Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies to various cellular components. Although many of therapies have shown great efficacy, they often associate with adverse effects. The development of safer therapies for SLE has led to recent emphasis on targeting selected pathways that can be important in the inflammatory process in SLE. The cytokine family of type I interferons (IFNs), and especially the IFNα subtypes, are implicated in pathogenesis of SLE. Genetic polymorphisms of several components of the IFN signaling pathway have been associated with an increased risk of SLE. Therefore, IFNα subtypes have been identified as a potential target for drug development in SLE. There have been developed three agents, IFNα-targeted therapy, Sifalimumab, Rontalizumab and NNC 0152-0000-0001. They are anti-IFNα monoclonal antibodies that bind to and specifically neutralizes most IFNα subtypes, preventing signaling through the type I IFN receptor. The safety and dose-proportional pharmacokinetics of those agents were demonstrated. A larger study is currently ongoing, further safety profile will be evaluated. This review provides an update on the ongoing clinical trials of anti-IFNα therapy and the promise and obstacles in the use of biologics in SLE.

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  Chemokines are a group of structurally related secretory and transmembrane proteins whose major tasks are to coordinately recruit various leukocyte populations into target tissue sites via specific receptors. In humans, there are close to 50 chemokines, 18 signal transducing receptors and 5 decoy/scavenger receptors. Functionally, chemokines are grouped into two major categories. Inflammatory chemokines are those attracting and activating cells such as neutrophils, monocytes, and eosinophils, and thus play major roles in acute-type inflammatory conditions. They are characterized by high ligand redundancy and receptor promiscuity. This probably enables robust recruitment of inflammatory cells in acute conditions. On the other hand, immune chemokines are those mainly attracting lymphoid cells and dendritic cells, and are thus involved in immune responses and chronic inflammatory diseases. Furthermore, their ligand-receptor relationships are relatively monogamous. Chemokine receptors are all seven-transmembrane G protein-couple receptors, the class of receptors frequently targeted by many successful drugs. Thus, chemokine receptors are considered to be highly promising drug targets for inflammatory and immunological diseases, and for the last two decades, many pharmaceutical companies have been trying to develop drugs blocking specific chemokine receptors. However, there are only few instances that have reached the approval for clinical use. There are several possible reasons for the present stalemate. For example, the intrinsic functional redundancy in the chemokine system may have made blocking a single receptor useless. Furthermore, the unprecedented species differences even between humans and mice may have caused problems in determination of clinical application of each chemokine receptor blockade from animal studies and also in conducting preclinical studies of candidate drugs in animals. Thus, the potential of the chemokine system as drug targets may still remain underexplored. This review first overviews current potential clinical applications of individual chemokine receptors and then describes in detail the drugs now in clinical use : Maraviroc (CCR5 antagonist), Plerixafor (CXCR4 antagonist), and Mogamulizmab (anti-CCR4).

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  Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

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  T helper (Th) cells are known to differentiate into several distinct subsets depending on their environment. The Interleukin 17 (IL-17)-producing subset Th17, which was reported and named in 2005, has been extensively analyzed because a strong association with inflammatory disorders has been suggested. The condition in which Th17 cells are differentiated, critical transcription factors, and similarity and difference between mouse and human Th17 cells have been reported one after the other. IL-23, which is believed to be important for the activation of Th17 cells, and IL-17 became promising targets for drug development. In fact, biological drugs that block the IL-23/IL-17 axis have demonstrated to be highly effective against the inflammatory skin disease psoriasis and have been approved for clinical use. Here an overview and brief history of the basic research on Th17 cells are provided, with the latter full of surprises and unexpected twists in the plot. The current state of biological drug development is also described.

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  Fifteen years have passed since discovery of RANKL (receptor activator of NF-κB ligand), resulting in identification of the mechanisms regulating osteoclast differentiation and function. The discovery of RANKL contributed to development of a fully human anti-RANKL monoclonal neutralizing antibody (denosumab). Denosumab has been clinically available for treatment of osteoporosis and cancer-induced bone diseases in the US, Europe and many countries since 2010. In Japan denosumab has been clinically available for treatment of cancer-induced bone diseases since 2012 and it was approved for the treatment of osteoporosis in March 2013. Because RANKL is the absolute factor for osteoclast differentiation, anti-RANKL antibody is very effective and its application is good news for many patients. In this review I described the mechanisms regulating osteoclast differentiation and the strong increase of bone mass in normal mice with anti-mouse RANKL antibody. The single injection of the antibody markedly reduced the number of osteoclasts, inhibited bone resorption, and increased bone mass within several days.

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  BACKGROUND : Most patients with eosinophilic granulomatosis with polyangiitis (EGPA ; Churg-Strauss syndrome) suffer from peripheral neuropathy. The neuropathy affects ADLs in not only the active stage, but also the remission stage of EGPA. Recently, high-dose intravenous immunoglobulin therapy (IVIg) is known to be effective for peripheral neuropathy in the active stage of EGPA. However, the effect of IVIG for peripheral neuropathy in the remission stage remains obscure. OBJECTIVE : This study assessed the efficacy of high-dose IVIg for peripheral neuropathy in the remission stage of EGPA. PATIENTS & METHODS : Six patients with peripheral neuropathy (duration : 3 months~7 years) in the remission stage of EGPA were investigated. IVIg was performed with an immunoglobulin dose of 400 mg/kg daily (intravenous drip) for 5 days. Neuropathy was evaluated with the manual muscle strength test (MMT) and the visual analogue scale (VAS). RESULTS : MMT improved in 4 of 7 patients (57.1%). MMT score increased 10.0±7.2 after IVIG. VAS (Numbness and neuralgia) improved in 6 of 7 patients (85.7%). Average VAS improved in the range of 46 mm to 61 mm. Side effect was detected in one patient (headache) only even though all patients underwent this therapy. CONCLUSION : These results suggested that IVIg therapy was safe and effective in patients with persistent peripheral neuropathy even in the remission stage of EGPA.

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  Chédiak-Higashi syndrome (CHS) is one of the primary immunodeficiency syndromes accompanied by oculocutaneous albinism. It is characterized by existence of giant granule of neutrophils, and development of symptoms of hemophagocytic lymphohistiocytosis. CHS is a rare disorder and recognition of the disease is indispensable for its diagnosis. In our case, a four-month-old boy, virus-associated hemophagocytic syndrome (VAHS) was suspected from generation of fever, hepatosplenomegaly, and existence of atypical lymphocytes on admission. However, elevation of serum AST, LDH and ferritin were quite slight as VAHS, and rapid exacerbation of the findings was not seen. Associated virus was undetected. He was finally diagnosed as CHS developing hemophagocyctic lymphohistiocytosis based on the existence of a giant granule of neutrophils in the peripheral blood smear and oculocutaneous albisum and laboratory findings. Clinical outcome was successful after receiving HLA-matched unrelated bone marrow transplantation.

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