A novel monoclonal antibody cross-reactive with both human and mouse α9 integrin useful for therapy against rheumatoid arthritis.

This study introduces a novel monoclonal anti-α9 integrin antibody (MA9-413) with human variable regions, isolated by phage display technology. MA9-413 specifically binds to both human and mouse α9 integrin by recognizing a conserved loop region designated as L1 (amino acids 104-122 of human α9 integrin). MA9-413 inhibits human and mouse α9 integrin-dependent cell adhesion to ligands and suppresses synovial inflammation and osteoclast activation in a mouse model of arthritis.

Immunoglobulin G Enhances Generation of Inducible T Regulatory Cells and Increases Their Regulatory Function.

Intravenous immunoglobulin (IVIg) has been shown to be effective in the treatment of a variety of autoimmune diseases. To clarify the role of T regulatory cells (Tregs) in the immunoregulatory effect of IVIg, we focused on human inducible T regulatory cells (iTregs) and investigated the mechanism of action of IVIg. When immunoglobulin G (IgG) was added to a culture system that differentiates iTregs from anti-CD3 antibody activated CD4+CD25- T cells in the presence of syngeneic immature dendritic cells, interleukin (IL)-2 and transforming growth factor-β (TGF-β), the expression of forkhead box P3 (FoxP3), which is the master transcription factor for Tregs in CD4+CD25+ T cells, increased in an IgG concentration-dependent manner.

Analysis of relationships between polymorphisms in the genes encoding the pentameric complex and neutralization of clinical cytomegalovirus isolates.

Introduction: As congenital cytomegalovirus (CMV) infection is one of the major causes of birth defects and developmental abnormalities, it is essential to develop vaccines and therapeutic antibodies against CMV. Clinical trials demonstrated that the subunit vaccine based on glycoprotein B, which had been believed to be the major target for neutralization, did not induce sufficient protective immunity. On the other hand, it has been reported that the immunization of animals with the Pentamer, the pentameric complex of gH/gL/UL128/UL130/UL131A, induced strong neutralizing antibodies.

Freeze-dried equine-derived redback spider antivenom: a local irritation study by intramuscular injection in rabbits and a repeated-dose toxicity study in rats.

The redback spider () is nonindigenous to Japan but has now spread throughout the country. Bites to humans are rare but can be fatal. We prepared freeze-dried redback spider antivenom for therapeutic use against bites in Japan by immunization of horse plasma.

High-risk screening for Gaucher disease in patients with neurological symptoms.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by the deficiency of glucocerebrosidase enzyme activity. Clinical phenotypes of GD are categorized into three groups: (i) non-neuronopathic GD (type 1), (ii) acute neuronopathic GD (type 2) and (iii) subacute neuronopathic GD (type 3). The high-risk screening of neuronopathic GD has been performed using an enzymatic assay on the dried blood spot (DBS) samples.

Venom and Antivenom of the Redback Spider (Latrodectus hasseltii) in Japan. Part I. Venom Extraction, Preparation, and Laboratory Testing.

The redback spider (Latrodectus hasseltii Thorell) reportedly invaded Japan in September 1995. To date, 84 redback spider bite cases have been reported; 7 of these cases employed the antivenom. Antivenom has been imported from Australia in the past, but because of restrictions on exportation it was evident that nearly all of the antivenom present in Japan would expire during 2014.

Potent Hemostatic Efficacy of a Novel Recombinant Fibrin Sealant Patch (KTF-374) in Rabbit Bleeding Models.

Purpose: Fibrin sealants are used for hemostasis during surgery. Commercially available fibrin sealants are made of materials of human or animal origin. We developed a novel recombinant fibrin sealant patch (KTF-374) that has thin and flexible properties.

Venom and Antivenom of the Redback Spider (Latrodectus hasseltii) in Japan. Part II. Experimental Production of Equine Antivenom against the Redback Spider.

This is the first report on large-scale experimental production of an equine antivenom against the redback spider (Latrodectus hasseltii) lived in Japan. We captured 10,000 redback spiders in Japan and prepared the toxoids of crude venom extract, mixed the toxoids with a mineral oil adjuvant, and immunized healthy horses repeatedly over a period of several weeks. Thereafter, we separated the horse plasma, purified the γ-globulin fraction, and stocked it as a purified antivenom concentrate.

