(IFN)-inducible chemokines that bind to CXCR3, their only known receptor. Both IFNa and IFNg can induce these chemokines. CXCR3 expression can be rapidly induced in a variety of immune cells, including T lymphocytes and NK cells, following dendritic cell activation of naive lymphocytes. 2 Binding of these chemokines to CXCR3 promotes lymphocyte migration to inflamed tissues. CXCR3 is also critical for the recruitment of alloreactive T cells in acute GVHD. 3 There is a critical need for biology-based biomarkers to confirm or aid the diagnosis of cGVHD after allogeneic hematopoietic stem cell transplantation or monitor its progression to facilitate evaluation of new therapies. 4 The 2014 Biomarker Working Group of the National Institutes of Health Consensus Development Project on criteria for trials in cGVHD established a critical framework for biomarker studies that includes 4 distinct steps and is designed to avoid previous mistakes. 4 The first step is identification in discovery experiments of candidate biomarkers of well-matched cases and controls for a specific outcome (eg, diagnosis of all cGVHD, diagnosis of skin cGVHD, predicting future occurrence of cGVHD at an early time point such as day 100 posttransplant). The second is verification of the test’s analytical validity including reproducibility and accuracy. At this stage, cutoff values and sample collection procedures are locked down and cannot be changed without reverification of the test under the revised conditions. The third step is qualification to assess the robustness of the test in all-comer samples from the intended use population for the specific clinical outcome as used in the discovery experiments. The qualification cohort for step 3 should be independent from the identification cohort previously studied in step 1. The final step is application in the clinic. In the present study, Kariminia et al evaluate previously identified potential biomarkers for cGVHD and search for other markers through discovery approaches followed by validation of 11 candidates in 2 independent cohorts (n 5 198 and n 5 83). In their series, both CXCL9 and CXCL10 are significantly correlated in multivariate analysis with cGVHD diagnosis in the first replication cohort, but only CXCL10 in the second. In addition, other candidates are significant in 1 but not both the replication cohorts. They also study, on a subcohort of patients, the correlation between CXCL9/CXCL10 and circulating CXCR3 1 immune cells (CD4 1, CD8 1, and CD3 2 CD56bright). They find CXCR3 1 NK cells are significantly lower in the peripheral blood of patients with cGVHD. This population’s frequency cannot be used as a “biomarker” at this point because it is only tested in a subset of patients without using the strict criteria described herein, but it gives a hint in terms of possible biological correlation. Additionally, the frequency of these cells in affected tissues, which should be increased, is not tested as previously done by Croudace et al in the case of T lymphocytes. 5 Several groups have now reported CXCL9 or CXCL10 as potential biomarkers of cGVHD with more or less rigor in following the biomarker criteria described herein. 5-7 Hakim et al recently and elegantly reported gene expression profiling of circulating monocytes from cGVHD patients. They found significant upregulation of IFN-inducible (including CXCL10) and damage-response genes in cGVHD patients as compared with controls. These pathways were further substantiated in plasma enzyme-linked immunosorbent assays showing elevated levels of CXCL9 and CXCL10 (see figure). 8 Altogether, the IFN-inducible chemokines CXCL9 and CXCL10, responsible for CXCR3-expressing …