to benefit most. Here, we discuss our recent findings based on the use of costimulation blockade in people with type 1 diabetes (T1D) and place them in the context of the current literature. We discuss how profiling follicular helper T cells (Tfh) in pre-treatment blood samples may have value in predicting which individuals are likely to benefit from costimulation blockade drugs such as abatacept.
    Language English
    Publishing date 2020-11-25
    Publishing country England
    Document type Journal Article
    ISSN 2732-4303
    ISSN (online) 2732-4303
    DOI 10.1093/immadv/ltaa003
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  2. Article ; Online: Targeting co-stimulatory molecules in autoimmune disease.

    Edner, Natalie M / Carlesso, Gianluca / Rush, James S / Walker, Lucy S K

    Nature reviews. Drug discovery

    2020  Volume 19, Issue 12, Page(s) 860–883

    Abstract: Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 ... ...

    Abstract Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.
    MeSH term(s) Autoimmune Diseases/immunology ; Autoimmune Diseases/therapy ; CD28 Antigens/antagonists & inhibitors ; CTLA-4 Antigen/antagonists & inhibitors ; Humans ; Immunotherapy/methods ; Inducible T-Cell Co-Stimulator Protein/antagonists & inhibitors ; Receptors, OX40/antagonists & inhibitors ; Signal Transduction
    Chemical Substances CD28 Antigens ; CTLA-4 Antigen ; CTLA4 protein, human ; ICOS protein, human ; Inducible T-Cell Co-Stimulator Protein ; Receptors, OX40 ; TNFRSF4 protein, human
    Language English
    Publishing date 2020-09-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2062954-0
    ISSN 1474-1784 ; 1474-1776
    ISSN (online) 1474-1784
    ISSN 1474-1776
    DOI 10.1038/s41573-020-0081-9
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    Zs.A 5564: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  3. Article ; Online: Publisher Correction: Targeting co-stimulatory molecules in autoimmune disease.

    Edner, Natalie M / Carlesso, Gianluca / Rush, James S / Walker, Lucy S K

    Nature reviews. Drug discovery

    2020  Volume 20, Issue 1, Page(s) 82

    Language English
    Publishing date 2020-11-18
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2062954-0
    ISSN 1474-1784 ; 1474-1776
    ISSN (online) 1474-1784
    ISSN 1474-1776
    DOI 10.1038/s41573-020-00116-x
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5564: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 334: Show issues
    Zs.MG 63: Show issues

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  4. Article ; Online: Follicular T Helper Cells: A New Marker of Type 1 Diabetes Risk?

    Heuts, Frank / Edner, Natalie M / Walker, Lucy S K

    Diabetes

    2017  Volume 66, Issue 2, Page(s) 258–260

    MeSH term(s) B-Lymphocytes ; Biomarkers ; Diabetes Mellitus, Type 1 ; Humans ; T-Lymphocytes, Helper-Inducer
    Chemical Substances Biomarkers
    Language English
    Publishing date 2017-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/dbi16-0062
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    Uh III Zs.175: Show issues Location:
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  5. Article ; Online: Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood.

    Edner, Natalie M / Ntavli, Elisavet / Petersone, Lina / Wang, Chun Jing / Fabri, Astrid / Kogimtzis, Alexandros / Ovcinnikovs, Vitalijs / Ross, Ellen M / Heuts, Frank / Elfaki, Yassin / Houghton, Luke P / Talbot, Toby / Sheri, Amna / Pender, Alexandra / Chao, David / Walker, Lucy S K

    Immunotherapy advances

    2023  Volume 3, Issue 1, Page(s) ltad001

    Abstract: Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1- ... ...

    Abstract Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.
    Language English
    Publishing date 2023-01-06
    Publishing country England
    Document type Journal Article
    ISSN 2732-4303
    ISSN (online) 2732-4303
    DOI 10.1093/immadv/ltad001
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  6. Article ; Online: Author Correction: Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity.

    Wang, Chun Jing / Petersone, Lina / Edner, Natalie M / Heuts, Frank / Ovcinnikovs, Vitalijs / Ntavli, Elisavet / Kogimtzis, Alexandros / Fabri, Astrid / Elfaki, Yassin / Houghton, Luke P / Hosse, Ralf J / Schubert, David A / Frei, Andreas P / Ross, Ellen M / Walker, Lucy S K

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 5724

    Language English
    Publishing date 2023-09-15
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41483-4
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  7. Article ; Online: IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation.

    Petersone, Lina / Wang, Chun Jing / Edner, Natalie M / Fabri, Astrid / Nikou, Spyridoula-Angeliki / Hinze, Claudia / Ross, Ellen M / Ntavli, Elisavet / Elfaki, Yassin / Heuts, Frank / Ovcinnikovs, Vitalijs / Rueda Gonzalez, Andrea / Houghton, Luke P / Li, Hannah M / Zhang, Yang / Toellner, Kai-Michael / Walker, Lucy S K

    The Journal of experimental medicine

    2023  Volume 220, Issue 10

    Abstract: Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic ... ...

