No abstract

Although the introduction of tumor necrosis factor (TNF) inhibitors represented a significant advance in the treatment of rheumatoid arthritis (RA), traditional anti-TNFα antibodies are somewhat immunogenic, and their use results in the formation of anti-drug antibodies (ADAs) and loss of efficacy (secondary failure). Ozoralizumab is a trivalent, bispecific NANOBODY® compound that differs structurally from IgGs. In this study we investigated the suppressant effect of ozoralizumab and adalimumab, an anti-TNFα IgG, on arthritis and induction of ADAs in human TNF transgenic mice. Ozoralizumab markedly suppressed arthritis progression and did not induce ADAs during long-term administration. We also developed an animal model of secondary failure by repeatedly administering adalimumab and found that switching from adalimumab to ozoralizumab was followed by superior anti-arthritis efficacy in the secondary-failure animal model. Moreover, ozoralizumab did not form large immune complexes that might lead to ADA formation. The results of our studies suggest that ozoralizumab, which exhibited low immunogenicity in the animal model used and has a different antibody structure from that of IgGs, is a promising candidate for the treatment of RA patients not only at the onset of RA but also during secondary failure of anti-TNFα treatment.

No abstract

The present study assesses the detectability of perfusion defect and the influence of breathhold on pulmonary magnetic resonance (MR) perfusion imaging using contrastenhanced thick-slice two-dimensional (2D) fast gradientecho sequence compared with three-dimensional (3D) fast spoiled gradient-recalled sequence. Dynamic studies were performed in 16 patients. MR perfusion images were interpreted by two independent observers using perfusion scintigraphy as the reference standard. The patients were divided into two groups according to the duration of holding the breath measured during MR imaging. The sensitivity and specificity of 2D MR perfusion imaging in detecting perfusion defects were 93% and 94%, respectively, while those of 3D MR perfusion imaging were 89% and 85%, respectively. The diagnostic accuracy of 2D MR perfusion imaging was significantly higher than that of 3D MR perfusion imaging (P < 0. Index terms: lung; magnetic resonance; perfusion; scintigraphy; breath-hold WITH RECENT ADVANCEMENTS in fast magnetic resonance (MR) imaging techniques, pulmonary MR perfusion imaging has become useful in the evaluation of lung disease, such as pulmonary embolism (1-4). The method originally proposed by Hatabu et al (5) consists of an intravenous bolus injection of a gadolinium-based contrast agent in conjunction with a gradient-echo pulse sequence with a very short echo time (TE). Under these conditions, pulmonary perfusion images can be obtained within a matter of seconds. To cover the whole lung, however, sequential two-dimensional (2D) or three-dimensional (3D) data sampling with breathhold has been generally used (1-4,6). One downside of these procedures is that data acquisition periods of about 5 seconds are required for appropriate spatial resolution. Therefore, the quality of images from patients who cannot hold their breath is degraded by respiratory motion.Contrast-enhanced time-resolved thick-slice 2D MR pulmonary angiography has been proposed (7-9). Like conventional digital subtraction angiography (DSA), 2D MR angiography allows dilution of the bolus in the vascular system during passage to be observed at a temporal resolution considerably below 1 second. This avoids the need for exact timing of the administration of the contrast agent bolus. In addition, enhanced pulmonary parenchyma can also be visualized by using this technique; so dynamic pulmonary perfusion images can also be simultaneously obtained with pulmonary MR angiography. However, the clinical utility of pulmonary MR perfusion imaging using contrast-enhanced thick-slice 2D fast gradient-echo (FGRE) sequence evidently remains unexplored. The feasibility of this technique for patients who cannot hold their breath also requires verification.The present study assesses the accuracy and potential of pulmonary MR perfusion imaging using contrastenhanced thick-slice 2D FGRE sequence compared with the 3D fast spoiled gradient-recalled (FSPGR) sequence in the evaluation of patients with a suspected pulmonary perfusion defect. To determine whether thi...

Osteoclasts are multinucleated cells responsible for bone resorption. The differentiation of osteoclasts from bone marrow macrophages (BMMs) is induced by receptor activator of NF-κB ligand (RANKL). Osteoprotegerin (OPG), a decoy receptor of RANKL, inhibits osteoclastogenesis by blocking RANKL signaling. Here we investigated the degradation of OPG in vitro. Osteoclasts, but not BMMs, secreted OPG-degrading enzymes. Using mass spectrometry and RNA-sequencing analysis, we identified high-temperature requirement A serine peptidase 1 (HtrA1) as an OPG-degrading enzyme. HtrA1 did not degrade OPG pre-reduced by dithiothreitol, suggesting that HtrA1 recognizes the three-dimensional structure of OPG. HtrA1 initially cleaved the amide bond between leucine 90 and glutamine 91 of OPG, then degraded OPG into small fragments. Inhibitory activity of OPG on RANKL-induced osteoclastogenesis was suppressed by adding HtrA1 in RAW 264.7 cell cultures. These results suggest that osteoclasts potentially prepare a microenvironment suitable for osteoclastogenesis. HtrA1 may be a novel drug target for osteoporosis.