Clinical efficacy and safety of multipotent adult progenitor cells (invimestrocel) for acute respiratory distress syndrome (ARDS) caused by pneumonia: a randomized, open-label, standard therapy-controlled, phase 2 multicenter study (ONE-BRIDGE).

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung injury with high mortality; no approved medication exists. Efficacy and safety of bone marrow-derived, allogeneic, multipotent adult progenitor cells (invimestrocel) plus standard treatment in patients with ARDS caused by pneumonia was evaluated. METHODS: A randomized, open-label, standard therapy-controlled, phase 2 study (January 2019-September 2021) conducted in 29 centers in Japan. Patients with ARDS caused by pneumonia, with extensive early fibroproliferation on high-resolution computed tomography and low risk of systemic organ failure identified by an Acute Physiology and Chronic Health Evaluation (APACHE II) score were included. Patients were randomized 2:1 to receive a single intravenous infusion of 9.0 × 108 cells of invimestrocel (administered at a rate of up to 10 mL/min over 30-60 min by free flow) plus standard treatment (N = 20) or standard treatment (N = 10) consistent with the clinical practice guidelines of the Japanese Respiratory Society for the management of ARDS. Primary endpoint was ventilator-free days (VFDs) through day 28 after study treatment. Analysis of covariance was performed with treatment group, age, partial pressure arterial oxygen/fraction of inspired oxygen ratio, and APACHE II score as covariates. RESULTS: Median (interquartile range) number of VFDs was numerically higher in the invimestrocel group versus standard group (20.0 [0.0-24.0] vs 11.0 [0.0-14.0]) but was not statistically significantly different (least square [LS] means [95% confidence interval (CI)]: invimestrocel group, 11.6 [6.9-16.3]; standard group, 6.2 [- 0.4 to 12.8]; LS mean difference [95% CI], 5.4 [- 1.9 to 12.8]; p = 0.1397). Ventilator weaning rate at day 28 was 65% (13/20) versus 30% (3/10), and mortality rate was 21% (4/19) versus 29% (2/7) at day 28 and 26% (5/19 patients) versus 43% (3/7 patients) at day 180, for the invimestrocel and standard groups, respectively. No allergic or serious adverse reactions were associated with invimestrocel. CONCLUSIONS: In Japanese patients with ARDS caused by pneumonia, invimestrocel plus standard treatment resulted in no significant difference in the number of VFDs but may result in improved survival compared with standard treatment. Invimestrocel was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03807804; January 8, 2019; https://clinicaltrials.gov/ct2/show/NCT03807804 .

A Japanese Bioventure Company's Application of Stem Cell Technology in Regenerative Medicine.

Regenerative medicine mediated by the transplantation of somatic stem cells and functional cells derived from induced pluripotent stem cells has great potential in the treatment of currently incurable diseases and thus has attracted significant public attention. To put this into practice, several functional cell lines were developed and laws regarding regenerative medicine were put in force in Japan. In this report, we introduce recent efforts of a bioventure company with special attention to the case of Healios K.K.

Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration.

We assessed the feasibility of transplanting a sheet of retinal pigment epithelial (RPE) cells differentiated from induced pluripotent stem cells (iPSCs) in a patient with neovascular age-related macular degeneration. The iPSCs were generated from skin fibroblasts obtained from two patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. The RPE cells and the iPSCs from which they were derived were subject to extensive testing. A surgery that included the removal of the neovascular membrane and transplantation of the autologous iPSC-derived RPE cell sheet under the retina was performed in one of the patients. At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present. (Funded by Highway Program for Realization of Regenerative Medicine and others; University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000011929 .).

IL-18 induces airway hyperresponsiveness and pulmonary inflammation via CD4+ T cell and IL-13.

IL-18 plays a key role in the pathogenesis of pulmonary inflammatory diseases including pulmonary infection, pulmonary fibrosis, lung injury and chronic obstructive pulmonary disease (COPD). However, it is unknown whether IL-18 plays any role in the pathogenesis of asthma. We hypothesized that overexpression of mature IL-18 protein in the lungs may exacerbate disease activities of asthma. We established lung-specific IL-18 transgenic mice on a Balb/c genetic background. Female mice sensitized- and challenged- with antigen (ovalbumin) were used as a mouse asthma model. Pulmonary inflammation and emphysema were not observed in the lungs of naïve transgenic mice. However, airway hyperresponsiveness and airway inflammatory cells accompanied with CD4(+) T cells, CD8(+) T cells, eosinophils, neutrophils, and macrophages were significantly increased in ovalbumin-sensitized and challenged transgenic mice, as compared to wild type Balb/c mice. We also demonstrate that IL-18 induces IFN-γ, IL-13, and eotaxin in the lungs of ovalbumin-sensitized and challenged transgenic mice along with an increase in IL-13 producing CD4(+) T cells. Treatment with anti-CD4 monoclonal antibody or deletion of the IL-13 gene improves ovalbumin-induced airway hyperresponsiveness and reduces airway inflammatory cells in transgenic mice. Overexpressing the IL-18 protein in the lungs induces type 1 and type 2 cytokines and airway inflammation, and results in increasing airway hyperresponsiveness via CD4(+) T cells and IL-13 in asthma.

Overexpression of chitinase 3-like 1/YKL-40 in lung-specific IL-18-transgenic mice, smokers and COPD.