Clinical Study of New Tetravalent (Type A, B, E, and F) Botulinum Toxoid Vaccine Derived from M Toxin in Japan.

Botulinum toxin is the most poisonous substance known, and is believed to be a highly lethal as a biological weapon; researchers of the toxin are exposed to this hazard. Botulinum toxoid vaccines have been produced and used in Japan. However, since clinical studies involving these vaccines were conducted before establishment of the Ethical Guidelines for Clinical Research in Japan, their immunogenicity and safety were not systematically assessed.

Novel Antibody for the Treatment of Transthyretin Amyloidosis.

Familial amyloidotic polyneuropathy (FAP) is a systemic amyloidosis mainly caused by amyloidogenic transthyretin (ATTR). This incurable disease causes death ∼10 years after onset. Although it has been widely accepted that conformational change of the monomeric form of transthyretin (TTR) is very important for amyloid formation and deposition in the organs, no effective therapy targeting this step is available.

A Total Pleural Covering for Lymphangioleiomyomatosis Prevents Pneumothorax Recurrence.

Background: Spontaneous pneumothorax is a major and frequently recurrent complication of lymphangioleiomyomatosis (LAM). Despite the customary use of pleurodesis to manage pnenumothorax, the recurrence rate remains high, and accompanying pleural adhesions cause serious bleeding during subsequent lung transplantation. Therefore, we have developed a technique of total pleural covering (TPC) for LAM to wrap the entire visceral pleura with sheets of oxidized regenerated cellulose (ORC) mesh, thereby reinforcing the affected visceral pleura and preventing recurrence.

Retrospective survey to evaluate the safety and efficacy of Japanese botulinum antitoxin therapy in Japan.

Japanese botulinum antitoxins have been used for more than 50 years; however, their safety and therapeutic efficacy are not clear. In order to analyze the available data on botulinum antitoxin therapy in Japan, we surveyed published reports about botulism cases in which botulinum antitoxins were used, and retrospectively analyzed the safety and efficacy of the therapy. A total of 134 patients administered botulinum antitoxins were identified from published reports.

Freeze-dried live attenuated smallpox vaccine prepared in cell culture "LC16-KAKETSUKEN": Post-marketing surveillance study on safety and efficacy compliant with Good Clinical Practice.

Background: In Japan, production of smallpox vaccine LC16m8 (named LC16-KAKETSUKEN) was restarted and was determined to be maintained as a national stockpile in March 2002.

Objective: To conduct a post-marketing surveillance study of the vaccination of freeze-dried live attenuated smallpox vaccine prepared in cell culture LC16-KAKETSUKEN using attenuated vaccinia strain LC16m8. The study complied with Good Clinical Practice, focusing on a comparison between primary vaccinees and re-vaccinees.

A clinical phase I study of an EB66 cell-derived H5N1 pandemic vaccine adjuvanted with AS03.

Background: We conducted a phase I clinical trial of a cell culture-derived AS03-adjuvanted influenza vaccine containing HA antigen (A/Indonesia/05/2005(H5N1)/PR8-IBCDC-RG2) derived from EB66 cells (KD-295).

Methods: Healthy male adult volunteers (20-40 years old, N=60) enrolled in the study were divided into 3 groups, the MA group (3.8 μg of HA+AS03), HA group (7.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine in healthy adults: a phase II, open-label, uncontrolled trial in Japan.

Two antigenically distinct B strain lineages of influenza virus have co-circulated since the mid-1980s; however, inactivated trivalent influenza vaccines contain only one B lineage. The mismatch between the circulating and vaccine lineages has been a worldwide issue. In this study, an inactivated quadrivalent influenza vaccine (QIV) candidate containing two B lineages was manufactured and its immunogenicity and safety evaluated in an open-label, uncontrolled trial.

Vaccinia virus strain LC16m8 defective in the B5R gene keeps strong protection comparable to its parental strain Lister in immunodeficient mice.

