Bevacizumab(Avastin®), a humanized therapeutic monoclonal antibody that targets vascular endothelial growth factor, is widely used in cancer treatment. Patients who are treated with bevacizumab have an increased risk of developing systemic hypertension. However, the relationship between bevacizumab‐induced hypertension and clinical outcome remains unclear. We aimed to evaluate the effect of bevacizumab‐induced hypertension in terms of prognosis in patients with colorectal cancer and non‐small cell lung cancer. The study included 632 patients, 317 patients with non‐small cell lung cancer and 315 patients with colorectal cancer. All patients were treated with bevacizumab in combination with standard chemotherapy protocols, between April 2007 and December 2014. Blood pressure was measured before each treatment cycle. In the patient group with colorectal cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 27.6%. In hypertensive patients with colorectal cancer, median overall survival was 42.6 months, compared with 20.6 months for normotensive patients in this group (P = 0.00071). In the patient group with non‐small cell lung cancer, treated with bevacizumab, Grade 2–3 hypertension was present in 20.5%. In hypertensive patients with non‐small cell lung cancer, median overall survival was 43.0 months, compared with 26.3 months for normotensive patients in this group (P = 0.00451). Patients who developed hypertension during treatment with bevacizumab for colorectal cancer and non‐small cell lung cancer had significantly prolonged overall survival when compared with normotensive patients. Bevacizumab‐induced hypertension may represent a biomarker for clinical benefit in cancer patients treated with bevacizumab.

Atopic dermatitis is a major allergic disease that develops through dysregulation of Th2-mediated inflammation. Although dendritic cells (DCs) have been thought to play a critical role in the upstream phase of the allergic cascade, conventional drugs such as steroids and chemical mediator antagonists target the effector cells or factors in allergic inflammation. Recently, it has been demonstrated that interaction between thymic stromal lymphopoietin (TSLP) and human DCs plays an essential role in evoking inflammatory Th2 responses in allergy through OX40 ligand expression on DCs. In this study, we provide evidence that R848, an imidazoquinoline compound, which is a TLR ligand and a strong Th1 response-inducing reagent, is a potent adjuvant for the alteration of the Th2-inducing potency of human DCs activated by TSLP (TSLP-DCs). R848 inhibited the inflammatory Th2-inducing capacity of TSLP-DCs and redirected them to possessing an IL-10 and IFN-γ-producing regulatory Th1-inducing capacity. This functional alteration depended on both repression of OX40 ligand expression and induction of IL-12 production from DCs by the addition of R848. Additionally, R848 had the ability to inhibit the TSLP-mediated expansion and maintenance of the Th2 memory response. These findings suggest that imidazoquinoline may be a useful in the treatment of allergic diseases that are triggered by TSLP.

SummaryWe have demonstrated previously that, in primary Sjögren's syndrome (SS), immature myeloid dendritic cells (DCs) are decreased in blood and mature myeloid DCs are accumulated in salivary glands, suggesting recruitment of the myeloid DCs from blood to salivary glands. To verify whether this finding is universal in patients of not only primary SS but also secondary SS, in this study we analysed the blood DCs of secondary SS patients. We examined 24 secondary SS and 29 primary SS patients. A direct correlation between the decreased number of myeloid DCs and the duration of Sicca syndrome in primary and secondary SS was observed; namely, the reduction of myeloid DCs in blood was restored spontaneously with duration time of Sicca syndrome. We also examined the immunohistochemical staining of salivary glands of SS patients with monoclonal antibodies against fascin, CD11c and human leucocyte antigen DR (HLA-DR). Fascin + or CD11c + /HLA-DR + mononuclear cells were present in the salivary glands of secondary SS patients, as in primary SS. However, fascin + mononuclear cells were barely detected in the salivary glands of a chronic phase of SS patients. We also found a negative correlation between the frequency of blood myeloid DCs and salivary glandinfiltrating DCs in secondary SS patients, as well as primary SS. Our results suggest that the reduction of blood myeloid DCs and preferential trafficking of myeloid DCs into salivary glands is a common event in the early stage of SS. Myeloid DCs may play essential roles in the pathogenesis of Sicca syndrome of SS by initiating T helper cell immune responses.

