HLA haploidentical HSCT: from immune imbalance to a platform for immune homeostasis restoration

Immune homeostasis is a dynamic equilibrium between immunogenicity and immune tolerance, essential for maintaining overall health. This balance relies on the immune system’s ability to distinguish between self and non-self antigens, a process governed by human leukocyte antigens (HLAs). While self-versus-non-self recognition serves as a crucial immunological barrier against foreign antigens in steady state, it also drives bidirectional alloreactivity in allogeneic hematopoietic stem cell transplantation (allo-HSCT). HLA mismatches in haploidentical HSCT (haplo-HSCT) pose significant challenges, increasing the risk of life-threatening graft-versus-host disease (GVHD) and graft rejection, historically leading to poor outcomes. However, over the past two decades, substantial advancements have optimized haplo-SCT, achieving outcomes comparable with those of HLA-matched HSCT. By successfully overcoming the HLA barrier, haplo-HSCT provides a unique opportunity to investigate the underlying cellular and molecular fundamentals governing immune homeostasis restoration following allo-HSCT. In this review, we discuss the foundation of immune homeostasis in steady state and its remodeling after allo-HSCT.