Abstract
Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but ...the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8
+
tissue-resident memory CD8
+
T (CD8
+
Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69
+
CD103
−
CD8
+
Trm cell enrichment in NASH resolution livers. The reduction of liver CD8
+
Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8
+
Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69
+
CD8
+
Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8
+
Trm in fibrosis resolution.
Recent clinical and experimental evidence has evoked the concept ofthe gut-brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated ...with the bidirectional effects of inflammatory bowel disease and central nervous system disorders. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius ofthe brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation ofthese receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development oftherapeutic strategies to treat or prevent immunological disorders of the gut.
Purpose
To analyze the clinical characteristics and treatment of noninfectious scleritis in Japanese patients, focusing on the efficacy of methotrexate (MTX).
Study design
Retrospective.
Patients and ...methods
A retrospective study of patients with noninfectious scleritis treated at Hiroshima University from February 2016 to May 2020 was performed. The patients’ clinical features, associated systemic diseases, treatments, and visual outcomes were studied. The efficacy of MTX was also analyzed.
Results
The study comprised 57 patients (88 eyes) with noninfectious scleritis, of whom 31 had bilateral involvement and the majority had anterior diffuse scleritis (n = 45). The commonest ocular complication was anterior chamber cells (38.6%), followed by ocular hypertension (28.1%). Associated systemic diseases were observed in 24.6% of the patients. Systemic immunosuppressive treatment was required in 78.9% of the patients, and 45.6% of the patients needed corticosteroid-sparing immunosuppressive treatment. Treatment success was achieved in 88.2% of the patients. Decreased vision was observed in 9.8% of the patients with ≥ 3-month follow-up. Seventeen patients were treated with MTX; the median maximum dose was 16 mg/week (range 8–16 mg). The scleritis was well controlled in almost 80% of the patients treated with MTX and systemic corticosteroids ≤ 5 mg. MTX adverse effects occurred in 47.1% of the MTX-treated patients; they were either tolerable or improved with dose adjustment in most cases.
Conclusion
Our study suggests the significance of prompt initiation of corticosteroid-sparing immunosuppressive treatment in treating patients with refractory scleritis or those intolerant of systemic corticosteroids. Moreover, MTX may be used effectively and safely for the treatment of noninfectious scleritis in Japanese patients.
To assess the efficacy and safety of adalimumab treatment in patients with Non-infectious uveitis.
This was a single-center retrospective chart review of patients with active Non-infectious uveitis ...who had received adalimumab in Japan. Outcome variables included change in systemic immunosuppressive treatment, intraocular inflammation, visual acuity, and relapse rate.
In total, 48 patients were included. After the initiation of adalimumab, more than 80% of the patients received systemic corticosteroid ≤5 mg from 3 months onwards. Intraocular inflammation, relapse rate, and visual acuity showed persistent improvement. Adalimumab and methotrexate combination therapy was required in 71.4% of the patients with Vogt-Koyanagi-Harada disease/sympathetic ophthalmia, whereas it was required in only 18.0% of the patients with Behçet's disease. There were no serious side effects that required discontinuation of adalimumab.
Adalimumab is efficacious and safe for the treatment of patients with Non-infectious uveitis. Differences in the efficacy of adalimumab treatment may exist between patients with Vogt-Koyanagi-Harada disease/sympathetic ophthalmia and patients with Behçet's disease.
Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12‐18 months. Frizzled homolog 10 (FZD10) is ...overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β‐radioimmunotherapy (RIT) with the 90Y‐labeled anti‐FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α‐RIT with OTSA101 labeled with the α‐emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac‐labeled OTSA101 to SYO‐1 synovial sarcoma cells was comparable to that of the imaging agent 111In‐labeled OTSA101. Biodistribution studies showed high uptake in SYO‐1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac‐labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y‐labeled OTSA101. 90Y‐ and 225Ac‐labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac‐labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac‐labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y‐labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment‐related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac‐labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO‐1. RIT with 225Ac‐labeled OTSA101 is a promising therapeutic option for synovial sarcoma.
FZD10‐targeted alpha‐radioimmunotherapy with 225Ac‐labeled OTSA101 provided a high radiation dose to tumors and achieved 60% complete response in the synovial sarcoma mouse model SYO‐1. This is the best outcome among FZD10‐targeted therapy to date. Our alpha‐radioimmunotherapy would provide an additional therapeutic option to synovial sarcoma patients that do not show a good response to conventional therapy.
We have previously shown that prophylactic oral administration of transgenic rice seeds expressing hypoallergenic modified antigens suppressed the development of allergic conjunctivitis induced by ...Japanese cedar pollen. We have now investigated the efficacy of oral immunotherapy with such transgenic rice for established allergic conjunctivitis in mice.
