(Vienna, 03 June 2024) Immunosuppressive drugs protect transplanted organs from harmful immune reactions. Nevertheless, rejection reactions can still occur. A MedUni Vienna research team led by Thomas Wekerle has deciphered mechanisms that lead to rejection despite the use of the latest immunosuppressive drugs. These findings point to new therapeutic options for preventing such rejection reactions in the future. The results were recently published in the journal "Nature Communications".
Costimulation blockers are a new class of immunosuppressive drugs used in kidney transplantation. Despite several benefits, they are rarely used clinically as they are associated with an increased rate of rejection. Why rejection reactions are more frequent with costimulation blockers, even when combined with T-cell depleting induction therapy (ATG), was previously unclear.
The research team led by Thomas Wekerle from the Division of Transplantation (Department of General Surgery), together with Heinz Regele (Department of Pathology) and Sophia Derdak (Core Facilities of MedUni Vienna), has investigated the mechanisms responsible for this phenomenon. They analyzed the balance between the effector T cells (Teff), which cause rejection, and the regulatory T cells (Treg), which prevent rejection, in animal models. They found that ATG therapy in addition to costimulation blockade positively influences the balance between Teff and Treg only in the periphery (e.g. in the spleen), but not in the transplanted organ, the crucial site. The pro-inflammatory cytokine interleukin-6 plays an important role here. The research team was able to show that the additional blockade of interleukin-6 positively influences the balance of Teff to Treg in the transplanted organ, thereby preventing rejection of the transplant. Since drugs for interleukin-6 blockade are already clinically approved for the treatment of other diseases, the results have a high potential for clinical implementation.
"Our results provide an important insight into the complex mechanisms of transplant rejection and show new ways in which transplants could be protected even better in the future," says Moritz Muckenhuber, the first author of the paper, summarizing the research results.
Publication: Nature Communications
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
Nature Communications DOI: 10.1038/s41467-024-48574-w
https://www.nature.com/articles/s41467-024-48574-w