Immunoregulation of RBC alloimmune responses mediated by Nrf2-activation 4655

Abstract Description During RBC transfusion, exposure to mismatched non-ABO antigens can trigger alloantibody production, leading to hemolytic complications. Currently, the only preventive measure is avoiding incompatible antigens. Inflammation significantly influences susceptibility to RBC alloimmunization. Nrf2, a transcription factor activated by oxidative stress, reduces inflammation and may regulate antibody responses. We hypothesized that Nrf2 activation regulates RBC alloimmunization, exploring its potential to reduce immune complications in transfusions. Co-culture of human macrophages with CFSE-labeled RBCs opsonized by anti-RBC antibodies led to enhanced erythrophagocytosis. RNA sequencing revealed increased expression of Nrf2-regulated genes (HMOX1, NQO1, AKR1C1) and upregulation of Nrf2 antioxidant pathways. To determine the role of Nrf2 activation in anti-RBC alloantibody responses, wild-type (WT) and Nrf2-deficient (Nrf2-/-) mice were pre-treated with the Nrf2 activator CDDO-Im and interferon-inducing agent poly(I:C) prior to transfusion of allogeneic RBCs expressing KEL antigen. CDDO-Im enhanced Nrf2-induced gene expression and reduced IFNα/β and NF?B-mediated cytokine production in WT but not Nrf2-/- mice. CDDO-Im significantly reduced anti-KEL IgG production in WT mice and improved RBC recovery, effects not observed in Nrf2-/- mice. These findings highlight Nrf2 activators could as a promising prophylactic approach to prevent alloimmune complications in transfusion settings. Funding Sources Supported by: NIH (R01HL165169-03) Topic Categories Therapeutic Approaches to Autoimmunity (THER)