IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48574-w.html
   My bibliography  Save this article

IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice

Author

Listed:
  • Moritz Muckenhuber

    (Medical University of Vienna)

  • Konstantinos Mengrelis

    (Medical University of Vienna)

  • Anna Marianne Weijler

    (Medical University of Vienna)

  • Romy Steiner

    (Medical University of Vienna)

  • Verena Kainz

    (Medical University of Vienna)

  • Marlena Buresch

    (Medical University of Vienna)

  • Heinz Regele

    (Medical University of Vienna)

  • Sophia Derdak

    (Medical University of Vienna)

  • Anna Kubetz

    (Medical University of Vienna)

  • Thomas Wekerle

    (Medical University of Vienna)

Abstract

The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.

Suggested Citation

  • Moritz Muckenhuber & Konstantinos Mengrelis & Anna Marianne Weijler & Romy Steiner & Verena Kainz & Marlena Buresch & Heinz Regele & Sophia Derdak & Anna Kubetz & Thomas Wekerle, 2024. "IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48574-w
    DOI: 10.1038/s41467-024-48574-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48574-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-48574-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Gabriele G. Schiattarella & Francisco Altamirano & Soo Young Kim & Dan Tong & Anwarul Ferdous & Hande Piristine & Subhajit Dasgupta & Xuliang Wang & Kristin M. French & Elisa Villalobos & Stephen B. S, 2021. "Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Chun Jing Wang & Lina Petersone & Natalie M. Edner & Frank Heuts & Vitalijs Ovcinnikovs & Elisavet Ntavli & Alexandros Kogimtzis & Astrid Fabri & Yassin Elfaki & Luke P. Houghton & Ralf J. Hosse & Dav, 2022. "Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Estelle Bettelli & Yijun Carrier & Wenda Gao & Thomas Korn & Terry B. Strom & Mohamed Oukka & Howard L. Weiner & Vijay K. Kuchroo, 2006. "Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells," Nature, Nature, vol. 441(7090), pages 235-238, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Agnieszka Strzelak & Aleksandra Ratajczak & Aleksander Adamiec & Wojciech Feleszko, 2018. "Tobacco Smoke Induces and Alters Immune Responses in the Lung Triggering Inflammation, Allergy, Asthma and Other Lung Diseases: A Mechanistic Review," IJERPH, MDPI, vol. 15(5), pages 1-35, May.
    2. Manuel A. Podestà & Cecilia B. Cavazzoni & Benjamin L. Hanson & Elsa D. Bechu & Garyfallia Ralli & Rachel L. Clement & Hengcheng Zhang & Pragya Chandrakar & Jeong-Mi Lee & Tamara Reyes-Robles & Reza A, 2023. "Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Tian Hong & Jianhua Xing & Liwu Li & John J Tyson, 2011. "A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells," PLOS Computational Biology, Public Library of Science, vol. 7(7), pages 1-13, July.
    4. Sina Riemschneider & Maximilian Hoffmann & Ulla Slanina & Klaus Weber & Sunna Hauschildt & Jörg Lehmann, 2021. "Indol-3-Carbinol and Quercetin Ameliorate Chronic DSS-Induced Colitis in C57BL/6 Mice by AhR-Mediated Anti-Inflammatory Mechanisms," IJERPH, MDPI, vol. 18(5), pages 1-17, February.
    5. Yang Cao & Laurent Vergnes & Yu-Chen Wang & Calvin Pan & Karthickeyan Chella Krishnan & Timothy M. Moore & Manuel Rosa-Garrido & Todd H. Kimball & Zhiqiang Zhou & Sarada Charugundla & Christoph D. Rau, 2022. "Sex differences in heart mitochondria regulate diastolic dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Benjamin P. Hurrell & Doumet Georges Helou & Emily Howard & Jacob D. Painter & Pedram Shafiei-Jahani & Arlene H. Sharpe & Omid Akbari, 2022. "PD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48574-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.