We report a case of a sudden onset of minimal change nephrotic syndrome (MCNS) in a 33-year-old woman with type 1 diabetes mellitus (T1DM), stable microalbuminuria, and chronic thyroiditis. She was successfully treated with intravenous corticosteroids to finally attain a complete remission. Four years later, she also experienced a relapse of MCNS in the same season as the first onset. The chronological levels of serum immunoglobulin E (IgE) showed that extremely high serum IgE levels preceded the onset or the relapse of MCNS, which may suggest an allergic mechanism of MCNS. Eicosapentaenoic acid (EPA) was reported to be beneficial in treating allergic diseases. Suplatast tosilate is an anti-allergic medication that suppresses serum IgE and was reported to be beneficial in reducing corticosteroid dose in nephrotic syndrome in a pilot study. Therefore, during the tapering of corticosteroids to the relapse of MCNS, suplatast tosilate and EPA were administered, and the IgE levels were considerably controlled. The patient was able to maintain remission even after the cessation of corticosteroids. In conclusion, suppressing IgE levels using suplatast tosilate and EPA may be beneficial in maintaining complete remission without corticosteroids in T1DM.

Breast cancer is a complex disease with a highly immunosuppressive tumor microenvironment, and has limited clinical response to immune checkpoint blockade (ICB) therapy. T-helper 2 (Th2) cells, an important component of the tumor microenvironment (TME), play an essential role in regulation of tumor immunity. However, the deep relationship between Th2-mediated immunity and immune evasion in breast cancer remains enigmatic.
Here, we first used bioinformatics analysis to explore the correlation between Th2 infiltration and immune landscape in breast cancer. Suplatast tosilate (IPD-1151 T, IPD), an inhibitor of Th2 function, was then employed to investigate the biological effects of Th2 blockade on tumor growth and immune microenvironment in immunocompetent murine breast cancer models. The tumor microenvironment was analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Furthermore, we examined the efficacy of IPD combination with ICB treatment by evaluating TME, tumor growth and mice survival.
Our bioinformatics analysis suggested that higher infiltration of Th2 cells indicates a tumor immunosuppressive microenvironment in breast cancer. In three murine breast cancer models (EO771, 4T1 and EMT6), IPD significantly inhibited the IL-4 secretion by Th2 cells, promoted Th2 to Th1 switching, remodeled the immune landscape and inhibited tumor growth. Remarkably, CD8+ T cell infiltration and the cytotoxic activity of cytotoxic T lymphocyte (CTL) in tumor tissues were evidently enhanced after IPD treatment. Furthermore, increased effector CD4+ T cells and decreased myeloid-derived suppressor cells and M2-like macrophages were also demonstrated in IPD-treated tumors. Importantly, we found IPD reinforced the therapeutic response of ICB without increasing potential adverse effects.
Our findings demonstrate that pharmaceutical inhibition of Th2 cell function improves ICB response via remodeling immune landscape of TME, which illustrates a promising combinatorial immunotherapy.

Suplatast tosilate, a Th2 cytokine inhibitor, was predicted to relieve interstitial cystitis symptoms. Four studies with suplatast tosilate in Japanese interstitial cystitis patients have been conducted: a single-arm clinical study, a phase II dose-ranging trial, a phase III trial with placebo, and a second phase PIII trial with placebo. Treatment efficacy was observed in the first two studies; however, in the phase PIII trials, no significant difference in interstitial cystitis symptom score changes was observed between suplatast tosilate and placebo. We summarized these four studies to investigate factors causing the difference in observed efficacy.
Placebo effects in the first two studies and differences regarding study design between the four studies were considered to be possible factors. Therefore, placebo effects were investigated by comparing interstitial cystitis symptom score changes, and the study designs were compared to investigate the effects on observed efficacy.
Interstitial cystitis symptom score changes in the phase PII treatment groups increased in a dose-dependent manner and showed an almost linear relationship with interstitial cystitis symptom score changes observed in placebo groups of 2 phase PIII studies. A major difference regarding the phase PIII study design was the use of diagnostic hydrodistention. Diagnostic hydrodistention and its washout period were applied only in the phase PIII trials.
Comparison of interstitial cystitis symptom score changes suggested that the placebo effect was very small. Use of diagnostic hydrodistention was considered to be a major difference in the population characteristics of the studies and may have resulted in different observed efficacies. Diagnostic hydrodistention, which potentially influences the treatment effect, is probably not essential for trials of suplatast in interstitial cystitis patients.

Although radiotherapy is important in the treatment of malignant thoracic tumors, it has harmful effects on healthy tissues. We previously showed that suplatast tosilate, an anti-allergic agent, scavenged reactive oxygen species (ROS), including hydroxyl radicals. Because ROS-mediated oxidative stress is involved in radiation-induced lung injury, we hypothesized that suplatast tosilate could reduce radiation-induced lung injury via suppression of oxidative stress.
Murine alveolar epithelial cells were irradiated with or without a medium containing suplatast tosilate in vitro to determine whether the agent had cytoprotective effects against radiation-induced injury. On the other hand, the thoracic region of C57BL/6 mice was exposed to a single irradiation dose of 15 Gy and the effects of suplatast tosilate were determined by a histological evaluation and assessment of the following parameters: cell number and inflammatory cytokine levels in bronchoalveolar lavage fluid, and oxidative stress markers and hydroxyproline content in pulmonary tissues.
Suplatast tosilate protected murine alveolar epithelial cells in vitro from irradiation-induced inhibition of cell proliferation, which was accompanied by the suppression of intracellular ROS and DNA double-strand breaks induced by irradiation. Oxidative stress markers and the levels of inflammatory and fibrogenic cytokines were upregulated in irradiated murine lungs in vivo. Suplatast tosilate suppressed both oxidative stress markers and the levels of cytokines, which resulted in reduced pulmonary fibrosis and clearly improved the survival rate after irradiation.
These findings demonstrate that suplatast tosilate could be a useful lung-protective agent that acts via suppression of oxidative stress associated with thoracic radiotherapy.

