Non-HLA antibodies in solid organ transplantation: recent concepts and clinical relevance.

PURPOSE OF REVIEW Humoral responses beyond major histocompatibility antigens continue to receive the attention of the transplantation community. We report on clinical studies testing clinical relevance of non-human leukocyte antigen (HLA) antigens in solid organ transplantation and provide an update on novel experimental findings. A conceptual framework on the role of graft microenvironment during initiation of non-HLA-related humoral immunity is addressed as well. RECENT FINDINGS Clinical relevance of antibodies targeting angiotensin type 1 receptor (AT1R-Abs) is broadly confirmed in renal and cardiac transplantation, where in addition antibodies against endothelin type A receptor (ETAR-Abs) were found. Obliterative lesions in lung allografts occur more commonly in the presence of antibodies directed against K-α 1 tubulin and collagen-V. Anti-perlecan antibodies are newly identified as accelerators of obliterative vascular lesions. Changes in the intragraft microenvironment, ischemia and alloimmunity seem to represent important permissive factors for non-HLA antibody responses. SUMMARY Confirmed clinical relevance of non-HLA humoral responses in solid organ transplantation emphasizes the need for revision of classical diagnostic approaches based solely on detection of HLA-donor-specific antibodies (DSA). A better understanding of intersections of HLA- and non-HLA-related mechanisms and identification of common effector mechanisms would represent an important step towards targeted therapies.