Chronic Graft-versus-Host Disease
Chronic Graft-versus-Host Disease: Biomarkers, Mediators, and Druggable Targets
An improved understanding of chronic graft-versus-host disease (cGVHD) and its pathogenesis has led to the development of novel treatments. Future advancements may be possible using tools to track donor cell expansion and localization.
Professor of Medicine
“The complexities of the immune response in cGVHD occur in many different dimensions, and it may be helpful to think in terms of fluidity and flow. We are interested in targets that represent choke points or valves (ie, targets that might cut off the flow of the immune response).”
Currently, all biomarkers for cGVHD are exploratory. It is important to consider not only just biomarkers but also biomarkers that are associated with pharmacodynamic changes that may be druggable. The complexities of the immune response in cGVHD occur in many different dimensions, and it may be helpful to think in terms of fluidity and flow. We are interested in targets that represent choke points or valves (ie, targets that might cut off the flow of the immune response).
GVHD has been classically defined as acute and chronic using a cutoff of 100 days post allogeneic hematopoietic stem cell transplantation. Prior to transplant, it is believed that tissue damage from conditioning regimens may represent an early influence in the development of GVHD. Acute GVHD is understood to be mediated by mature effector T cells from the donor that become activated after encountering alloantigens in the recipient. In cGVHD, shared cooperative B-cell and T-cell responses in the lymph nodes are involved, which likely explains why cGVHD occurs most commonly during the 6 to 12 months after transplantation. Currently druggable targets act at differing points in the relevant pathways. For example, relative to alloantigen recognition, ibrutinib acts upstream at immune receptor activation, whereas ruxolitinib has widespread T-cell inhibitory effects and belumosudil may inhibit peripheral sclerosis further downstream in cGVHD pathogenesis.
In looking to the future of biomarkers and potential targets, a few of the key players include regulatory T cells (Treg cells) and T follicular regulatory cells (Tfr cells). Treg cells are key mediators of immune tolerance that suppress auto- and alloreactive immune responses, and their absence is strongly associated with cGVHD. Tfr cells, which comprise only a small proportion of Treg cells, are also a target of interest and might be druggable. Tfr cells regulate interactions between B cells and T follicular helper cells (Tfh cells) within the germinal center, leading to the production of antibodies that are associated with cGVHD, and antibodies can drive fibrosis through macrophage activation.
In light of the importance of Treg cells, BCL6 and CXCR4 are potential targets of particular interest. The transcription factor BCL6 is at the center of gene regulation in Tfh cell biology, and the inhibition of this pathway has been shown to have a dramatic effect on cGVHD in a preclinical model. CXCR4, which is a binding molecule that Treg cells use to enter lymph nodes, is another interesting potential target. That is, given that the exponential growth and expansion of cGVHD occur in the lymph nodes (spurred on by the T-cell help, the cytokine environment, and the architecture of the lymph nodes), the following question arises: Might we eliminate this dramatic expansion by keeping the Tfh cells out of the lymph nodes? This is the Tfh cell–CXCR4 idea.
The biomarkers and targets in cGVHD that have been developed thus far represent important steps forward; however, advancements in both preclinical biology and correlative science are needed and will likely stem from an improved capacity to account for single-cell immune response complexity and tracking the fluidity of the immune effector cells in cGVHD pathogenesis. It is likely that the path forward will involve genetically labeling individual cells in a barcoded fashion, just like we do with single-cell RNA analyses. This would facilitate tracking the maturation and disposition of donor cells in the host, enabling us to determine which cell phenotypes dominate and localize at the site of cGVHD.
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