We analyzed the lung mRNA expression profiles of a murine model of COPD developed using a lung-specific IL-18-transgenic mouse. In this transgenic mouse, the expression of 608 genes was found to vary more than 2-fold in comparison with control WT mice, and was clustered into 4 groups. The expression of 140 genes was constitutively increased at all ages, 215 genes increased gradually with aging, 171 genes decreased gradually with aging, and 82 genes decreased temporarily at 9 weeks of age. Interestingly, the levels of mRNA for the chitinase-related genes chitinase 3-like 1 (Chi3l1), Chi3l3, and acidic mammalian chitinase (AMCase) were significantly higher in the lungs of transgenic mice than in control mice. The level of Chi3l1 protein increased significantly with aging in the lungs and sera of IL-18 transgenic, but not WT mice. Previous studies have suggested Chi3l3 and AMCase are IL-13-driven chitinase-like proteins. However, IL-13 gene deletion did not reduce the level of Chi3l1 protein in the lungs of IL-18 transgenic mice. Based on our murine model gene expression data, we analyzed the protein level of YKL-40, the human homolog of Chi3l1, in sera of smokers and COPD patients. Sixteen COPD patients had undergone high resolution computed tomography (HRCT) examination. Emphysema was assessed by using a density mask with a cutoff of -950 Hounsfield units to calculate the low-attenuation area percentage (LAA%). We observed significantly higher serum levels in samples from 28 smokers and 45 COPD patients compared to 30 non-smokers. In COPD patients, there was a significant negative correlation between serum level of YKL-40 and %FEV(1). Moreover, there was a significant positive correlation between the serum levels of YKL-40 and LAA% in COPD patients. Thus our results suggest that chitinase-related genes may play an important role in establishing pulmonary inflammation and emphysematous changes in smokers and COPD patients.

Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis.

INTRODUCTION: There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor α (IL-18Rα). In this study, we evaluated the levels and characteristics of soluble IL-18Rα (sIL-18Rα) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations. METHODS: The sIL-18Rα complex was isolated from pooled human blood serum using an anti-IL-18Rα monoclonal antibody affinity column. The purified sIL-18Rα was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-γ. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18Rα complex. RESULTS: The isolated sIL-18Rα complex can be associated with IL-18 and the soluble form of the IL-18Rß chain. The sIL-18Rα complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-γ production by the cells. The serum levels of sIL-18Rα complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18Rα complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-γ in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18Rα indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18Rα in the sera of 29 RA patients 6 months after treatment. CONCLUSIONS: The sIL-18Rα complex could be a potentially useful biomarker for the diagnosis of RA.

Endogenous and exogenous thioredoxin 1 prevents goblet cell hyperplasia in a chronic antigen exposure asthma model.

BACKGROUND: Goblet cell hyperplasia with mucus hypersecretion contribute to increased morbidity and mortality in bronchial asthma. We have reported that thioredoxin 1 (TRX1), a redox (reduction/oxidation)-active protein acting as a strong antioxidant, inhibits pulmonary eosinophilic inflammation and production of chemokines and Th2 cytokines in the lungs, thus decreasing airway hyperresponsiveness (AHR) and airway remodeling in mouse asthma models. In the present study, we investigated whether endogenous or exogenous TRX1 inhibits goblet cell hyperplasia in a mouse asthma model involving chronic exposure to antigen. METHODS: We used wild-type Balb/c mice and Balb/c background human TRX1-transgenic mice constitutively overproducing human TRX1 protein in the lungs. Mice were sensitized 7 times (days 0 to 12) and then challenged 9 times with ovalbumin (OVA) (days 19 to 45). Every second day from days 18 to 44 (14 times) or days 35 to 45 (6 times), Balb/c mice were treated with 40 microg recombinant human TRX1 (rhTRX1) protein. Goblet cells in the lungs were examined quantitatively on day 34 or 45. RESULTS: Goblet cell hyperplasia was significantly prevented in TRX1-transgenic mice in comparison with TRX1 transgene-negative mice. rhTRX1 administration during OVA challenge (days 18 to 44) significantly inhibited goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. Moreover, rhTRX1 administration after the establishment of goblet cell hyperplasia (days 35 to 45) also significantly ameliorated goblet cell hyperplasia in OVA-sensitized and -challenged wild-type mice. CONCLUSIONS: Our results suggest that TRX1 prevents the development of goblet cell hyperplasia, and also ameliorates established goblet cell hyperplasia.

Obesity and smoking: relationship with waist circumference and obesity-related disorders in men undergoing a health screening.

This study investigated whether smoking habits had a differential influence on waist circumference and obesity-related disorders in nonobese and obese men. We investigated 359 men with smoking habits confirmed by their spouses, including 172 nonobese men (BMI<25) and 187 obese men (BMI>or=25). There were 113 nonobese smokers and 129 obese smokers. Obesity-related disorders were defined as hypertension, dyslipidemia, hyperglycemia, hyperuricemia, or treatment for one or more of these disorders. Nonobese subjects showed no differences of age, BMI, and waist circumference between smokers and nonsmokers, but smokers had a higher incidence of obesity-related disorders. Obese smokers were younger than obese nonsmokers and had a larger waist circumference, but a similar prevalence of obesity-related disorders. The prevalence of obesity-related disorders was similar between obese nonsmokers and smokers, but the smokers were younger. In nonobese subjects, smoking may increase obesity-related disorders by a mechanism other than visceral fat accumulation. In obese subjects, however, smoking may promote visceral fat accumulation. Further investigations will be necessary to better elucidate the relationship between the promotion of visceral fat accumulation in obese subjects by smoking and obesity-related disorders.