Use of a mouse model to identify a blood biomarker for IFNγ activity in pediatric secondary hemophagocytic lymphohistiocytosis

Life-threatening cytokine release syndromes include primary (p) and secondary (s) forms of hemophagocytic lymphohistiocytosis (HLH). Below detection in healthy individuals, interferon γ (IFNγ) levels are elevated to measurable concentrations in these afflictions suggesting a central role for this cytokine in the development and maintenance of HLH. Mimicking an infection-driven model of sHLH in mice, we observed that the tissue-derived levels of IFNγ are actually 500- to 2000-fold higher than those measured in the blood. To identify a blood biomarker, we postulated that the IFNγ gene products, CXCL9 and CXCL10 would correlate with disease parameters in the mouse model. To translate this into a disease relevant biomarker, we investigated whether CXCL9 and CXCL10 levels correlated with disease activity in pediatric sHLH patients. Our data demonstrate that disease control in mice correlates with neutralization of IFNγ activity in tissues and that the 2 chemokines serve as serum biomarkers to reflect disease status. Importantly, CXCL9 and CXCL10 levels in pediatric sHLH were shown to correlate with key disease parameters and severity in these patients. Thus, the translatability of the IFNγ-biomarker correlates from mouse to human, advocating the use of serum CXCL9 or CXCL10 as a means to monitor total IFNγ activity in patients with sHLH. Life-threatening cytokine release syndromes include primary (p) and secondary (s) forms of hemophagocytic lymphohistiocytosis (HLH). Below detection in healthy individuals, interferon γ (IFNγ) levels are elevated to measurable concentrations in these afflictions suggesting a central role for this cytokine in the development and maintenance of HLH. Mimicking an infection-driven model of sHLH in mice, we observed that the tissue-derived levels of IFNγ are actually 500- to 2000-fold higher than those measured in the blood. To identify a blood biomarker, we postulated that the IFNγ gene products, CXCL9 and CXCL10 would correlate with disease parameters in the mouse model. To translate this into a disease relevant biomarker, we investigated whether CXCL9 and CXCL10 levels correlated with disease activity in pediatric sHLH patients. Our data demonstrate that disease control in mice correlates with neutralization of IFNγ activity in tissues and that the 2 chemokines serve as serum biomarkers to reflect disease status. Importantly, CXCL9 and CXCL10 levels in pediatric sHLH were shown to correlate with key disease parameters and severity in these patients. Thus, the translatability of the IFNγ-biomarker correlates from mouse to human, advocating the use of serum CXCL9 or CXCL10 as a means to monitor total IFNγ activity in patients with sHLH. Buatois V, et al.At a Glance CommentaryBackgroundMouse models show that interferon γ (IFNγ) is central to the immune pathogenesis in hemophagocytic lymphohistiocytosis (HLH). The ubiquitous expression of the IFNγ receptor, however, results in the cytokine acting locally in tissues making its spillover into the blood for detection of a challenge. Identifying IFNγ signature biomarkers in blood reflecting disease in organs, therefore, is pivotal.Translational SignificanceUsing a mouse model mimicking infection-driven HLH, we identified IFNγ-driven chemokines, CXCL9 and CXCL10, as blood biomarkers of IFNγ activity in tissues. Levels of these chemokines correlated with disease parameters in mice and, importantly, to disease parameters and severity in pediatric patients with secondary HLH. Mouse models show that interferon γ (IFNγ) is central to the immune pathogenesis in hemophagocytic lymphohistiocytosis (HLH). The ubiquitous expression of the IFNγ receptor, however, results in the cytokine acting locally in tissues making its spillover into the blood for detection of a challenge. Identifying IFNγ signature biomarkers in blood reflecting disease in organs, therefore, is pivotal. Using a mouse model mimicking infection-driven HLH, we identified IFNγ-driven chemokines, CXCL9 and CXCL10, as blood biomarkers of IFNγ activity in tissues. Levels of these chemokines correlated with disease parameters in mice and, importantly, to disease parameters and severity in pediatric patients with secondary HLH.