Antibody-mediated immunity across the ABO barrier: natural isoagglutinins, effector injury, accommodation, and targeted intervention

ABO-incompatible kidney transplantation (ABOi-KT) provides a clinical setting in which antibody-mediated injury and graft accommodation can be examined. Naturally occurring anti-A/B IgM and IgG differ in distribution and effector activity. After binding to graft endothelial glycans, these antibodies may activate complement, Fc-receptor-bearing cells, platelets, and coagulation, contributing to outcomes ranging from subclinical microvascular changes to thrombotic microangiopathy and antibody-mediated rejection. Although ABO and HLA antibodies can converge on complement- and Fc-mediated microvascular injury, ABO antigens are variably expressed terminal glycans whereas HLA antigens are polymorphic proteins; accordingly, persistent anti-A/B after accommodation may be clinically silent, while persistent HLA donor-specific antibody continues to signal potential ongoing alloimmune risk. Yet the same antibody specificity may later coexist with a functioning graft through accommodation, a dynamic state involving complement regulation, cytoprotective endothelial programs, altered antibody -glycan interactions, and partial downregulation of donor-specific antibody output. This Review integrates mechanistic and clinical evidence through August 2026 and maps each therapeutic intervention to its principal immune target: apheresis removes circulating antibody; rituximab depletes CD20-positive B cells but spares mature plasma cells; CD38- or proteasome-directed agents reduce antibody-secreting cells; and complement inhibitors interrupt downstream effector injury without eliminating antibody or its source. Conventional titers are method-dependent and do not capture all features relevant to antibody pathogenicity, including subclass, fine specificity, and complement-fixing activity. Functional assays may add information, but they require standardization and prospective validation before routine use. Low-titer protocols should therefore be evaluated prospectively, while intensified treatment for high-titer recipients should be guided by center capacity, prespecified safety limits, and clinical and pathological findings. Accommodation also remains incompletely defined and may reflect different combinations of graft adaptation and changes in antibody pathogenicity. Evidence for plasma-cell-directed therapy is explicitly hierarchical: ABO-specific support is confined to isolated rescue experience, whereas prospective anti-CD38 and controlled proteasome-inhibitor data derive from HLA sensitization or HLA-related ABMR and cannot establish routine efficacy in ABOi-KT.