Research Topic

Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation

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Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for advanced and high-risk hematopoietic malignancies. Optimized donor selection, tailored preparative conditioning regimes and advanced supportive care have significantly contributed to improved patient outcome and have increased ...

Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for advanced and high-risk hematopoietic malignancies. Optimized donor selection, tailored preparative conditioning regimes and advanced supportive care have significantly contributed to improved patient outcome and have increased long-term survival, even in aged and co-morbid patient populations. However, graft-versus-host disease (GVHD) and relapse are still major reasons for significant morbidity and mortality following allogeneic HCT.

Donor-mediated inflammation of host tissues and efficient tumor control are both sustained by allo-reactive donor lymphocytes. Post-transplant immune reconstitution of lymphocyte subsets is a delicate and well-orchestrated process involving distinct immunological sites within the host. Spatial and temporal disruption of these sites consequently lead to deregulated, dysfunctional or insufficient immune responses of donor lymphocytes against host antigens, tumor cells and/or infectious agents. Modulation of post-transplant immunity by immunosuppression or immunostimulation, such as via the infusion of donor lymphocytes or checkpoint inhibitors, increases the risk for relapse or GVHD, respectively. Recent studies have shown the tolerogenic impact of graft manipulation via increasing the numbers of regulatory cells, such as FoxP3-expressing T regulatory cells (Tregs) or invariant natural killer T (iNKT) cells, while maintaining graft-versus-tumor (GVT) effects. Moreover, the administration of (i) cytokines such as low dose interleukin 2; (ii) monoclonal antibodies targeting critical epitopes of inflammation; (iii) tyrosine kinase inhibitors or (iv) chimeric antigen receptor (CAR) T cells have been demonstrated to be beneficial for suppressing destructive immune responses against host tissues and therefore, preventing GVHD. The induction of sustained immune tolerance, while maintaining potent graft-versus-tumor effects, is paramount to separate GVHD from tumor control and thereby, further improve survival following allogeneic HCT. Moreover, combinatorial hematopoietic cell and solid organ transplant protocols have been established to prevent solid organ transplant rejection while enabling the withdrawal of immunosuppressive drugs. Understanding the pathophysiological background of immune reconstitution will enable us to identify strategies for sustaining immune tolerance with efficient tumor control, improving patient outcome post allogeneic HCT.

In this Research Topic, we aim to gather novel Original Research and Review articles focusing on the cellular and humoral principles of immune reconstitution as well as novel approaches to induce immune tolerance following allogeneic HCT. We welcome the submission of pre-clinical and clinical studies that reveal the mechanisms underlying successful immune reconstitution and therefore, that pave avenues for clinical translation. Articles covering graft manipulation, adoptive immunotherapies, regulatory T cells, immunoregulatory cytokines or novel compounds are welcomed.


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