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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
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    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.
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