The curative potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for many hematologic malignancies derives in large part from reconstitution of normal donor immunity and the development of a potent graft-versus-leukemia (GVL) immune response capable of rejecting tumor cell in vivo. Elucidation of the mechanisms of GVL by studies of animal models and analysis of clinical data has yielded important insights into how clinically effective tumor immunity is generated following allo-HSCT. These studies have identified NK cells and B cells as well as T cells as important mediators of the GVL response. A variety of antigenic targets of the GVL response have also been identified, and include tumor-associated antigens as well as minor histocompatibility antigens. The principles of effective GVL can now be applied to the development of novel therapies that enhance the therapeutic benefit of allogeneic HSCT while minimizing the toxicities associated with treatment. Moreover, many components of this approach that result in elimination of tumor cells following allogeneic HSCT can potentially be adapted to enhance the effectiveness of tumor immunity in the autologous setting.
"However, the majority of allo-HCT procedures are performed for patients with leukemias, lymphomas and other clonal hematological disorders. In these cases, the allogeneic graft provides T cells and other immune cells that play major therapeutic roles through recognition and elimination of cancer cells in the host (graft-versus-tumor, or GVT, effect)   . Unfortunately, donor-derived T cells also lead to immune-mediated damage in normal host tissues, a life-threatening complication referred to as graft-versushost disease (GVHD)   . "
[Show abstract][Hide abstract] ABSTRACT: Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients.
"Second, DZNep has broad and potent antiviral activity, including against vesicular stomatitis virus, rotavirus, and vaccinia virus (30, 31). In particular, this antiviral spectrum of DZNep extends to human cytomegalovirus (31), which causes serious infection in patients after organ transplantation (32). Third, DZNep has been investigated as an effective therapy in mice model target on PRC2 to treat the breast cancer (20, 33), acute myeloid leukemia (34), glioblastoma (35), and so on. "
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with solid-organ transplantation is a feasible method to achieve long-lasting organ allograft tolerance through the induction of hematopoietic chimerism in recipients. However, the allo-HSCT engraftment puts recipients at risk of life-threatening graft-versus-host disease (GVHD). Novel immunomodulatory approaches are required to effectively control GVHD while preserving the status of hematopoietic chimerism. We have reported that histone methylation inhibitor 3-deazaneplanocin A (DZNep) can control ongoing GVHD in mice by selectively inducing apoptosis of alloreactive effector T cells.
Using donor-derived CD8 T cell-mediated mouse GVHD model, we further investigated the effect of in vivo administration of DZNep on allogeneic CD8 T cell response and the hematopoietic chimerism in recipients.
We found that DZNep delayed the in vivo proliferation of donor-derived alloreactive CD8 T cells and also reduced the interleukin-2 production by these T cells. Moreover, DZNep treatment resulted in a significant decrease of interferon-γ, tumor necrosis factor-α, granzyme B, TRAIL, and Fas ligand expressing donor-derived CD8 T cells, suggesting a multilevel modulation role on T-cell survival and effect in vivo. Notably, DZNep treatment did not hamper the generation of hematopoietic chimerism in recipients.
These findings suggest that modulation of histone methylation through DZNep may be a potential strategy for the induction of hematopoietic chimerism to achieve donor-specific organ allograft tolerance through donor allo-HSCT combined with solid-organ transplantation.
[Show abstract][Hide abstract] ABSTRACT: The last 2 years have seen much excitement in the field of genetics with the identification of a formerly unappreciated level of "structural variation" within the normal human genome. Genetic structural variants include deletions, duplications, and inversions in addition to the recently discovered, copy number variants. Single nucleotide polymorphisms are the most extensively evaluated variant within the genome to date. Combining our knowledge from these studies with our rapidly accumulating understanding of structural variants, it is apparent that the extent of genetic dissimilarity between any 2 individuals is considerable and much greater than that which was previously recognized. Clearly, this more diverse view of the genome has significant implications for allogeneic hematopoietic stem cell transplantation, not least in the generation of transplant antigens but also in terms of individual susceptibility to transplant-related toxicities. With advances in DNA sequencing technology we now have the capacity to perform genome-wide analysis in a high throughput fashion, permitting a detailed genetic analysis of patient and donor prior to transplantation. Understanding the significance of this additional genetic information and applying it in a clinically meaningful way will be one of the challenges faced by transplant clinicians in the future.
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