IL-17C Mitigates Murine Acute Graft-vs.-Host Disease by Promoting Intestinal Barrier Functions and Treg Differentiation

Acute graft-vs.-host disease (aGVHD) is one of the major complications and results in high mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-17C is involved in many inflammatory immune disorders. However, the role of IL-17C in aGVHD remains unknown. Here we demonstrated that IL-17C deficiency in the graft significantly promoted alloreactive T cell responses and induced aggravated aGVHD compared with wildtype donors in a fully MHC-mismatched allo-HSCT model. In contrast, IL-17C overexpression ameliorated aGVHD. IL-17C deficiency increased intestinal epithelial permeability and elevated inflammatory cytokine production, leading to an enhanced aGVHD progression. Tregs was reduced in recipients of IL-17C−/− graft, whilst restored after IL-17C overexpression. Decreased Treg differentiation was abrogated after neutralizing IFN-γ, but not IL-6. Moreover, depletion of Tregs diminished the protective effect of IL-17C. Of note, patients with low IL-17C expression displayed higher aGVHD incidence together with poor overall survival, thereby IL-17C could be an independent risk factor for aGVHD development. Our results are the first demonstrating the protective role of IL-17C in aGVHD by promoting intestinal barrier functions and Treg differentiation in a MHC fully mismatched murine aGVHD model. IL-17C may serve as a novel biomarker and potential therapeutic target for aGVHD

Inhibition of Acute Graft-versus-Host Disease with Retention of Graft-versus-Tumor Effects by Dimethyl Fumarate

10.3389/fimmu.2017.01605Frontiers in Immunology8NOV160

Inhibition of Acute Graft-versus-Host Disease with Retention of Graft-versus-Tumor Effects by Dimethyl Fumarate

Acute graft-versus-host disease (aGVHD) remains a clinical challenge and a major source of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dimethyl fumarate (DMF), an activator of Nrf2, has been shown to have anti-inflammatory and immunomodulatory properties without significant immunosuppression. We therefore hypothesized that DMF could be potentially harnessed for the treatment of aGVHD with retention of graft-versus-tumor effect. In this study, we showed that DMF significantly inhibited alloreactive T cell responses in vitro in mixed lymphocyte reaction assay. Administration of DMF significantly alleviated the severity, histological damage, and the overall mortality of aGVHD in an MHC-mismatched aGVHD model. DMF administration reduced the activation and effector function of donor T cells in vitro and in vivo. In addition, DMF treatment upregulated antioxidant enzymes heme oxygenase-1 and glutathione S-transferase-α1 expressions. Furthermore, DMF treatment markedly increased the frequencies of Treg cells. Depletion of CD25+ cells in DMF recipients aggravated aGVHD mortality compared with IgG control recipients. DMF could promote Treg cell differentiation in a dose dependent manner by upregulating TGF-β expression in vitro. Most importantly, DMF administration preserved graft-versus-leukemia effect after bone marrow transplantation. In conclusion, our findings demonstrated DMF as a promising agent for the prevention of aGVHD after allo-HSCT

Natural β‑Dihydroagarofuran-Type Sesquiterpenoids as Cognition-Enhancing and Neuroprotective Agents from Medicinal Plants of the Genus Celastrus

Alzheimer’s disease (AD) is an irreversible, multifaceted, and progressive neurodegenerative disorder. Over the past 30 years, the search for anti-AD drugs has been primarily based on the cholinergic deficiency hypothesis and/or the β-amyloid (Aβ) cascade hypothesis. In this study, we report the identification of 16 new and 38 known β-dihydroagarofuran-type sesquiterpenoids from Celastrus flagellaris and Celastrus angulatus. The β-dihydroagarofuran-type sesquiterpenoids <b>58</b>, <b>59</b>, <b>61</b>, and <b>63</b> significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the control group. At 10 μM, 21 of the 62 tested β-dihydroagarofuran-type sesquiterpenoids rescued Aβ_25–35-induced SH-SY5Y cells from viability reduction, which increased the cell viability from 64.6% for the model to more than 74.0%. The majority of the β-dihydroagarofuran-type sesquiterpenoids with ester groups exhibited stronger activity than those with free hydroxy groups or without substituents at the same positions. These results identified a new chemical skeleton as drug lead for the investigation of novel therapeutic agents against AD

Natural β‑Dihydroagarofuran-Type Sesquiterpenoids as Cognition-Enhancing and Neuroprotective Agents from Medicinal Plants of the Genus Celastrus

Alzheimer’s disease (AD) is an irreversible, multifaceted, and progressive neurodegenerative disorder. Over the past 30 years, the search for anti-AD drugs has been primarily based on the cholinergic deficiency hypothesis and/or the β-amyloid (Aβ) cascade hypothesis. In this study, we report the identification of 16 new and 38 known β-dihydroagarofuran-type sesquiterpenoids from Celastrus flagellaris and Celastrus angulatus. The β-dihydroagarofuran-type sesquiterpenoids <b>58</b>, <b>59</b>, <b>61</b>, and <b>63</b> significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the control group. At 10 μM, 21 of the 62 tested β-dihydroagarofuran-type sesquiterpenoids rescued Aβ_25–35-induced SH-SY5Y cells from viability reduction, which increased the cell viability from 64.6% for the model to more than 74.0%. The majority of the β-dihydroagarofuran-type sesquiterpenoids with ester groups exhibited stronger activity than those with free hydroxy groups or without substituents at the same positions. These results identified a new chemical skeleton as drug lead for the investigation of novel therapeutic agents against AD