Details

Autor(en) / Beteiligte

• Heine, Annkristin
• Held, Stefanie Andrea Erika
• Daecke, Solveig Nora
• Wallner, Stephanie
• Yajnanarayana, Sowmya Parampalli
• Kurts, Christian
• Wolf, Dominik
• Brossart, Peter

Titel

The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo

Ist Teil von

• Blood, 2013-08, Vol.122 (7), p.1192-1202

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• The Janus kinase (JAK)–inhibitor ruxolitinib decreases constitutional symptoms and spleen size of myelofibrosis (MF) patients by mechanisms distinct from its anticlonal activity. Here we investigated whether ruxolitinib affects dendritic cell (DC) biology. The in vitro development of monocyte-derived DCs was almost completely blocked when the compound was added throughout the differentiation period. Furthermore, when applied solely during the final lipopolysaccharide-induced maturation step, ruxolitinib reduced DC activation as demonstrated by decreased interleukin-12 production and attenuated expression of activation markers. Ruxolitinib also impaired both in vitro and in vivo DC migration. Dysfunction of ruxolitinib-exposed DCs was further underlined by their impaired induction of allogeneic and antigen-specific T-cell responses. Ruxolitinib-treated mice immunized with ovalbumin (OVA)/CpG induced markedly reduced in vivo activation and proliferation of OVA-specific CD8+ T cells compared with vehicle-treated controls. Finally, using an adenoviral infection model, we show that ruxolitinib-exposed mice exhibit delayed adenoviral clearance. Our results demonstrate that ruxolitinib significantly affects DC differentiation and function leading to impaired T-cell activation. DC dysfunction may result in increased infection rates in ruxolitinib-treated patients. However, our findings may also explain the outstanding anti-inflammatory and immunomodulating activity of JAK inhibitors currently used in the treatment of MF and autoimmune diseases. •The JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.