Jurnal Internasional Int “Dll” mengendalikan ganas patologi T-sel di GVHD
GVHD remains a major complication after allogeneic hematopoietic bone marrow transplantation. Acute Gute (aGVHD), usually treated with glucocorticoids, is often followed by a destructive chronic form of this disease whose treatment options are limited. What if the limited number of antibody injections after a bone marrow transplant can reduce or even prevent aGVHD and cGVHD? This vision received support from data presented in 3 studies that identified Notch signaling as a very promising target to reduce excessive T and B cell activity. 1 ⇓ – 3
Notch signaling provides communication channels for cells. The four members of the Notch receptor family in mammals are activated by binding to 1 of 5 different ligands, named Dll1, Dll3, Dl4, Jagged1, and Jagged2. Initially, Notch protein was recognized as a determinant of cell fate. In the hematopoietic system, activation of the Notch receptor guides early differentiation of T cells. 4 Constitutive Notch signaling activation can be oncogenic; activating Notch1 mutations, for example, is a well-known driver of acute T cell lymphoblastic leukemia. 5 Small molecular inhibitors of the Notch signal have been tested in clinical trials; However, they do not have specificity for single receptors and treatment-related toxicity limits their widespread use. The use of blocking antibodies overcomes this limitation.
During aGVHD, the inflammatory immune reaction occurs mediated by adult donor T cells directed against host alloantigen. Various approaches to drain donor T cells from hematopoietic transplantation products have been tried to minimize the incidence and severity of subsequent GVHD. 6 The Maillard group identified in previous studies played an important role in Notch1 / 2 in this reactive T-host. cells in aGVHD pathology. 2 7 Suppressing Notch signaling by the dominant negative expression expression Mastermind-like, important signaling component of the Notch pathway, decreases the production of inflammatory cytokines and increases the number of regulator T cells, which causes reduced organ damage. Restoring antigen-specific tolerance by inducing regulator T cells is an elegant way to suppress a dangerous immune reaction while leaving general immunity competencies intact. 8 Furthermore, after receiving an allogeneic bone marrow transplant (allo-BMT), mice survived for a long time free from severe GVHD when the interaction of Notch1-Dll4 was blocked by antidote antibodies. In contrast to the notch-directed antibodies, which are poorly tolerated, targeting Dll proteins does not have systemic side effects.
Frequently following aGVHD, cGVHD displays a broader spectrum of clinical manifestations. 9 The underlying complex immunity. reactions involve T cells, B cells, and other antigen-presenting cells. Pathological events include destruction of the thymus tissue, appearance of allo- and autoreactive T cells with a bias towards Th17 polarization, and reduced number of regulator T cells. Macrophages become polarized towards M2 phenotype and stimulate the production of transformation of growth factor-β, which ultimately promotes fibrosis in some tissues and disrupts organ function. 10 B cells are potentially pathologically elevated and are characterized by constitutive B-cell receptor signals and pathways regulated by BAFF. Notch2 signaling contributes to B-cell pathology associated with cGVHD, increases B-cell receptor response by lowering the threshold for response to alloantigen, and Notch2 blockade reverses the hyperactivity of pathogenic B cells. 3
T-cGVHD cell pathology is in the focus of current research, Radojcic et al. Confirm that targeting Notch signaling in donor T cells achieves immunomodulation that benefits and inhibits GVHD after allo-BMT. In humans, cGVHD usually manifests in several organs and usually includes skin pathology and bronchiolitis obliterans, obstruction of inflammatory lung bronchioles. However, its manifestations vary and cannot be replicated in a single mouse model. Radojcic et al used 2 models to mimic 2 findings in human cGVHD: the first was characterized by systemic fibrosis including scleroderma (Scl-cGVHD), and the second was characterized by prominent lung involvement with bronchiolitis obliterans. Using antibody-mediated blockages of specific members of the Notch family receptors and their ligands, the main candidates responsible for pathological changes are identified. In the Scl-cGVHD model, the inhibition of Dll4-stimulated Notch activation is sufficient to prevent cGVHD manifestations, while blocking Dll1 has almost no beneficial effect. Most interestingly, the application of a single blocking antibody is sufficient for long-term protection, but must be given in the first 48 hours after transplantation. In this model, Notch blockade also results in the expansion of alloantigen regulatory regulatory T cells. In the obliterans-cGVHD bronchiolitis model, antibody-mediated neutralization in Dll1 or Dll4 provides the same protection of the disease, and treatment is also effective after disease manifestations are present, thus alleviating even existing cGVHD. human system. The Murine model mimics certain aspects of cGVHD immunopathogenesis, but interspecies differences in immune cell signals, details of disease pathogenesis, and treatment efficacy remain alarming. Despite these concerns, Notch's target signal is an attractive potential therapeutic approach. Short-term treatment that blocks Notch signals during the first days after transplantation may be sufficient to prevent aGVHD and at least some manifestations of cGVHD.
Although the heterogeneous nature of cGVHD might prevent simple treatment adjusting all manifestations, the complexity of molecular interactions also offers specific targets interfere with the pathways that are important for the emergence and maintenance of disease. Therefore, identification of additional details of interaction notch-signaling, such as cell types expressing ligand critical or possible cross-talking of Notch with other signaling pathways, is justified in finding additional therapeutic targets.
In short, Notch signaling in the initial posttransplant environment was identified as important for subsequent cGVHD. Modulating the signal Takch using a genetic or pharmacological approach with antibodies to Dll1 / Dll4 produces a therapeutic effect. In the near future it will be expected to show whether targeting Ignition Notch is a feasible and curative approach to treating GVHD humans.
- © 2018 by The American Society of Hematology