    Abstract Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.
    MeSH term(s) Animals ; Mice ; Cyclin D3 ; Germinal Center ; T-Lymphocytes, Helper-Inducer ; Up-Regulation
    Chemical Substances Cyclin D3 ; interleukin-21 (MKM3CA6LT1) ; Ccnd3 protein, mouse
    Language English
    Publishing date 2023-07-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20221653
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    Ua VI Zs.107: Show issues Location:
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  8. Article ; Online: Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity.

    Wang, Chun Jing / Petersone, Lina / Edner, Natalie M / Heuts, Frank / Ovcinnikovs, Vitalijs / Ntavli, Elisavet / Kogimtzis, Alexandros / Fabri, Astrid / Elfaki, Yassin / Houghton, Luke P / Hosse, Ralf J / Schubert, David A / Frei, Andreas P / Ross, Ellen M / Walker, Lucy S K

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 6757

    Abstract: Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 ... ...

    Abstract Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous. Here we probe the relative roles of CD28 and IL-2 in maintaining Treg. We find provision of IL-2 counteracts the regulatory T cell loss induced by costimulation blockade while minimally affecting the conventional T cell compartment. These data suggest that combining costimulation blockade with IL-2 treatment may selectively impair effector T cell responses while maintaining regulatory T cells. Using a mouse model of autoimmune diabetes, we show combined therapy supports regulatory T cell homeostasis and protects from disease. These findings are recapitulated in humanised mice using clinically relevant reagents and provide an exemplar for rational use of a second immunotherapy to offset known limitations of the first.
    MeSH term(s) T-Lymphocytes, Regulatory ; CD28 Antigens ; Autoimmunity ; Interleukin-2/pharmacology ; CTLA-4 Antigen ; Lymphocyte Activation ; Abatacept/pharmacology ; Immunomodulation
    Chemical Substances CD28 Antigens ; Interleukin-2 ; CTLA-4 Antigen ; Abatacept (7D0YB67S97)
    Language English
    Publishing date 2022-11-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-34477-1
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  9. Article ; Online: T Cell/B Cell Collaboration and Autoimmunity: An Intimate Relationship.

    Petersone, Lina / Edner, Natalie M / Ovcinnikovs, Vitalijs / Heuts, Frank / Ross, Ellen M / Ntavli, Elisavet / Wang, Chun J / Walker, Lucy S K

    Frontiers in immunology

    2018  Volume 9, Page(s) 1941

    Abstract: Co-ordinated interaction between distinct cell types is a hallmark of successful immune function. A striking example of this is the carefully orchestrated cooperation between helper T cells and B cells that occurs during the initiation and fine-tuning of ...

    Abstract Co-ordinated interaction between distinct cell types is a hallmark of successful immune function. A striking example of this is the carefully orchestrated cooperation between helper T cells and B cells that occurs during the initiation and fine-tuning of T-cell dependent antibody responses. While these processes have evolved to permit rapid immune defense against infection, it is becoming increasingly clear that such interactions can also underpin the development of autoimmunity. Here we discuss a selection of cellular and molecular pathways that mediate T cell/B cell collaboration and highlight how
    MeSH term(s) Animals ; Autoimmunity ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; CD28 Antigens/immunology ; CTLA-4 Antigen/immunology ; Genome-Wide Association Study ; Germinal Center/immunology ; Germinal Center/pathology ; Humans ; Inflammation/immunology ; Inflammation/pathology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/pathology
    Chemical Substances CD28 Antigens ; CTLA-4 Antigen ; CTLA4 protein, human
    Language English
    Publishing date 2018-08-27
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.01941
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  10. Article ; Online: CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells.

    Ovcinnikovs, Vitalijs / Ross, Ellen M / Petersone, Lina / Edner, Natalie M / Heuts, Frank / Ntavli, Elisavet / Kogimtzis, Alexandros / Kennedy, Alan / Wang, Chun Jing / Bennett, Clare L / Sansom, David M / Walker, Lucy S K

    Science immunology

    2019  Volume 4, Issue 35

    Abstract: CTLA-4 is a critical negative regulator of the immune system and a major target for immunotherapy. However, precisely how it functions in vivo to maintain immune homeostasis is not clear. As a highly endocytic molecule, CTLA-4 can capture costimulatory ... ...

    Abstract CTLA-4 is a critical negative regulator of the immune system and a major target for immunotherapy. However, precisely how it functions in vivo to maintain immune homeostasis is not clear. As a highly endocytic molecule, CTLA-4 can capture costimulatory ligands from opposing cells by a process of transendocytosis (TE). By restricting costimulatory ligand expression in this manner, CTLA-4 controls the CD28-dependent activation of T cells. Regulatory T cells (T
    MeSH term(s) Animals ; Antigen Presentation/immunology ; Autoantigens/immunology ; B7-1 Antigen/metabolism ; B7-2 Antigen/metabolism ; CTLA-4 Antigen/genetics ; CTLA-4 Antigen/metabolism ; Cell Movement/immunology ; Dendritic Cells/immunology ; Female ; Lymphocyte Activation/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Phenotype ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes, Regulatory/immunology ; Transcytosis/immunology
    Chemical Substances Autoantigens ; B7-1 Antigen ; B7-2 Antigen ; CTLA-4 Antigen ; Cd86 protein, mouse ; Ctla4 protein, mouse ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2019-06-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.aaw0902
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