title: 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.
authors: Novimmune S.A., Plan-les-Ouates, Switzerland. Electronic address: vbuatois@novimmune.com.
authors: Vanessa
authors: V
authors: Buatois
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Laurence
authors: L
authors: Chatel
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Laura
authors: L
authors: Cons
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Sabrina
authors: S
authors: Lory
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Françoise
authors: F
authors: Richard
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Florence
authors: F
authors: Guilhot
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Zoë
authors: Z
authors: Johnson
authors: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors: Claudia
authors: C
authors: Bracaglia
authors: Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors: Fabrizio
authors: F
authors: De Benedetti
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Cristina
authors: C
authors: de Min
authors: Novimmune S.A., Plan-les-Ouates, Switzerland.
authors: Marie H
authors: MH
authors: Kosco-Vilbois
authors: Novimmune S.A., Plan-les-Ouates, Switzerland. Electronic address: wferlin@novimmune.com.
authors: Walter G
authors: WG
authors: Ferlin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood; D054370:Chemokine CXCL9 / Q000097:blood; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000097:blood* / Q000473:pathology; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D013577:Syndrome
chemical_list: D015415:Biomarkers; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D009838:Oligodeoxyribonucleotides; D007371:Interferon-gamma