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

Abstract

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.

Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome

“…Furthermore, some of us demonstrated in the model of HLH secondary to infection induced by repeated TLR9 stimulation that total IFN-g levels produced in tissues are 500-to 2000-fold higher than those measured in blood and identified the spleen and liver as major sites of IFN-g production. 28 These results are consistent with our finding of a trend for increased circulating levels of IFN-g in our mice with MAS. Together, these observations in patients with MAS and in MAS animal models support the hypothesis that IFN-g production is markedly increased, that high IFN-g production is biologically relevant, and that overactivation of the IFN-g pathway appears to occur in peripheral tissues, which are typically involved by the disease, such as the liver and spleen.…”

“…These results are consistent with recent observations demonstrating that production of IFN-g typically occurs in peripheral tissues. 28 In this respect circulating levels of the IFN-g-inducible chemokines CXCL9 and CXCL10 have been suggested as possible markers of tissue IFN-g production. Indeed in LPS-challenged IL-6TG mice, high levels of CXCL9 and CXCL10 were found in plasma (Fig 2).…”

Muscle Expression of Type I and Type II Interferons Is Increased in Juvenile Dermatomyositis and Related to Clinical and Histologic Features

“…They also found that high serum IFNγ levels were correlated over time with decreased muscle strength in juvenile DM and adult DM patients, suggesting a correlation between IFNγ and muscle inflammation. It should be pointed out that measurement of blood levels of IFNγ may be unreliable and may not reflect tissue production as shown in other diseases in both animals and humans . Our data showed marked overproduction of IFNγ in the muscle and an association of IFNγ with disease severity at the time of biopsy.…”

Interleukin‐18: Biological properties and role in disease pathogenesis

“…184,187,190 Among them, IFNγ seems to play the important pathogenic role, since inhibition of IFNγ appears protective in most murine models. 184,187,191 It is not completely clear, however, since some models depend also on TNFα or other cytokines. 189,192,193 The role of IL-18 in HLH is likely due to its capacity to induce IFNγ and pro-inflammatory cytokines.…”

“…Several reports have found elevated IL-18 concentrations in the serum of patients with both primary and secondary HLH as well as in animal models and IL-18 correlated with the biological criteria and evolution of the disease. 56,184,187,191,194,195 Usually, the concentrations of IL-18 range from 0.6 to 3 ng/mL in HLH patients. There is the exception in two conditions, in which IL-18 concentrations are higher than 5 ng/mL, namely XLP type 2 due to XIAP mutations and sJIA/AOSD.…”