Although murine models are not perfect surrogates for human biology, these models generate phenomenological and mechanistic hypotheses of RBC alloimmunization and lay the groundwork for follow-up human studies

Although murine models are not perfect surrogates for human biology, these models generate phenomenological and mechanistic hypotheses of RBC alloimmunization and lay the groundwork for follow-up human studies. and share a degree of orthology GNF-7 with the Kell, Duffy, and Kidd RBC antigens [60]. GNF-7 Thus, exposure to these pathogens may primary an individual (presumably at the T-cell level) to respond more vigorously upon subsequent exposure to RBC antigens with overlapping peptide sequences. Because the pathogens have orthology only at the level of linear peptides, and not three-dimensional proteins, exposure will not induce alloantibodies detected by immunohematology, but will rather primary a recipient such that subsequent transfusion will result in a strong and quick humoral response to a given RBC alloantigen. Evidence for past non-RBC exposure priming for subsequent responses to RBC antigens exists in humans [73] and in animals [60]. Peripheral blood mononuclear cells from humans with no detectable anti-KEL alloantibodies were stimulated with overlapping KEL peptides, with evidence of T-cell reactivity present in subjects with no prior RBC exposure [73]. This reactivity appeared to be a memory response, given the thymidine incorporation observed in CD45 RO-positive T cells after peptide activation. Animal studies using a model RBC antigen have also demonstrated this concept: sequences contained within non-RBC antigens (in this case an ovalbumin sequence contained within a polyoma computer virus) have been shown to primary a recipient to generate a strong response upon subsequent exposure to a shared epitope within a RBC antigen [60]. Of interest (as above) is the fact that traditional antibody-focused blood bank screens would not detect this prior priming phenomenon. In theory, priming may lead to quick and strong alloantibody responses following main RBC exposure, which may result in early delayed hemolytic transfusion reactions. Tolerance to RBC Antigens It is possible that non-responders to RBC antigens are actually tolerized (through mechanisms not yet defined), though this hypothesis is usually difficult to test in humans given relatively low baseline rates of alloimmunization with each transfusion event. Small recipient age at the time of initial RBC exposure has been shown to influence rates of RBC alloimmunization in patients with sickle cell disease [14, 79] and thalassemia major [115], leading to a hypothesis that relative tolerance to RBC antigens may be possible in young transfusion recipients. To GNF-7 date, only one animal study has been published investigating the relationship between recipient age at initial RBC exposure and RBC alloimmunization, with no or very low levels of anti-HOD alloantibodies observed in juvenile animals (3 weeks of age) compared to adult animals [80]. However, these studies did not evaluate repeat antigen exposure, as it has been shown that subsequent HEL antigen exposures do not result in immunologic improving [96] for reasons that remain under investigation. Ongoing experiments using KEL transgenic RBCs, which are capable of generating memory and boostable responses in C57BL/6 animals [97], are investigating the impact of RBC exposure as neonates and subsequent responses when these same animals are re-transfused as adults. Characteristics of the transfused RBC antigens themselves also play important functions in determining recipient responsiveness versus non-responsiveness. For example, non-responsiveness/tolerance to the hGPA antigen occurs when the initial antigen exposure takes place in the absence of an adjuvant [96]. This non-responsiveness LAMB2 antibody is usually antigen-specific, with non-responders to the hGPA antigen being fully capable of responding to other unique RBC antigens. RBC antigen copy number may contribute to whether a particular antigen is usually capable of inducing an immune response following transfusion, as suggested by studies that have shown antigen density to be a important determinant of immunologic responsiveness to non-RBC antigens [119, 120, 121]. Although hGPA copy number has not been formally evaluated, flow-cytometric cross-matching of these RBCs with.