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

Abstract

Key Points• The JAK-inhibitor ruxolitinib affects dendritic cell differentiation, phenotype, and function leading to impaired T-cell activation.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 CD81 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. (Blood. 2013; 122(7):1192-1202)

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

“…Ruxolitinib has remarkable antiinflammatory and immunomodulating activities, but the drug also affects DC differentiation and impairs T cell and NK cell activation. 48,49 The DC impairments might result in increased infection rates, while the NK cell dysfunction may impair the GVL effect. 50 Conversely, JAK inhibitors appear to reduce acute GVHD in murine models by increasing T-regulatory cells, which has led to the successful treatment of six patients with ruxolitinib for steroidrefractory acute GVHD.…”

JAK inhibitors: a home run for GVHD patients?

“…First, it has been shown that ruxolitinib also potently impairs APC functions. 4 It remains unclear whether reduction of GVHD is chiefly mediated by T-cell suppression, Treg generation, or APC inhibition. Furthermore, mechanisms of GVHD suppression in patients are unclear; clinical study focuses on treatment of steroid refractory GVHD, whereas the mouse study evaluates prevention of GVHD without steroids.…”

“…3 Earlier efforts to localize the organs making factor VIII showed that the liver of a normal dog transplanted into a dog with hemophilia corrected the bleeding tendency by elevating the dog's blood factor VIII level up to 50% of normal. 4 In the reverse experiment, a normal dog with a hemophilic liver still maintained a factor VIII level of 50%. Later, we found that a hepatocyte-rich cell fraction from human donor liver contained factor VIII messenger RNA and factor VIII antigen, 5 but there remained lingering doubt about the actual cell type involved.…”

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

“…Thus suppression of proinflammatory cytokines could potentially reduce disease severity. Moreover, although most conventional immunosuppressive agents target T-cell function, ruxolitinib was shown to impair differentiation, maturation, and cytokine production of dendritic cells (DCs), 10 which may further increase its efficacy in GVHD. Major T-cell activation events via type II cytokine receptors are mediated by JAK 1, 2, and 3 kinases (eg, JAK1 is required for responses to IFN-g and IL-6).…”