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Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals. As the affected cells primarily die by apoptosis, we tested several anti-apoptotic small molecules to protect these cells from drug-induced toxicity. We found that the general caspase inhibitor Emricasan could significantly counteract the toxic effects of cisplatin in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, phoenix auditory cells, and primary SGNs. Importantly, the anti-cytotoxic effect in neuronal cells was even more pronounced than the effect of sodium thiosulfate (STS), which is currently the only approved prevention option for cisplatin-induced ototoxicity. Finally, we tested the protective effect of Emricasan treatment in the context of another ototoxic drug, i.e., the aminoglycoside antibiotic neomycin, and again found a significant increase in cell viability when the cultures were co-treated with Emricasan. These results suggest a promising strategy to prevent ototoxicity in patients by temporarily blocking the apoptotic pathway when applying cisplatin or aminoglycoside antibiotics. KEY MESSAGES: Anti-apoptotic small molecules can reduce cisplatin-induced toxicity. Emricasan can effectively exert its anti-apoptotic effect on cochlear cells. Strong protection from cisplatin- and neomycin-induced cytotoxicity with Emricasan. Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity., (© 2024. The Author(s).)

Background: Solid organ transplantation is hindered by immune-mediated chronic graft dysfunction and the side effects of immunosuppressive therapy. Regulatory T cells (Tregs) are crucial for modulating immune responses post-transplantation; however, the transfer of polyspecific Tregs alone is insufficient to induce allotolerance in rodent models., Methods: To enhance the efficacy of adoptive Treg therapy, we investigated different immune interventions in the recipients. By utilizing an immunogenic skin transplant model and existing transplantation medicine reagents, we facilitated the clinical translation of our findings. Specifically, antigen-specific Tregs were used., Results: Our study demonstrated that combining the available induction therapies with drug-induced T-cell proliferation due to lymphopenia effectively increased the Treg/T effector ratios. This results in significant Treg accumulation within the graft, leading to long-term tolerance after the transfer of antigen-specific Tregs. Importantly, all the animals achieved operational tolerance, which boosted the presence of adoptively transferred Tregs within the graft., Conclusions: This protocol offers a means to establish tolerance by utilizing antigen-specific Tregs. These results have promising implications for future trials involving adoptive Treg therapy in organ transplantation.