Immune reset: what do we learn from bone marrow transplantation

Abstract Bone marrow transplantation (BMT) has traditionally been viewed as a curative strategy for hematologic malignancies through replacement of the diseased hematopoietic system. However, accumulating evidence indicates that BMT represents a far more profound biological process: an enforced collapse and subsequent reconstruction of the hematopoietic and immune system. This process provides a unique human model to investigate how immune homeostasis can be reprogrammed beyond physiological conditions. Importantly, post-transplant immunity does not revert to a pre-existing state but instead converges on a newly defined equilibrium shaped by conditioning-induced injury, donor-recipient immune interactions, stromal regeneration, and therapeutic interventions. In this review, we conceptualize BMT as an immune reset and synthesize emerging insights into the mechanisms that govern tolerance reinstallation and immune stability after transplantation. By reframing BMT as a model of immune reset rather than simple immune reconstitution, we highlight general principles of immune homeostasis restoration that extend beyond transplantation and may inform therapeutic strategies for autoimmunity, immune aging, and immune-mediated diseases.