Resolvin E1 enhances cyclosporine A efficacy and mitigates toxicity in bone marrow failure 4203

Abstract Description Cyclosporine A (CsA) is the common immunosuppressant therapy used for organ transplantation and autoimmune diseases, such as severe aplastic anemia (SAA). SAA patients must receive a high dose of CsA (10mg/kg) to achieve therapeutic effects, but clinical outcomes remain suboptimal and significant toxicity is noted. Here we show that high-dose CsA therapy induces an influx of inflammatory immune cells and increased cell death in the kidney and liver, which is sustained 30 days post-treatment. CsA also caused prolonged reductions in red blood cells (RBCs) and platelets, alongside abnormal hematopoietic stem and progenitor cell (HSPC) counts. Previously we have shown that the specialized pro-resolving mediator, Resolvin E1 (RvE1), enhances survival and the resolution of inflammation in SAA. Here we show that RvE1 mitigates chronic inflammation and toxicity associated with high-dose CsA, and ultimately restores tissue homeostasis. RvE1 normalizes the CsA-mediated influx of immune cells, increases RBCs and platelets, and restores HSPC balance. Remarkably, RvE1 also increased the therapeutic efficacy of low-dose (3 mg/kg) CsA, improving survival rates from 25% to 75%, while simultaneously reducing toxicity. Mechanistically, RvE1 directly acts on T cells through its receptor ChemR23 and antagonizes leukotriene B4-BLT1 signaling. These findings highlight the limitations of current immunosuppressants in restoring tissue homeostasis and suggest RvE1 as a promising adjunct therapy. Funding Sources This work was supported by CDMRP Bone Marrow Failure Research Program-IDA (BM190079 and BM220031) and NHLBI R01HL159411. Topic Categories Translational and Interventional Immunology (TI)