Simple SummaryGraft-versus-host disease is a potentially life-threatening complication after bone marrow transplantation from an unrelated donor. The multi-organ damage is triggered by the donor cells that attack the host tissue. Patients manifest signs and symptoms in the skin, liver, lungs and other body organs. Treatment is usually by suppressing the immune system to limit foreign immune cells attacking the host tissues/organs. In this pilot study, we hypothesized that populations of cells termed senescent cells that produce inflammatory proteins might contribute to the disease pathology. Therefore, using a mouse model of chronic graft-versus-host disease, we tested a drug combination that has been shown to target and kill such populations. These types of agents are referred to as senolytics. We show promising therapeutic efficacy of this combination approach in the mouse model of disease, which could have implications for human disease.AbstractGraft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days. Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6 and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy.