Blockade of the CD40–CD154 costimulatory signal is an attractive strategy for immunosuppression and tolerance induction in organ transplantation. Treatment with anti‐CD154 monoclonal antibodies ...(mAbs) results in potent immunosuppression in nonhuman primates (NHPs). Despite plans for future clinical use, further development of these treatments was halted by complications. As an alternative approach, we have been focusing on the inhibition of the counter receptor, CD40 and have shown that a novel human anti‐CD40 mAb, ASKP1240, markedly prolongs renal allograft survival in NHPs, although allografts eventually underwent chronic allograft nephropathy. On the basis of our previous findings that a CD40–CD154 costimulation blockade induces tolerance to hepatic, but not cardiac, allografts in rodents, we tested here our hypothesis that a blockade of CD40 by ASKP1240 allows acceptance of hepatic allografts in NHPs. A 2‐week ASKP1240 induction treatment prolonged liver allograft survival in NHPs; however, the graft function deteriorated due to chronic rejection. In contrast, a 6‐month ASKP1240 maintenance monotherapy efficiently suppressed both cellular and humoral alloimmune responses and prevented rejection on the hepatic allograft. No serious side effects, including thromboembolic complications, were noted in the ASKP1240‐treated monkeys. We conclude that CD40 blockade by ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
The authors find that the blockade of CD40 by ASKP1240 ameliorated cellular and humoral alloimmune responses and prevented rejection on hepatic allograft in nonhuman primates, and conclude that ASKP1240 would be a desirable immunosuppressant for clinical liver transplantation.
A strategy for inhibiting CD40 has been considered as an alternative approach for immunosuppression because of undesirable effects of anti‐CD154 monoclonal antibodies (mAbs). Previously, we ...demonstrated that ASKP1240, which is a fully human anti‐CD40 mAb, significantly prolonged kidney and liver allograft survival in cynomolgus monkeys without causing thromboembolic complications. Herein, we evaluated the effect of ASKP1240 on pancreatic islet transplantation (PITx) in cynomolgus monkeys. Diabetes was induced by total pancreatectomy, and islet allografts were transplanted into the liver. Following PITx (8201–12 438 IEQ/kg), blood glucose levels normalized promptly in all animals. Control islet allografts were rejected within 9 days (n = 3), whereas ASKP1240 (10 mg/kg) given on postoperative days 0, 4, 7, 11 and 14 (induction treatment, n = 5) significantly prolonged graft survival time (GST) to >15, >23, 210, 250 and >608 days, respectively. When ASKP1240 (5 mg/kg) was administered weekly thereafter up to post‐PITx 6 months (maintenance treatment, n = 4), GST was markedly prolonged to >96, >115, 523 and >607 days. During the ASKP1240 treatment period, both anti‐donor cellular responses and development of anti‐donor antibodies were abolished, and no serious adverse events were noted. ASKP1240 appears to be a promising candidate for immunosuppression in clinical PITx.
The authors find that the blockade of CD40 by ASKP1240 suppresses cellular and humoral alloimmune responses, prolongs pancreatic islet allograft survival in nonhuman primates, and might be a promising approach for immunosuppression in clinical pancreatic islet transplantation.
We studied the electrical resistance and crystal structure of epitaxial chromium (Cr) films. The lattice constant of the Cr films was larger than that of the bulk Cr because of MgO substrate on which ...Cr was epitaxially deposited. A chromium oxide layer having a thickness of 1 nm was found on all films from the result of X-ray reflectivity measurements. The electrical resistivity ρ(T) shows metallic behavior for all epitaxial Cr films in contrast with polycrystalline one. However, the magnitude of ρ tends to increase and the antiferromagnetic interaction is suppressed as decreasing thickness of film.
Methylglyoxal (MG) is a typical 2-oxoaldehyde derived from glycolysis, although it inhibits the growth of cells in all types of organism. Hence, it has been questioned why such a toxic metabolite is ...synthesized via the ubiquitous energy-generating pathway. We have previously reported that expression of GLO1, coding for the major enzyme detoxifying MG, was induced by osmotic stress in a high osmolarity glycerol (HOG)-mitogen-activated protein (MAP) kinase-dependent manner in Saccharomyces cerevisiae. Here we show that MG activates the HOG-MAP kinase cascade. Two osmosensors, Sln1 and Sho1, have been identified to function upstream of the HOG-MAP kinase cascade, and we reveal that MG initiates the signal transduction to this MAP kinase cascade through the Sln1 branch. We also demonstrate that MG activates the Msn2 transcription factor. Moreover, MG activated the uptake of Ca2+ in yeast cells, thereby stimulating the calcineurin/Crz1-mediated Ca2+ signaling pathway. We propose that MG functions as a signal initiator in yeast.
Blocking the CD40–CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti‐CD154 ...mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti‐CD40 mAb ASKP1240, as an alternative to anti‐CD154 mAb. In vitro ASKP1240 concentration‐dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti‐human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed‐type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.
In a nonclinical in vitro and in vivo study, the authors demonstrate that a CD40‐specific antibody, ASKP1240, suppresses both cellular and humoral immunity without evidence of prothrombotic changes, drug‐specific antibody emergence, or depletion of CD40+ cells.
A superconducting dipole magnet for a large-acceptance spectrometer named SAMURAI has been constructed and installed at the RIKEN RI Beam Factory. The important features of the SAMURAI ...superconducting dipole magnet are a large pole gap, a wide horizontal opening, and a large momentum bite. The magnet is an H-type dipole, having circular superconducting coils and cylindrical pole pieces with a diameter of 2 m and a pole gap of 880 mm. The coils are orderly wound by the wet winding method developed by Toshiba using a Nb/Ti superconducting wire. The upper and lower coils are installed in two separate cryostats and cooled by the liquid helium bath cooling method. Each cryostat has six cryocoolers: one for a coil vessel at 4 K, four for thermal shields, and one for high- T C superconducting power leads. The size of the iron yoke is 6.7 m wide, 3.5 m deep, 4.64 m tall, and the total weight of the magnet is about 650 tons. The maximum magnetic field is 3.08 T at 563 A (1.922 MA turns/coil), which gives a bending power (field integral) of 7.05 Tm. The maximum stored energy amounts to 27.4 MJ and the inductance varies from 396 H to 150 H as the magnetic field increases. The fringe fields are smaller than 5 mT at 0.5 m from the magnet. The construction of the SAMURAI magnet started in 2008 and was completed in June 2011. The commissioning of the SAMURAI spectrometer was successfully performed using RI beams in March 2012.
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