Hematopoietic cell transplantation (HCT), also known as bone marrow transplantation, is a critical treatment for blood cancers such as leukemia, lymphoma, and myeloma, as well as certain genetic and non-cancerous blood disorders. The procedure replaces a patient’s diseased or damaged stem cells with healthy ones from a donor, restoring the body’s ability to produce normal blood cells.
While HCT can be curative, it comes with significant risks. One major complication is chronic graft-versus-host disease (cGVHD), which affects up to 30-50% of long-term survivors. This condition occurs when the donor’s cells, instead of simply protecting the patient, mistakenly attack the recipient’s healthy tissues and organs. Instead of defending against infections, immune cells that grow from the donor’s stem cells drive persistent inflammation, leading to debilitating symptoms such as skin thickening, lung complications, and joint stiffness.
To illustrate how this process unfolds, imagine a neighborhood watch group that starts off protecting a community by monitoring for real threats. Over time, however, they become overly vigilant—mistaking friendly neighbors for intruders and escalating unnecessary responses. Soon, innocent people are being targeted, disrupting the very community the watch group was meant to protect. In cGVHD, a similar misidentification occurs: the new immune cells recognize the patient’s own tissues as foreign and attack them, leading to widespread damage.
Over the past 15 years, researchers at Fred Hutch have made significant strides in understanding cGVHD, which has led to new FDA-approved therapies that target key immune pathways of disease. However, these treatments, two of which target IL-17 and CSF-1, are not universally effective. Some patients experience only partial relief before symptoms return, while others see no benefit at all. Recognizing this variability, researchers in the Hill lab in Translational Science and Therapeutics at Fred Hutch set out to determine why. In a recent study published in Blood, Drs. Julie Boiko and Geoffrey Hill investigated how different immune pathways might drive cGVHD, laying the groundwork for more personalized treatment approaches.
“With this observation that not every targeted therapy works for every patient with cGVHD, we speculate that cGVHD is predominantly driven by different dysregulated immune cells and molecules from patient to patient,” Boiko explained. “Two of these molecules (called cytokines) are interleukin-17 (IL-17) and colony-stimulating factor-1 (CSF-1), which control the migration of immune cells called monocytes from the blood into cGVHD target tissue, followed by their development into macrophages that directly mediate organ damage.”
To investigate this, the team used longitudinal single-cell RNA sequencing (scRNAseq) on blood samples from mice that receive HCT and subsequently develop GVHD-driven sclerosis, a condition defined by thickened fibrotic skin due to excessive production of collagen. Comparing untreated mice with mice where IL-17 and, separately, CSF-1 signaling were disrupted enabled identification of distinct gene expression signatures associated with IL-17 and CSF-1 in major cell types in blood.
“By comparing the baseline GVHD model’s gene expression changes with those in animals where IL-17 or CSF-1 pathways were blocked, as well as with control HCT mice that did not develop GVHD, we identified the blood cells and genes most influenced by these cytokines,” Boiko said. “Not surprisingly, the cells with the most gene expression variation were peripheral blood monocytes. We defined these variable genes as the ‘gene signatures’ of IL-17 and CSF-1 dysregulation in the context of cGVHD.”
Monocytes are crucial immune cells that circulate in our blood and – when activated – migrate into tissue and differentiate into macrophages and dendritic cells. They’re also some of the ‘first responders’ for the immune system, and are themselves capable of phagocytosing invading bacteria, secreting cytokines that drive inflammation, and activating members of the adaptive immune system.
Building on their pivotal findings of monocyte dysregulation in IL-17- and CSF-1-driven cGVHD in mice, the researchers next turned to patient samples. “We then measured the expression of these IL-17 and CSF-1 gene signatures in blood monocytes from patients with newly developed cGVHD, as well as from patients who were 100 days post-HCT and later developed cGVHD,” Boiko noted. “We could detect expression of consolidated versions of these signatures at day +100 post-HCT in half of patients who went on to develop cGVHD. At the time of cGVHD development, up to 70% of patients expressed at least one signature, whereas these signatures were absent in patients without cGVHD.”
In short, by examining how blood cells change when IL-17 and CSF-1 signaling is blocked in mice, Boiko and Hill identified monocyte-associated transcriptional signatures that are detectable in a large subset of patients both before, and during cGVHD. Their findings suggest that testing for an IL-17 or CSF-1 gene signature before, or at the time of diagnosis could offer the potential for more precise interventions targeting these immune pathways to prevent or treat cGVHD.
By moving toward a more personalized approach to cGVHD therapy, this research opens the door to interventions tailored to the specific immune drivers of each patient’s disease, potentially improving outcomes and quality of life for transplant recipients.
The spotlighted research was funded by the National Institutes of Health, National Cancer Institute, and the National Center for Advancing Translational Sciences.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Ted Gooley, Stephanie Lee, Scott Furlan, Geoffrey Hill contributed to this work.
Boiko JR, Ensey KS, Waltner OG, Jenkins IC, Bhise SS, MacDonald KP, Blazar BR, Hall AM, Gooley TA, Minnie SA, Lee SJ, Furlan SN, Hill GR. 2025. Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease. Blood. DOI: 10.1182/blood.2024025337.