Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice

<p>Abstract</p> <p>Background</p> <p>Knock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759).</p> <p>Methods</p> <p>We backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA.</p> <p>Results</p> <p>C57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-γ, IL-17, TNF-α, IL-9, and MIP-1β 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA.</p> <p>Conclusion</p> <p>The Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.</p

ARG098, a novel anti-human Fas antibody, suppresses synovial hyperplasia and prevents cartilage destruction in a severe combined immunodeficient-HuRAg mouse model

<p>Abstract</p> <p>Background</p> <p>The anti-human Fas/APO-1/CD95 (Fas) mouse/human chimeric monoclonal IgM antibody ARG098 (ARG098) targets the human Fas molecule. The cytotoxic effects of ARG098 on cells isolated from RA patients, on normal cells <it>in vitro</it>, and on RA synovial tissue and cartilage <it>in vivo </it>using implanted rheumatoid tissues in an SCID mouse model (SCID-HuRAg) were investigated to examine the potential of ARG098 as a therapy for RA.</p> <p>Methods</p> <p>ARG098 binding to each cell was analyzed by cytometry. The effects of ARG098 on several cells were assessed by a cell viability assay <it>in vitro</it>. Effects on the RA synovium, lymphocytes, and cartilage were assessed <it>in vivo </it>using the SCID-HuRAg mouse model.</p> <p>Results</p> <p>ARG098 bound to cell surface Fas molecules, and induced apoptosis in Fas-expressing RA synoviocytes and infiltrating lymphocytes in the RA synovium in a dose-dependent manner. However, ARG098 did not affect the cell viability of peripheral blood mononuclear cells of RA patients or normal chondrocytes. ARG098 also induced apoptosis in RA synoviocytes and infiltrating lymphocytes in the RA synovium <it>in vivo</it>. The destruction of cartilage due to synovial invasion was inhibited by ARG098 injection in the modified SCID-HuRAg mouse model.</p> <p>Conclusions</p> <p>ARG098 treatment suppressed RA synovial hyperplasia through the induction of apoptosis and prevented cartilage destruction <it>in vivo</it>. These results suggest that ARG098 might become a new therapy for RA.</p

Chronic cadmium treatment induces islet B cell injury in ovariectomized cynomolgus monkeys

In an attempt to establish a primate model of chronic cadmium (Cd) toxicosis, we ovariectomized cynomolgus monkeys and treated with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed an increase in blood glucose from Month 10 and a decrease in blood insulin at Month 11 of the Cd-treatment. Histopathological examination of the Cd-treated animals revealed islet atrophy with reduction in islet number and vacuolation of the islet cells, whereas there was no remarkable change in the acinar cells of the exocrine pancreas. In histomorphometrical examination, insulin-positive areas in the islets were significantly decreased, accompanying a relative increase of glucagon-positive areas. Large amounts of Cd accumulated in the pancreas, and metallothionein (MT), a Cd binding protein, was localized in the islets of Cd-treated animals. The present study demonstrated that the chronic intravenous injection of Cd to cynomolgus monkeys induced the accumulation of the metal in the pancreas, degeneration of islet B cells and the diabetic clinical signs. Therefore the islet B cell is one of the major targets of the chronic Cd poisoning in monkeys

Chemical proteasome inhibition as a novel animal model of inner retinal degeneration in rats.

Chemical proteasome inhibition has been a valuable animal model of neurodegeneration to uncover roles for the ubiquitin-proteasome system in the central nervous system. However, little is known about the effects of chemical proteasome inhibitors on retinal integrity. Therefore, we characterized the effects of structurally different chemical proteasome inhibitors on the retinal morphology and the mechanisms of their action in the normal adult rat eyes. Intravitreal injection of MG-262 and other proteasome inhibitors led to inner retinal degeneration. MG-262-induced inner retinal degeneration was accompanied by reduced proteasome activity, increased poly-ubiquitinated protein levels, and increased positive immunostaining of ubiquitin, 20S proteasome subunit and GADD153/CHOP in the retina. Its retinal degenerative effect was also associated with reduced retinal neurofilament light chain gene expression, reflecting retinal ganglion cell death. MG-262-induced neurofilament light chain downregulation was largely resistant to pharmacological modulation including endoplasmic reticulum stress, apoptosis or MAP kinase inhibitors. Thus, this study provides further evidence of roles for the ubiquitin-proteasome system in the maintenance of the retinal structural integrity. Chemical proteasome inhibition may be used as a novel animal model of inner retinal degeneration, including retinal ganglion cell loss, which warrants further analysis of the molecular mechanisms underlying its retinal degenerative effect

Whole-body counting of Fukushima residents after the TEPCO Fukushima Daiichi Nuclear Power Station accident