IntroductionPlasmacytoid dendritic cells (pDCs) play not only a central role in the antiviral immune response in innate host defense, but also a pathogenic role in the development of the autoimmune process by their ability to produce robust amounts of type I interferons (IFNs), through sensing nucleic acids by toll-like receptor (TLR) 7 and 9. Thus, control of dysregulated pDC activation and type I IFN production provide an alternative treatment strategy for autoimmune diseases in which type I IFNs are elevated, such as systemic lupus erythematosus (SLE). Here we focused on IκB kinase inhibitor BAY 11-7082 (BAY11) and investigated its immunomodulatory effects in targeting the IFN response on pDCs.MethodsWe isolated human blood pDCs by flow cytometry and examined the function of BAY11 on pDCs in response to TLR ligands, with regards to pDC activation, such as IFN-α production and nuclear translocation of interferon regulatory factor 7 (IRF7) in vitro. Additionally, we cultured healthy peripheral blood mononuclear cells (PBMCs) with serum from SLE patients in the presence or absence of BAY11, and then examined the inhibitory function of BAY11 on SLE serum-induced IFN-α production. We also examined its inhibitory effect in vivo using mice pretreated with BAY11 intraperitonealy, followed by intravenous injection of TLR7 ligand poly U.ResultsHere we identified that BAY11 has the ability to inhibit nuclear translocation of IRF7 and IFN-α production in human pDCs. BAY11, although showing the ability to also interfere with tumor necrosis factor (TNF)-α production, more strongly inhibited IFN-α production than TNF-α production by pDCs, in response to TLR ligands. We also found that BAY11 inhibited both in vitro IFN-α production by human PBMCs induced by the SLE serum and the in vivo serum IFN-α level induced by injecting mice with poly U.ConclusionsThese findings suggest that BAY11 has the therapeutic potential to attenuate the IFN environment by regulating pDC function and provide a novel foundation for the development of an effective immunotherapeutic strategy against autoimmune disorders such as SLE.

Summary Dendritic cells (DCs) are initiators of innate immunity and acquired immunity as cells linking these two bio‐defence systems through the production of cytokines such as interferon‐α (IFN‐α) and interleukin‐12 (IL‐12). Nucleic acids such as DNA from damaged cells or pathogens are important activators not only for anti‐microbial innate immune responses but also in the pathogenesis of IFN‐related autoimmune diseases. Plasmacytoid DCs are regarded as the main effectors for the DNA‐mediated innate immunity by possessing DNA‐sensing toll‐like receptor 9 (TLR9). We here found that double‐stranded DNA (dsDNA) complexed with lipotransfectants triggered activation of human monocyte‐derived DCs (moDCs), leading to the preferential production of IFN‐α but not IL‐12. This indicates that myeloid DCs also function as supportive effectors against the invasion of pathogenic microbes through the DNA‐mediated activation in innate immunity. The dsDNA with lipotransfectants can be taken up by moDCs without co‐localization of endosomal LAMP1 staining, and the dsDNA‐mediated IFN‐α production was not impaired by chloroquine. These findings indicate that moDC activation by dsDNA does not involve the endosomal TLR pathway. In contrast, single‐stranded RNA (ssRNA) stimulated moDCs to secrete IL‐12 but not IFN‐α. This process was inhibited by chloroquine, suggesting an involvement of the TLR pathway in ssRNA‐mediated moDC activation. As might be inferred from our findings, myeloid DCs may function as a traffic control between innate immunity via IFN‐α production and acquired immunity via IL‐12 production, depending on the type of nucleic acids. Our results provide a new insight into the biological action of myeloid DCs underlying the DNA‐mediated activation of protective or pathogenic immunity.