The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo
- 15 August 2013
- journal article
- Published by American Society of Hematology in Blood
- Vol. 122 (7), 1192-1202
- https://doi.org/10.1182/blood-2013-03-484642
Abstract
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.Keywords
This publication has 34 references indexed in Scilit:
- JAK2 inhibitors for myelofibrosis: why are they effective in patients with and without JAK2V617F mutation?Anti-Cancer Agents in Medicinal Chemistry, 2012
- JAK Inhibition with Ruxolitinib versus Best Available Therapy for MyelofibrosisThe New England Journal of Medicine, 2012
- Cross-priming in health and diseaseNature Reviews Immunology, 2010
- Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasmsBlood, 2010
- Loss of Jak2 Selectively Suppresses DC-Mediated Innate Immune Response and Protects Mice from Lethal Dose of LPS-Induced Septic ShockPLOS ONE, 2010
- Role of JAK2 in the pathogenesis and therapy of myeloproliferative disordersNature Reviews Cancer, 2007
- JAK-STAT Signaling: From Interferons to CytokinesJournal of Biological Chemistry, 2007
- The V617F JAK2 mutation and the myeloproliferative disordersHematological Oncology, 2005
- Myelofibrosis with Myeloid MetaplasiaThe New England Journal of Medicine, 2000
- Immunobiology of Dendritic CellsAnnual Review of Immunology, 2000