Combining pro-resolving therapy with cyclosporine A restores immune homeostasis and reduces toxicity in autoimmune bone marrow failure.

Immunosuppressive therapies (ISTs), including calcineurin inhibitors like cyclosporine A (CsA), are essential therapeutics for autoimmunity; however, they often fail and cause dose-limiting toxicity. Severe aplastic anemia (SAA) is a fatal autoimmune bone marrow (BM) failure disorder that is treated with ISTs. BM single-cell RNA sequencing (scRNA-seq) from SAA patients reveals enhanced T cell effector programs, maladaptive myelopoiesis, and impaired inflammation resolution despite standard-of-care therapy, suggesting incomplete restoration of immune homeostasis with ISTs. In murine SAA, CsA improves survival but induces persistent inflammatory T cells, emergency myelopoiesis, and nephrotoxicity following withdrawal. The pro-resolving lipid mediator resolvin E1 (RvE1) similarly prevents SAA-induced mortality but without toxicity or persistent inflammation. Co-treatment with RvE1, concurrently or after CsA, achieves complete survival, restores immune and hematopoietic homeostasis, and reduces toxicity in a ChemR23-dependent manner. These findings support a paradigm shift toward curative therapies that simultaneously engage endogenous repair programs and suppress pathogenic responses to enhance treatment safety and durability.