The Role of N-acetylcysteine Amide in Acute Graft-versus-host Disease Mouse Model

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic hematopoietic cell transplantation (allo-HCT), resulting in reduced quality of life, morbidity, and mortality in transplanted patients. Clinical strategies to prevent GvHD are frequently associated with off-target effects and dose-related toxicity. Given that oxidative stress is elevated in allo-HCT recipients and contributes to the pathogenesis of GvHD, the current study aims to characterize the role of N-acetylcysteine amide (NACA), a novel antioxidant, as the prophylactic treatment for acute GvHD. Using a murine GvHD model, we found that oral administration of NACA significantly reduced GvHD severity, prolonged survival, and improved the clinical manifestations and integrity of target organs compared to saline or N-acetylcysteine (NAC) treatment. NACA modulated splenic T cells differentiation with an increase in the regulatory (Treg) subset and a decrease in the cytotoxic (CD8+) subset. Moreover, inflammatory mediators, such as ROS and pro-inflammatory cytokines were downregulated by NACA treatment. In addition, NACA hindered donor T-cell proliferation in the recipients, and restrained Th1 and Th17, but not Th2 polarization. Importantly, NACA did not influence full donor engraftment in bone marrow and spleen. Taken together, our findings provide a new candidate for GvHD prophylactic treatment by targeting oxidative stress that can be easily translated to clinical use. Key PointsO_LINACA provides superior prophylactic effect against aGvHD compared to NAC in an allogeneic transplantation mouse model. C_LIO_LINACA treatment neither showed systemic toxicity nor altered the engraftment of the donor cells. C_LI