As HLA antigen analysis progressed using antisera, previously recognized antigens were either subdivided or found to exhibit broad specificity, leading to their classification as broad antigens, split antigens, and related antigens. Conversely, antigens with differing gene sequences may sometimes be recognized serologically as identical. Within the HLA-A2 antigen group, some allele-derived antigens are distinguished as related antigens, while others derived from different alleles are not distinguished and may be treated as the same antigen. This difference is thought to arise from whether the amino acid substitution site is located in an α-helix, which is readily recognized by anti-HLA antibodies, or in a β-sheet, which is less easily recognized.

Furthermore, many HLA antisera react with multiple HLA antigens. Groups exhibiting such common reaction patterns are termed cross-reactive groups (CREG).

Related donor hematopoietic stem cell transplantation (HSCT) remains an important donor source due to its high availability and rapid accessibility. Historically, the degree of HLA matching has been a key determinant of transplantation outcomes. However, the development of graft-versus-host disease (GVHD) prophylaxis strategies, particularly post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG), has significantly improved the safety of HLA-mismatched related donor transplantation. Recent studies have demonstrated that the impact of donor characteristics varies depending on the GVHD prophylaxis strategy, making donor selection based solely on HLA matching insufficient. In addition, advances in immunological understanding, including mechanisms of immune evasion such as HLA loss and epitope-based analyses such as PIRCHE, have provided new insights into donor selection. This review summarizes recent advances in GVHD prophylaxis in related donor HSCT, discusses the clinical significance of HLA mismatch, and highlights emerging strategies for precision donor selection based on immunological compatibility.