At the request of Fukushima Prefecture, the Japan Atomic Energy Agency (JAEA) started whole-body counting of residents on July 11, 2011 to assess radiation exposure after the TEPCO Fukushima Daiichi Nuclear Power Station accident. The JAEA has examined residents in Iitate, Kawamata, Namie, and 8 other local communities. The measurement capacity of the whole-body counting device is approximately 100 persons per day and the total number of people to measure reached 9,927 by the end of January 2012. Two types of whole body counters equipped with large-size NaI(Tl) detectors were used to perform the measurements. Routinely used phantoms (Canberra RMC-II transfer phantom or water-filled block phantom developed by JAEA) were used to perform peak efficiency calibration of the counters and the results of peak efficiency calibration were verified with different-sized bottle mannequin absorber (BOMAB) phantoms imitating an adult male, a 10-year-old and a 4-year-old. As the measurement started at 4 month after the accident, short half-life radionuclides such as 131I originating from the accident were not detected in this work. Approximately 80% of the residents had levels below the minimum detectable amount (MDA). No artificial nuclides other than 134Cs and 137Cs were found in the present whole-body counting. The maximum whole-body content of radiocesium (134Cs and 137Cs together) was 2.7 kBq for children 1 mSv, and the maximum CED was 3 mSv. The extrapolated 50th percentiles (medians) of the CED for 13-17 years old and those >17 years old were 0.02 mSv and 0.025 mSv, respectively. These values represent the basic knowledge for the reconstruction of internal exposure of the entire resident population

Direct measurements of employees involved in the Fukushima Daiichi nuclear power station accident for internal dose estimates: JAEA\u27s experiences

Japan Atomic Energy Agency (JAEA) performed internal dose measurements of employees involved in the Fukushima Daiichi nuclear power station accident. Nuclear Fuel Cycle Engineering Laboratories (NFCEL), one of the JAEA\u27s core centers, examined 560 of these employees by direct (in vivo) measurements during the period from April 20 to August 5 in 2011. These measurements consisted of whole-body counting for radiocesium and thyroid counting for radioiodine. The whole-body counting was conducted with two types of whole-body counters (WBCs): a standing-type WBC with two large NaI(Tl) detectors (FastscanTM, Canberra Inc.) and a chair-type WBC with HPGe detectors (GC5021, Canberra Inc.) installed in a shielded chamber made of 20-cm-thick steel. The thyroid counting was mainly performed using one of the two HPGe detectors equipped with the chair-type WBC. The subjects examined in this work were divided into two groups: Group 1 was the first 39 subjects who were measured up to June 17, 2011 and Group 2 was the remaining 521 subjects who were measured on and after June 18, 2011. We validated the performance of our direct measurements by comparing measurement results of the Group 1 subjects using two different methods (e.g., the standing-type WBC vs. the chair-type WBC). Tentative internal dose estimates of the subjects of Group 1 were also performed based on the assumption of a single intake scenario on either March 12, when the first hydrogen explosion occurred at the station or the first day of work after the accident. It was found that the contribution of 131I to the total internal dose greatly exceeded those of 134Cs and 137Cs, the other major nuclides detected in the measurements. The maximum committed effective dose (CED) was found in a male subject whose thyroid content of 131I was 9760 Bq on May 23, 2011; the CED of this subject was estimated to be 600 mSv including a small contribution of 134Cs and 137Cs. The typical minimum detectable activity for 131I in the present thyroid counting was 10 Bq for a counting time of 10 min, making it difficult to identify a residual thyroid content corresponding to a CED of 20 mSv for the subjects of Group 2

Results of whole body counting for JAEA staff members engaged in the emergency radiological monitoring for the Fukushima nuclear disaster

A massive earthquake and tsunami on March 11, 2011, resulted in the release of an enormous amount of radioactive materials into the environment. On the day after the earthquake the Japan Atomic Energy Agency (JAEA) began emergency radiological monitoring. Measurements with a whole body counter (WBC) for the staff members who had returned from Fukushima began at the end of March because a power blackout for several days and lingering increased ambient radiation levels had rendered the WBCs inoperable. The measured activity level for I-131 due to inhalation for emergency staff varied from below detection limit to 7 kBq, which corresponds to an estimated initial intake range of <1 to 60 kBq when extrapolated back to the date the staff began the monitoring in Fukushima. The measured activity levels for Cs-134 and Cs-137 were both in the ranges from below detection limit to 3 kBq. When using the median values for each set of measurements, the ratio of the initial intake of I-131 to Cs-137 was 11. The maximum committed effective dose of 0.8 mSv was recorded for a member of the 4th monitoring team dispatched from March 15 to 20