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

Moritz Muckenhuber, Konstantinos Mengrelis, Anna Marianne Weijler, Romy Steiner, Verena Kainz, Marlena Buresch, Heinz Regele, Sophia Derdak, Anna Kubetz and Thomas Wekerle ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48574-w

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