Non-HLA antibodies in transplantation: when do they matter?

A growing interest in the contribution of non-human leukocyte antigens (non-HLA) antibodies to allograft rejection has led to the identification of multiple target antigens and investigation into the possible mechanisms of injury. Although several non-HLA antibody specificities have been identified, the largest cohorts studied are those detected using commercial assays. This review focuses on the phenotypes of injury associated with non-HLA antibody and defines in-vivo environmental characteristics that may be conducive to non-HLA antibody-mediated injury.

Mechanistic studies in animal models and clinical data suggest that an inflammatory environment, increased antigen expression, and development of neoantigens through posttranslational modifications contribute to non-HLA antibody development and their subsequent contribution to allograft injury. Furthermore, many reports show worse outcomes when HLA and non-HLA antibodies are present, suggesting possible interactions between these antibodies that lead to increased injury. Plasmapheresis and intravenous immunoglobulin are currently used to reduce HLA and non-HLA antibodies; however, therapeutic strategies targeting B cells and plasma cells simultaneously may lead to more durable antibody elimination.

Immune triggers that lead to non-HLA antibody formation are complex and poorly understood. The ability of non-HLA antibodies to mediate allograft injury may depend upon their specificity and affinity, density of the target antigen, and synergy with HLA antibodies.