Background: Attenuated vaccinia virus strain, LC16m8, defective in the B5R envelope protein gene, is used as a stockpile smallpox vaccine strain in Japan against bioterrorism: the defect in the B5R gene mainly contributes to its highly attenuated properties.

Methods: The protective activity of LC16m8 vaccine against challenge with a lethal dose of vaccinia Western Reserve strain was assessed in wild-type and immunodeficient mice lacking CD4, MHC class I, MHC class II or MHC class I and II antigens.

Results: The immunization with LC16m8 induced strong protective activity comparable to that of its parent strain, Lister (Elstree) strain, in wild-type mice from 2 days to 1 year after vaccination, as well as in immunodeficient mice at 2 or 3 weeks after vaccination.

Pleiotropic Effects of Levofloxacin, Fluoroquinolone Antibiotics, against Influenza Virus-Induced Lung Injury.

Reactive oxygen species (ROS) and nitric oxide (NO) are major pathogenic molecules produced during viral lung infections, including influenza. While fluoroquinolones are widely used as antimicrobial agents for treating a variety of bacterial infections, including secondary infections associated with the influenza virus, it has been reported that they also function as anti-oxidants against ROS and as a NO regulator. Therefore, we hypothesized that levofloxacin (LVFX), one of the most frequently used fluoroquinolone derivatives, may attenuate pulmonary injuries associated with influenza virus infections by inhibiting the production of ROS species such as hydroxyl radicals and neutrophil-derived NO that is produced during an influenza viral infection.

Clinical characteristics of redback spider bites.

Background: Redback spiders (Latrodectus hasselti) (RBSs) are venomous spiders that have recently spread to Asia from Australia. Since the first case report in 1997 (Osaka), RBS bites have been a clinical and administrative issue in Japan; however, the clinical characteristics and effective treatment of RBS bites, particularly outside Australia remains unclear. This study aimed to elucidate the clinical characteristics of RBS bites and to clarify the effectiveness of the administration of antivenom for treatment.

Effect of antivenom therapy of Rhabdophis tigrinus (Yamakagashi snake) bites.

Background: Rhabdophis tigrinus (Yamakagashi snake) is a rear-fanged colubrid snake present throughout Russia and Asia. Its venom induces life-threatening hemorrhagic symptoms and severe disseminated intravascular coagulation with a fibrinolytic phenotype. R.

Rhabdophis tigrinus is not a pit viper but its bites result in venom-induced consumptive coagulopathy similar to many viper bites.

As a response to the recent article by Hifumi et al. published in the Journal of Intensive Care, the present correspondence clarifies the family-level taxonomy of the yamakagashi (Rhabdophis tigrinus). Further, the relevance of the term 'venom-induced consumptive coagulopathy,' instead of disseminated intravascular coagulation, in describing the procoagulant coagulopathy of R.

Therapeutic impact of human serum albumin-thioredoxin fusion protein on influenza virus-induced lung injury mice.

Reactive oxygen species (ROS) are the primary pathogenic molecules produced in viral lung infections. We previously reported on the use of a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx) for extending the half-life Trx, an endogenous protein with anti-oxidant properties. As a result, it was possible to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx.

Comparison of Systemic Toxicity between Botulinum Toxin Subtypes A1 and A2 in Mice and Rats.

The adverse events caused by botulinum toxin type A (subtype A1) product, thought to be after-effects of toxin diffusion after high-dose administration, have become serious issues. A preparation showing less diffusion in the body than existing drugs has been sought. We have attempted to produce neurotoxin derived from subtype A2 (A2NTX) with an amino acid sequence different from that of neurotoxin derived from subtype A1 (A1NTX).

Structural basis of clade-specific HIV-1 neutralization by humanized anti-V3 monoclonal antibody KD-247.

Humanized monoclonal antibody KD-247 targets the Gly(312)-Pro(313)-Gly(314)-Arg(315) arch of the third hypervariable (V3) loop of the HIV-1 surface glycoprotein. It potently neutralizes many HIV-1 clade B isolates, but not of other clades. To understand the molecular basis of this specificity, we solved a high-resolution (1.