[Novel HLA-mediated mechanisms of GVHD: multifaceted roles of HLA class II in GVHD and GVL].

HLA class II molecules play a central role in antigen presentation that underlies the pathogenesis of graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. This review introduces the concept of "neo-self" antigens observed in autoimmune diseases and applies it to chronic GVHD, where DBY/HLA class II complexes trigger pathological B cell activation, complement deposition, and tissue fibrosis. In acute GVHD, non-hematopoietic epithelial cells such as intestinal epithelial cells also contribute to disease by presenting antigens via HLA class II. In acute myeloid leukemia relapse, downregulation of HLA class II on leukemic cells allows immune evasion, but this suppression can be reversed by IFN-γ or flotetuzumab, a CD123×CD3 bispecific antibody, restoring immunogenicity and potentially enhancing the graft versus leukemia (GVL) effect. Collectively, HLA class II molecules function not only in conventional antigen presentation to CD4+ T cells but also in neo-self antigen recognition, immune evasion, and tissue-specific disease expression. A deeper understanding of HLA class II biology may pave the way toward therapeutic strategies that separate GVHD from the GVL effect.