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Induction of Graft-versus-host Disease and In Vivo T Cell Monitoring Using an MHC-matched Murine Model
Published on: August 29, 2012
Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death
Brent R Logan1, Denggang Fu2, Alan Howard3
1Division of Biostatistics and Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Insights
Plasma biomarkers measured 3 months after allogeneic hematopoietic cell transplantation (HCT) can identify patients at high risk for developing chronic graft-versus-host disease (cGVHD). This finding aids in early risk stratification for cGVHD.
Area of Science:
- Hematology
- Immunology
- Transplantation Science
Background:
- Chronic graft-versus-host disease (cGVHD) is a significant complication following allogeneic hematopoietic cell transplantation (HCT).
- Accurate prediction of cGVHD risk is crucial for patient management.
- The role of different graft types (bone marrow vs. peripheral blood) in cGVHD risk necessitates refined biomarker strategies.
Purpose of the Study:
- To identify and validate plasma proteomic biomarkers for predicting cGVHD risk.
- To assess the association of these biomarkers with cGVHD development in patients receiving peripheral blood (PB) or bone marrow (BM) grafts.
- To evaluate the utility of these biomarkers in both human clinical trials and a preclinical mouse model.
Main Methods:
- Plasma proteomics was performed on samples from HCT recipients at day 90 post-transplant.
- Five novel risk markers were identified and combined with eight previously known markers.
- Marker associations with cGVHD risk were analyzed using Cox-proportional-hazards models in two multicenter BMTCTN cohorts, and validated in a mouse model.
Main Results:
- Specific biomarkers (CXCL9, DKK3, CXCL10, MMP3) showed significant correlations and associations with increased cGVHD risk in both PB and BM recipients across cohorts.
- PB recipients with elevated biomarkers demonstrated a significantly higher incidence of cGVHD (22%-32%) compared to those with low biomarkers (8%-12%).
- Elevated circulating biomarkers were detected in a mouse model prior to the onset of cGVHD clinical signs.
Conclusions:
- Plasma biomarker levels at 3 months post-HCT are effective in identifying patients at risk for developing cGVHD.
- These validated biomarkers offer a promising tool for early risk stratification and personalized management of HCT recipients.
- The findings support the use of biomarker scores for predicting cGVHD risk, irrespective of graft source.
Abstract:
BACKGROUNDChronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT). More accurate information regarding the risk of developing cGVHD is required. Bone marrow (BM) grafts contribute to lower cGVHD, which creates a dispute over whether risk biomarker scores should be used for peripheral blood (PB) and BM.METHODSDay 90 plasma proteomics from PB and BM recipients developing cGVHD revealed 5 risk markers that were added to 8 previous cGVHD markers to screen 982 HCT samples of 2 multicenter Blood and Marrow Transplant Clinical Trials Network (BMTCTN) cohorts. Each marker was tested for its association with cause-specific hazard ratios (HRs) of cGVHD using Cox-proportional-hazards models. We paired these clinical studies with biomarker measurements in a mouse model of cGVHD.RESULTSSpearman correlations between DKK3 and MMP3 were significant in both cohorts. In BMTCTN 0201 multivariate analyses, PB recipients with 1-log increase in CXCL9 and DKK3 were 1.3 times (95% CI: 1.1-1.4, P = 0.001) and 1.9 times (95%CI: 1.1-3.2, P = 0.019) and BM recipients with 1-log increase in CXCL10 and MMP3 were 1.3 times (95%CI: 1.0-1.6, P = 0.018 and P = 0.023) more likely to develop cGVHD. In BMTCTN 1202, PB patients with high CXCL9 and MMP3 were 1.1 times (95%CI: 1.0-1.2, P = 0.037) and 1.2 times (95%CI: 1.0-1.3, P = 0.009) more likely to develop cGVHD. PB patients with high biomarkers had increased likelihood to develop cGVHD in both cohorts (22%-32% versus 8%-12%, P = 0.002 and P < 0.001, respectively). Mice showed elevated circulating biomarkers before the signs of cGVHD.CONCLUSIONBiomarker levels at 3 months after HCT identify patients at risk for cGVHD occurrence.FUNDINGNIH grants R01CA168814, R21HL139934, P01CA158505, T32AI007313, and R01CA264921.
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