Harnessing the potential of red blood cells in immunotherapy.

Red blood cell (RBC) transfusion represents one of the earliest and most widespread forms of cellular therapy. While the primary purpose of RBC transfusions is to enhance the oxygen-carrying capacity of the recipient, RBCs also possess unique properties that make them attractive vehicles for inducing antigen-specific immune tolerance. Preclinical studies have demonstrated that RBC transfusion alone, in the absence of inflammatory stimuli, often fails to elicit detectable alloantibody formation against model RBC antigens. Several studies also suggest that RBC transfusion without inflammation may not only fail to generate a detectable alloantibody response but can also induce a state of antigen-specific non-responsiveness, a phenomenon potentially influenced by the density of the corresponding RBC alloantigen. The unique properties of RBCs, including their inability to divide and their stable surface antigen expression, make them attractive platforms for displaying exogenous antigens with the goal of leveraging their ability to induce antigen-specific non-responsiveness. This could facilitate antigen presentation to the host's immune system without triggering innate immune activation, potentially enabling the induction of antigen-specific tolerance for therapeutic applications in autoimmune disorders, preventing immune responses against protein therapeutics, or reducing alloreactivity in the setting of transfusion and transplantation.