BALB/c mice were sensitized with two intraperitoneal injections of Japanese cedar pollen in alum, challenged with pollen in eyedrops, and then fed for 16 days with transgenic rice seeds expressing modified Japanese cedar pollen allergens Cry j 1 and Cry j 2 or with nontransgenic rice seeds as a control. They were then challenged twice with pollen in eyedrops, with clinical signs being evaluated at 15 min after the first challenge and the eyes, blood, spleen, and lymph nodes being isolated at 24 h after the second challenge.
The number of eosinophils in the conjunctiva and the clinical score for conjunctivitis were both significantly lower in mice fed the transgenic rice than in those fed nontransgenic rice. Oral vaccination with transgenic rice seeds also resulted in a significant increase in the production of IFN-γ by splenocytes, whereas it had no effect on the number of CD4+CD25+Foxp3+ regulatory T cells in the spleen or submandibular or mesenteric lymph nodes.
Oral administration of transgenic rice seeds expressing hypoallergenic allergens ameliorated allergic conjunctivitis in the established setting. Such a rice-based edible vaccine is potentially both safe and effective for oral immunotherapy in individuals with allergic conjunctivitis.
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We report four cases of syphilitic uveitis with diverse clinical presentations. All patients were men who have sex with women, and were aged 19-68 years, and none were HIV-positive. All cases were ...bilateral. One case presented with anterior uveitis, while three exhibited panuveitis. One patient had acute syphilitic posterior placoid chorioretinitis and two had retinal vasculitis resulting in damage to the outer retinal and retinal pigment epithelium. The rapid plasma reagin (RPR) test and Treponema pallidum (TP) hemagglutination test were both positive in all cases. Six of eight eyes had improved vision and best-corrected visual acuity better than 20/20 after antibiotic treatment. Serological testing is mandatory for the diagnosis of syphilitic uveitis. Additionally, multimodal imaging, including optical coherence tomography (OCT), fundus autofluorescence (FAF), and fluorescein angiography (FA), can provide useful adjunctive information for early diagnosis and assessment of treatment response.
To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is ...known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.
Background Optic nerve diseases include inflammatory optic nerve diseases such as vasculitis, metabolic optic neuropathy, ischemic optic neuropathy, and optic neuritis. In this study, patients with ...acute optic neuritis are classified with better and poor visual acuity based on visual acuity after one month of steroid pulse therapy. To determine prognosis, initial visual acuity and critical fusion frequency (CFF) values will be compared with those recorded one month after treatment and at the last visit. Methods Visual acuity and CFF were evaluated one month after the start of treatment in patients diagnosed with acute optic neuritis, and follow-up was available for at least three months at Hiroshima University Hospital. Results All patients received steroid pulse therapy as initial treatment. After one month of treatment, visual acuity and CFF at the last visit were significantly improved in the group with improved visual acuity compared to the group with impaired visual acuity. Conclusions Visual acuity at the initial visit did not affect treatment outcome, and final visual acuity and CFF after one month of treatment for acute optic neuritis were better in patients with better visual acuity. Therefore, visual acuity values one month after treatment initiation may affect treatment outcomes.
Purpose
To investigate the incidence and pre/post-treatment risk factors of glaucoma in patients with Vogt-Koyanagi-Harada (VKH) disease.
Methods
Data regarding secondary glaucoma were collected from ...the medical records of patients with VKH disease who were followed up at the uveitis service at Hiroshima University for more than 6 months. We examined the incidence of glaucoma and pre/post-treatment risk factors for glaucoma in patients with VKH disease.
Results
Forty-nine patients with VKH disease were included in this study (31 women and 18 men). The mean age at onset was 50.4 ± 15.4 years and the mean length of follow-up was 40.7 ± 25.5 months. The most common initial treatment was pulse intravenous corticosteroid therapy (89.8%). Fifteen patients developed secondary glaucoma during follow-up. The median time of glaucoma onset from VKH development was 4.5 months (range 0–44 months). Disc swelling type as a pre-treatment factor (
p
= 0.089, hazard ratio = 7.268), worse final best corrected visual acuity (
p
= 0.099, odds ratio = 1.545), and cataract progression (
p
= 0.076, odds ratio = 7.886) as post-treatment factors showed trends for glaucoma development. The patients who progressed to the chronic recurrent stage had more complications including glaucoma.
Conclusion
Secondary glaucoma occurred in more than 30% of patients with VKH disease. The factors that showed a trend toward glaucoma development may reflect an association with delayed treatment initiation and prolonged ocular inflammation.
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