Hypothetical schema of immune response to RBC antigens in alloimmunized versus nonalloimmunized patients. Multiple participants in alloimmunization versus no alloimmunization states are outlined. Preventive interventions and the specific steps in prevention of alloimmunization are shown in yellow. In addition, the possible modes of action of steroids and IVIg for treatment of DHTR are also shown in yellow. The hypothetical model predicts that the chronic inflammatory state in SCD creates a microenvironment with increased inflammatory cytokines, which favors antigen-presenting cells (APCs), such as macrophages and dendritic cells to increase consumption of the transfused allogenic RBCs, and also favor generation of immunogenic peptides in APCs. The person's HLA repertoire will then dictate whether these peptides are presented to the naive CD4⁺ T helper (Th) cells or not. Alloimmunized sickle patients have increased Th2 frequency, normally associated with humoral immune response, or decreased Treg activity associated with alloimmunization. The skewing toward Th2 or decreased Treg is proposed to be associated with B-cell activation and antibody production. In SCD patients who may have a genetic predisposition to be nonresponders, or patients who do not produce antibodies after allogeneic transfusions, the APCs may be less immunostimulatory such that the peptides presented to the naive CD4 cells are tolerizing and result in the induction of Tregs that can reduce Th2 and/or B cell and APC activation (“?”).