Pacritinib protects dendritic cells more efficiently than ruxolitinib.

Targeting Janus kinase (JAK) has revolutionized the treatment of myeloproliferative neoplasms. The JAK inhibitor ruxolitinib has improved the outcome and quality of life of patients dramatically at the cost of increased risk of infections. As previously reported, ruxolitinib severely impairs the differentiation of peripheral blood mononuclear cells to monocyte-derived dendritic cells and inhibits the function of dendritic cells in vitro and in vivo, which expanded its use as an immunomodulatory compound. Pacritinib is a novel JAK inhibitor that will soon be approved for the treatment of myeloproliferative neoplasms, and early results are promising. We investigated the impact of the novel JAK inhibitor pacritinib on the function of monocyte-derived dendritic cells and compared it with that of ruxolitinib. In contrast to ruxolitinib, pacritinib exhibits only mild suppressive effects on dendritic cells. The upregulation of activation markers and CCR7 after TLR4 ligation is not or is only marginally affected by pacritinib. Pacritinib, at concentrations reflecting patients' plasma levels, reduces interleukin (IL)-12 secretion, whereas IL-6 and tumor necrosis factor α levels are unchanged at this concentration. In conclusion, the immunosuppressive effect of pacritinib on dendritic cells is significantly less pronounced than the effect of ruxolitinib. Therefore, our data may help to identify those patients with myelofibrosis who may benefit from pacritinib treatment.

The PI3Kδ inhibitor idelalisib impairs the function of human dendritic cells.

The PI3Kδ-inhibitor Idelalisib is approved for the treatment of Non-Hodgkin lymphoma. However, its use has been decreased within the last years due to deleterious infections such as cytomegalovirus and pneumocystis jirovecii. Here, we have investigated the effect of Idelalisib on human monocyte-derived dendritic cells (DCs) as important players in the induction of immune responses. We found that Idelalisib-treated DCs displayed impaired T cell stimulatory function. PI3Kδ inhibition during differentiation resulted in decreased Interleukin-12, Interleukin-13 and TNFα production by DCs after lipopolysaccharide stimulation. Moreover, DCs showed decreased expression of the activation marker CD83 after Idelalisib treatment. Further, in line with this was the failure of Idelalisib-treated DCs to properly induce allogeneic T cells in a dose-dependent manner. Finally, activation of the NFκB pathway was also ablated in Idelalisib-treated DCs. Our results implicate that severe infectious complications may not only result from direct PI3Kδ-inhibition in T cells, but also from impaired DC function in Idelalisib-treated patients. Here, we provide new insight into the pathogenesis of Idelalisib-associated infectious complications. Our study may further provide a rationale for the use of Idelalisib as a novel therapeutic option in inflammatory diseases.

Critical role of nucleotide-binding oligomerization domain-like receptor 3 in vascular repair.

Vascular remodeling characterized by hyperproliferative neointima formation is an unfavorable repair process that is triggered by vascular damage. This process is characterized by an increased local inflammatory and proliferative response that critically involves the pro-inflammatory cytokine interleukin-1ß (IL-1ß). IL-1ß is expressed and cytosolically retained as a procytokine that requires additional processing prior to exerting its pro-inflammatory function. Maturation and release of pro IL-1ß is governed by a cytosolic protein scaffold that is known as the inflammasome. Here we show that NLRP3 (NOD-like receptor family, pryin domain containing 3), an important activating component of the inflammasome, is involved in neointima formation after vascular injury. NLRP3 deficiency itself does not affect the functional cardiovascular phenotype and does not alter peripheral differential blood counts. However, neointima development following wire injury of the carotid artery was significantly decreased in NLRP3-deficient mice as compared to wild-type controls. In all, NLRP3 plays a non-redundant role in vascular damage mediated neointima formation. Our data establish NLRP3 as a key player in the response to vascular damage, which could open new avenues to therapeutic intervention.