CDDO-Imidazole regulates RBC alloimmunization to the KEL antigen by activating Nrf2.
Publication Year:
2025
PubMed ID:
40235992
Funding Grants:
Public Summary:
When people receive a blood transfusion, their immune system can sometimes see the donated red blood cells as “foreign” and make antibodies against them. This can lead to dangerous reactions where the transfused blood cells are destroyed. However, most people don’t develop these antibodies, and scientists want to understand why—so they can prevent these reactions.
In this study, researchers looked at a natural protective pathway in the body controlled by a protein called Nrf2, which helps reduce inflammation and protect cells from stress. They tested a drug (called CDDO-Im) that activates this pathway.
They found that activating Nrf2 reduced signals in the immune system that normally promote antibody production. In mice given a blood transfusion, treatment with this drug lowered the production of harmful antibodies and helped the transfused red blood cells survive longer. However, this effect didn’t happen in mice that lacked Nrf2, showing that the benefit depends on this pathway.
Overall, the results suggest that turning on the Nrf2 pathway may help prevent the immune system from attacking transfused blood. If confirmed in humans, this approach could lead to new ways to make blood transfusions safer.
Scientific Abstract:
During red blood cell (RBC) transfusion, production of alloantibodies can promote significant hemolytic events. However, most transfusion recipients do not form anti-RBC alloantibodies. Identifying mechanisms that inhibit alloimmunization may lead to prophylactic interventions. One potential regulatory mechanism is activation of the transcription factor, nuclear factor erythroid-derived 2-like 2 (Nrf2), a master regulatory of antioxidant pathways. Pharmacologic Nrf2 activators improve sequelae of sickle cell disease in pre-clinical models. The Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), suppresses production of inflammatory cytokines including type 1 interferons (IFNalpha/beta), which have been implicated in promoting RBC alloimmunization in transfusion models. Thus, we tested the hypothesis that the Nrf2 activator, CDDO-Im, regulates RBC alloimmunization. Here, we report that CDDO-Im induced Nrf2 activated gene expression and suppressed poly(I:C)-induced IFNalpha/beta-stimulated gene (ISG) expression in human macrophages and murine blood leukocytes. In addition, following transfusion of wildtype mice with RBCs expressing the KEL antigen, CDDO-Im treatment inhibited poly(I:C)-induced anti-KEL IgG production and promoted post-transfusion recovery of KEL+ RBCs, but failed to do so in Nrf2 (-/-) mice. Results indicate that activation of the Nrf2 antioxidant pathway regulates RBC alloimmunization to the KEL antigen in a pre-clinical model. If findings translate to other models and human studies, Nrf2 activators may represent a potential prophylactic intervention to inhibit alloimmunization.