2025 International Conference on Cell Therapy and Biomedical Frontiers
Editor’s Note: On October 31, 2025, the International Conference on Cell Therapy and Biomedical Frontiers was grandly held in Xiong’an, Hebei Province. The event was hosted by the Xiong’an Institute for Translational Medicine and Engineering, Peking University People’s Hospital, and organized by the National Clinical Research Center for Hematologic Diseases and the Institute of Hematology, Peking University. At the conference, Professor Huang Xiaojun, Director of the National Clinical Research Center for Hematologic Diseases and of the Institute of Hematology, Peking University, delivered a keynote lecture titled “Decoding Homeostasis Remodeling in Haplo-SCT: From HLA Mismatch to Immune Rebalancing.” His talk systematically elaborated on the mechanisms underlying immune homeostasis remodeling following haploidentical transplantation and its clinical implications. The core content of his presentation is summarized below.
Revisiting HLA Mismatch and Immune Homeostasis in Haploidentical Transplantation
Although graft-versus-host disease (GVHD) remains one of the most common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), nearly 50% of patients can achieve long-term survival free from disease, immunosuppressants, and relapse. This indicates that these patients have effectively reached a state of immune homeostasis post-transplantation.
Traditionally, human leukocyte antigen (HLA) mismatch was viewed as a major barrier to successful transplantation. However, advances in haploidentical stem cell transplantation (haplo-SCT) have demonstrated outcomes comparable to those of HLA-matched sibling transplants. Consequently, HLA mismatch is no longer the key determinant of transplantation outcomes, suggesting that this immunological barrier has been effectively overcome.
Hematopoietic stem cell transplantation differs fundamentally from solid organ transplantation, particularly in haploidentical settings where patients can ultimately achieve immune equilibrium. Immune homeostasis refers to the balanced physiological state of the immune system, maintained through multiple regulatory mechanisms that prevent overactivation or immunodeficiency, thereby preserving overall health. The establishment of immune homeostasis depends on both central and peripheral immune tolerance. Thus, key scientific questions arise:
- How is the HLA barrier overcome to reconstruct immune balance?
- How are central and peripheral tolerance reestablished in haploidentical transplantation?
Mechanisms Underlying Immune Homeostasis Reconstruction Across the HLA Barrier
The ability of haploidentical transplantation to overcome HLA disparity involves two critical mechanisms:
- Inhibition and guided reconstruction of peripheral T-cell activation, establishing peripheral immune homeostasis; and
- Restoration of thymic function to promote central T-cell reconstitution and thus achieve central immune tolerance.
Regulating T-cell activation is pivotal. Uncontrolled activation can trigger GVHD. Multiple strategies have been developed to suppress T-cell activation — for instance, blocking co-stimulatory signals or cytokine pathways — to induce T-cell anergy, reduce GVHD incidence, and promote peripheral tolerance.
Professor Huang’s team discovered that granulocyte colony-stimulating factor (G-CSF) can remodel the three-dimensional chromatin architecture of T cells, inducing a hypo-responsive phenotype. G-CSF also upregulates SOCS1, thereby inhibiting the JAK-STAT pathway, which further promotes peripheral T-cell tolerance. Similarly, anti-thymocyte globulin (ATG) depletes B and T lymphocytes while expanding regulatory T cells (Tregs). Post-transplant cyclophosphamide (PT-Cy) likewise promotes Treg expansion, facilitating the establishment of peripheral immune tolerance.
Central Immune Homeostasis: Reconstruction and Remodeling
While clinical observations show that some recipients can successfully rebuild immune homeostasis, the underlying mechanisms remain incompletely understood. Key questions include:
- What are the cellular and molecular characteristics of patients who achieve post-transplant immune equilibrium?
- Do haploidentical and HLA-matched sibling transplants follow similar immune remodeling patterns?
To address these questions, Professor Huang’s group analyzed patients who had achieved stable immune homeostasis — defined as being over one year post-transplant without GVHD, infection, relapse, or the need for ongoing immunosuppression. Using single-cell transcriptomic profiling, the team systematically compared immune cell subpopulations. Findings showed that all donor-derived immune subsets were fully reconstituted in recipients, but their relative proportions differed. Moreover, haploidentical and matched sibling transplants exhibited distinct immune remodeling patterns.
Unique TCR Clonotypes and T-Cell Reconstitution
In haploidentical transplants, T-cell receptor (TCR) repertoires of recipients differed significantly from those of their donors, whereas matched sibling recipients showed highly concordant TCR profiles. Shared TCR clones were defined as public clones, while those unique to recipients were termed private clones. Haploidentical recipients exhibited a higher proportion of private clones, which expressed elevated levels of ZNF683 and genes associated with thymic selection signaling, indicating a greater contribution from central T-cell reconstitution.
Further analysis revealed that ZNF683 was specifically activated in CD8⁺ T cells of haploidentical transplant recipients and was highly expressed in effector CD8⁺ T cells. Both clinical and animal studies demonstrated that suppressing peripheral T-cell activation can promote central thymic T-cell regeneration, which is critical for maintaining immune balance — particularly in haploidentical settings.
Additionally, among patients who achieved immune homeostasis, the team identified a novel subset of CD8⁺ regulatory precursor cells that expanded markedly post-transplant. These cells exhibited immunomodulatory properties capable of suppressing alloreactive T cells, contributing to the maintenance of peripheral tolerance. Collectively, these findings reveal that haploidentical transplantation follows a unique pattern of immune reconstitution.
Thymic Function and Immune Equilibrium
Professor Huang’s latest studies show that HLA mismatch independently impairs thymic function and delays T-cell recovery — one of the major challenges in haploidentical transplantation. Current clinical regimens, including those based on ATG and PT-Cy, have achieved impressive results. The efficacy of these protocols likely lies, at least in part, in their capacity to restore thymic function, since thymus-mediated central tolerance is fundamental to immune homeostasis after haploidentical transplantation.
Understanding thymic development and T-cell tolerance formation provides key insights into central immune rebalancing. The establishment of central tolerance depends on the coordinated action of multiple cell types within the thymus — particularly during negative selection — to maintain self-tolerance. Haploidentical transplantation offers a unique model for studying post-transplant thymic re-education. Critical scientific questions remain:
- How do donor- and recipient-derived antigen-presenting cells (APCs) coordinate MHC presentation and negative selection?
- How can clinical interventions restore thymic function to facilitate central immune equilibrium?
The Role of G-CSF in Thymic Recovery
In the “Beijing Protocol” led by Professor Huang’s team, G-CSF plays an indispensable role in ensuring the success of haploidentical transplantation. Unpublished data from the team demonstrate that G-CSF improves the thymic microenvironment and facilitates the re-establishment of central tolerance. Previous studies also showed that G-CSF and ATG can repair thymic injury and promote central T-cell pathway reconstruction, whereas high-dose PT-Cy may cause thymic damage, thereby hindering central reconstitution.
Conclusion
Distinct transplantation models display differential immune homeostasis remodeling patterns. Clinical interventions that repair thymic function and foster central tolerance are essential for successful immune reconstitution. A deeper understanding of these regulatory mechanisms is key to elucidating thymus-mediated immune balance.
Haploidentical transplantation thus serves not only as a powerful clinical therapeutic approach but also as an ideal model system for studying immune homeostasis remodeling. Insights gained from these studies will inform immune tolerance strategies in solid organ transplantation and help promote long-term immune equilibrium and stability.
