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 Fcγ receptors (FcγRs) thought to be required for antigen modulation. Therefore, we sought to determine the mechanism behind AMIS following HOD RBC exposure.

Following transfer of HOD RBCs into wild‐type or FcγR‐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.

Our results demonstrate that anti‐HEL antibodies individually or in combination suppressed anti‐HOD 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 FcγR‐independent manner. Pre‐exposure of HOD RBCs to anti‐HEL antibodies reduced antigen levels and suppressed anti‐HOD antibody formation following HOD RBC exposure.

These results suggest that antibody‐mediated antigen modulation may reflect a mechanism of AMIS that can occur independent of activating FcγRs and may provide a surrogate to identify antibodies capable of inducing AMIS against different RBC antigens.