Painful bladder syndrome/interstitial cystitis (PBS/IC) is an enigmatic disease characterized by lack of evidence-based knowledge and an ongoing scientific debate regarding its definition, pathogenesis, diagnostic and treatment algorithm. An autoimmune theory for PBS/IC etiology has suggested immunotherapy as a potential treatment choice. Areas covered: In this review, the authors report existing and future immunotherapeutic options, potentially valuable to the management of PBS/IC while evidence for the immunological aspect of PBS/IC pathogenesis are also presented. Relevant data reported in human clinical studies but also in experimental studies using animal PBS/IC models have been reviewed. Expert opinion: Promising data has emerged lately regarding use of immunotherapy drugs for PBS/IC treatment. Specifically, human monoclonal antibodies inhibiting nerve growth factor and tumor necrosis factor-a have shown high efficacy in pain control for PBS/IC. Also, many other agents modulating immunopathways linked to PBS symptom etiology and leading to positive treatment effects have been reported lately mainly in experimental animal studies. Immunotherapy could potentially improve disease-related and patient-reported outcome; nevertheless, lack of consensus regarding PBS/IC diagnostic criteria, leading to high heterogeneity of patients enrolled in PBS/IC treatment studies, and low number of well-designed randomized clinical trials are limitations which must be addressed in the future.

Prolonged exposure to hyperoxia produces extraordinary amounts of reactive oxygen species (ROS) in the lung and causes hyperoxic lung injury. Although supraphysiological oxygen is routinely administered for the management of respiratory failure, there is no effective strategy to prevent hyperoxic lung injury. In our previous study, we showed that suplatast tosilate, an asthma drug that inhibits T helper 2 (Th2) cytokines, ameliorated bleomycin-induced lung injury and fibrosis through Th2-independent mechanisms. Because bleomycin also generates ROS, we hypothesized that suplatast tosilate might have antioxidant activity and protect the lung against hyperoxic lung injury. To test this hypothesis, mice exposed to hyperoxia were given suplatast tosilate through drinking water. Treatment with suplatast tosilate significantly prolonged mouse survival, reduced the increases in the numbers of inflammatory cells, levels of the pro-inflammatory cytokines/chemokines IL-6 and MCP-1, and protein in bronchoalveolar lavage fluid, and ameliorated lung injury in histological assessment. Suplatast tosilate treatment also significantly inhibited hyperoxia-induced elevations in the levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in bronchoalveolar lavage fluid and 8-isoprostane, a marker of lipid peroxidation, in lung tissue. This finding suggests that suplatast tosilate exerts an antioxidant activity in vivo. In addition, we investigated whether suplatast tosilate has a scavenging effect on hydroxyl radical, the most reactive and harmful ROS, using electron paramagnetic resonance spin-trapping. Suplatast tosilate was shown to scavenge hydroxyl radicals in a dose-dependent manner, and its reaction rate constant with hydroxyl radical was calculated as 2.6×1011M-1S-1, which is faster than that of several well-established antioxidants, such as ascorbate, glutathione, and cysteine. These results suggest that suplatast tosilate protects the lung against hyperoxic lung injury by decreasing the degree of oxidative stress induced by ROS, particularly by scavenging hydroxyl radicals. Suplatast tosilate might become a potential therapeutic for hyperoxic lung injury.

Histamine H1 receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.

We found four new polymorphic forms (γ-, ε-, ζ-, and η-forms) of suplatast tosilate (ST) by recrystallization and seeding with ST-analogous compounds; three polymorphic forms (α-, β-, and δ-forms) of ST have been previously reported. The physicochemical properties of these new forms were investigated using infrared (IR) spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry. The presence of hydrogen bonds in the new forms was assessed from the IR and solid-state NMR spectra. The crystal structures of the ε- and η-forms were determined from their powder X-ray diffraction data using the direct space approach and the Monte Carlo method, followed by Rietveld refinement. The structures determined for the ε- and η-forms supported the presence of hydrogen bonds between the ST molecules, as the IR and solid-state NMR spectra indicated. The thermodynamic characteristics of the seven polymorphic forms were evaluated by determining the solubility of each form. The α-form was the most insoluble in 2-propanol at 35°C, and was thus concluded to be the most stable form. The ε-form was the most soluble, and a polymorphic transition from the ε- to the α-form was observed during solubility testing.

We report the treatment course of a 29-year-old man who has had unique oscillating FIP1L1-PDGFRA fusion gene-negative hypereosinophilic syndrome (HES) for nearly 6 years. His periodic oscillating pattern of eosinophilia associated with angioedematous soft tissue swelling has shown two to three seasonal peaks (>15,000/μL absolute eosinophil counts [AEC]) a year. Initially, the patient, who was thought to have distinct HES not compatible with previously described cases, did not respond to treatment except for a temporary response to imatinib mesylate. For 6 years, from 2005 to 2010, he was treated with a combination of oral cyclosporine A, suplatast tosilate, and a small dose of prednisolone, which significantly reduced the peak heights of AEC as well as blunting the oscillating patterns.