Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T-cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis

Faguer, Stanislas; Vergez, François; Pérès, Michaël; Ferrandiz, Inès; Casemayou, Audrey; Béllière, Julie; Cointault, Olivier; Lavayssière, Laurence; Nogier, Marie-Béatrice; Prévôt, Grégoire; Huart, Antoine; Récher, Christian; Rostaing, Lionel

doi:10.1002/hon.2174

Cited by 19 publications

(14 citation statements)

References 11 publications

(12 reference statements)

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“…In both murine models, ruxolitinib significantly diminished the levels of TNF-a and IL-6, cytokines that serve as alternative therapeutic targets for patients with HLH. 5,[45][46][47] IFN-g induces TNF-a production by myeloid cells, 48,49 so the reduction in serum TNF-a levels might be partially explained by ruxolitinibmediated inhibition of IFN-g signaling. Ruxolitinib also lowered the serum levels of G-CSF, a cytokine elevated in the primary HLH model.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Albeituni¹,

Verbist²,

Tedrick³

et al. 2019

Blood

116

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Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-γ (IFN-γ). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1−/−) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-γ, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-γ signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-γ–neutralizing antibody (αIFN-γ) in 2 murine HLH models. In both models, ruxolitinib and αIFN-γ reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-γ–dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-γ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1−/− mice exhibited enhanced survival compared with mice in which αIFN-γ was discontinued. This protective effect could be mimicked by transient treatment with αIFN-γ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-γ–dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Albeituni¹,

Verbist²,

Tedrick³

et al. 2019

Blood

116

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“…16,21 As 1 example for the latter, plasma exchange in conjunction with IVIG or CS has shown to be effective in reactive childhood HLH 29 and been incorporated upfront into algorithms of care for these patients. 14 Also, the era of biologics and small molecules has, in addition to anakinra, produced an armory of promising agents currently being investigated for the treatment of all forms of HLH (eg, ruxolitinib 30,31 —NCT02400463, tocilizumab 32,33 —NCT02007239, emapalumab 34 —NCT01818492). Concerns about the use of etoposide in reactive HLH mainly address limited efficacy and toxicity in patients with extensive organ dysfunction 28,35 or infection control in those with sepsis–HLH overlap.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis

Wohlfarth

Agis

Gualdoni

et al. 2017

J Intensive Care Med

103

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“…Tocilizumab, a monoclonal antibody targeting the receptor of IL6, fully reverses the multi-organ failure and the cytokine profile of the CAR-T cell-induced cytokinerelease syndrome [3]. This prompted some groups including ours to treat severe HLH secondary to acute autoimmune disease with tocilizumab [4]. Targeting one of the major cytokines that orchestrate the cytokine storm may be an alternative to etoposide in patients with HLH not related to hematological malignancies.…”

Section: Il6-r Blocking With Tocilizumab In Critically Ill Patients Wmentioning

confidence: 99%

IL6-R blocking with tocilizumab in critically ill patients with hemophagocytic syndrome

et al. 2020

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Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T-cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis

Cited by 19 publications

References 11 publications

Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis

IL6-R blocking with tocilizumab in critically ill patients with hemophagocytic syndrome

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