Antibody-mediated immunosuppression can result from RBC antigen loss independent of Fcγ receptors in mice

BACKGROUND: Anti-RhD administration can prevent de novo anti-RhD formation following RhD+ red blood cell (RBC) exposure, termed antibody-mediated immunosuppression (AMIS). Recent studies suggest that AMIS may occur through target antigen alterations, known as antigen modulation. However, studies suggest that AMIS may occur independent of antigen modulation. In particular, AMIS to RBCs that transgenically express the fusion hen egg lysozyme-ovalbumin-Duffy (HOD) antigen have been shown to occur independent of activating Fc gamma receptors (Fc gamma Rs) thought to be required for antigen modulation. Therefore, we sought to determine the mechanism behind AMIS following HOD RBC exposure. STUDY DESIGN AND METHODS: Following transfer of HOD RBCs into wild-type or Fc gamma R-chain knockout recipients in the presence or absence of monoclonal anti-hen egg lysozyme (HEL) antibody, individually or in combination, HOD antigen levels and anti-HOD antibody formation were examined. RESULTS: Our results demonstrate that anti-HEL antibodies individually or in combination suppressed antiHOD IgM, which correlated with the rate of detectable decrease in HEL on HOD RBCs. Furthermore, exposure to anti-HEL antibodies alone or in combination equally suppressed anti-HOD IgG formation. Unexpectedly, combination or individual anti-HEL antibodies induced AMIS and antigen modulation in an Fc gamma R-independent manner. Pre-exposure of HOD RBCs to anti-HEL antibodies reduced antigen levels and suppressed antiHOD antibody formation following HOD RBC exposure. CONCLUSION: These results suggest that antibodymediated antigen modulation may reflect a mechanism of AMIS that can occur independent of activating Fc gamma Rs and may provide a surrogate to identify antibodies capable of inducing AMIS against different RBC antigens.