Regulatory T cells (Treg) play essential roles in maintaining immune homeostasis. Resident Treg in visceral adipose tissue (VAT-Treg) decrease in male obese mice, which leads to the development of ...obesity-associated chronic inflammations and insulin resistance. Although gender differences in immune responses have been reported, the effects of the difference in metabolic environment on VAT-Treg are unclear. We investigated the localization of VAT-Treg in female mice in comparison with that in male mice. On a high-fat diet (HFD), VAT-Treg decreased in male mice but increased in female mice. The increase was abolished in ovariectomized and HFD-fed mice, but was restored by estrogen supplementation. The IL33 receptor ST2, which is important for the localization and maturation of VAT-Treg in males, was reduced in CD4+CD25+ T cells isolated from gonadal fat of obese mice of both genders, suggesting that a different system exists for VAT-Treg localization in females. Extensive analysis of chemokine expression in gonadal fat and adipose CD4+CD25+T cells revealed several chemokine signals related to female-specific VAT-Treg accumulation such as CCL24, CCR6, and CXCR3. Taken together, the current study demonstrated sexual dimorphism in VAT-Treg localization in obese mice. Estrogen may attenuate obesity-associated chronic inflammation partly through altering chemokine-related VAT-Treg localization in females.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was ...undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval CI, 13.2, 52.9. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.
Tucidinostat is an oral novel benzamide HDACi of HDAC isoenzymes 1, 2, 3 and 10 selectively. 23 patients with relapsed/refractory ATLL were treated with tucidinostat 40mg orally twice a week. Out of 23 patients, 7 showed objective responses including 1 CR, and ORR was 30.4%.
Aims/hypothesis
The imbalance between maternal insulin resistance and a relative lack of insulin secretion underlies the pathogenesis of gestational diabetes mellitus (GDM). Alterations in T cell ...subtypes and increased levels of circulating proinflammatory cytokines have been proposed as potential mechanisms underlying the pathophysiology of insulin resistance in GDM. Since oestrogen modulates T cell immunity, we hypothesised that oestrogen plays a homeostatic role in visceral adipose tissue by coordinating T cell immunity through oestrogen receptor α (ERα) in T cells to prevent GDM.
Methods
Female CD4-cre ERα
fl/fl
(KO) mice on a C57BL/6 background with ERα ablation specifically in T cells, and ERα
fl/fl
(ERα-floxed FL) mice were fed 60 kJ% high-fat diet (HFD) for 4 weeks. Female mice mated with male BALB/c mice to achieve allogenic pregnancy and were maintained on an HFD to generate the GDM model. Mice were divided into four experimental groups: non-pregnant FL, non-pregnant KO, pregnant FL (FL-GDM) and pregnant KO (KO-GDM). GTTs and ITTs were performed on day 12.5 or 13.5 and 16.5 after breeding, respectively. On day 18.5 after breeding, mice were killed and T cell subsets in the gonadal white adipose tissue (gWAT) and spleen were analysed using flow cytometry. Histological examination was also conducted and proinflammatory gene expression in gWAT and the liver was evaluated.
Results
KO mice that mated with BALB/c mice showed normal fertility rates and fetal weights as compared with FL mice. Body and tissue weights were similar between FL and KO mice. When compared with FL-GDM mice, KO-GDM mice showed decreased insulin secretion (serum insulin concentration 15 min after glucose loading: 137.3 ± 18.3 pmol/l and 40.1 ± 36.5 pmol/l, respectively;
p
< 0.05), impaired glucose tolerance (glucose AUC in GTT: 2308.3 ± 54.0 mmol/l × min and 2620.9 ± 122.1 mmol/l × min, respectively;
p
< 0.05) and increased numbers of T helper (Th)17 cells in gWAT (0.4 ± 0.0% vs 0.8 ± 0.1%;
p
< 0.05). However, the contents of Th1 and regulatory T cells (Tregs) in gWAT remained similar between FL-GDM and KO-GDM. Glucose-stimulated insulin secretion was similar between isolated islets derived from FL and KO mice, but was reduced by IL-17A treatment. Moreover, the levels of proinflammatory gene expression, including expression of
Emr1
and
Tnfa
in gWAT, were significantly higher in KO-GDM mice than in FL-GDM mice (5.1-fold and 2.7-fold, respectively;
p
< 0.01 for both). Furthermore, KO-GDM mice showed increased expression of genes encoding hepatokines,
Ahsg
and
Fgf21
(both were 2.4-fold higher vs FL-GDM mice;
p
< 0.05 and
p
= 0.09, respectively), with no changes in inflammatory gene expression (e.g.,
Tnfa
and
Ifng
) in the liver compared with FL-GDM mice.
Conclusions/interpretation
Deletion of ERα in T cells caused impaired maternal adaptation of insulin secretion, changes in hepatokine profiles, and enhanced chronic inflammation in gWAT alongside an abnormal increase in Th17 cells. These results suggest that the ERα-mediated oestrogen signalling effects in T cells regulate T cell immunity and contribute to glucose homeostasis in pregnancy.
Graphical abstract
Introduction & Objective: To appreciate the pathophysiological changes in the transcriptome and cell type landscape during obesity, single-nucleus (sn)RNA-seq overcomes the difficulty of maintaining ...intact transcripts. Sedimentation of dissociated live cells is used to concentrate adipocytes (Ads) and stromal cells. The current study compared the single cell level transcriptome in libraries with and without the fractionation. Methods: C57BL/6J mice were fed an HFD for 12 weeks starting at 8 weeks of age. Dissected epididymal fat from the same donor was divided into three conditions: 1) nuclei from unfractionated frozen fat (UF), 2) nuclei from the Ad fraction (AF) after enzymatic digestion and centrifugation, and 3) cells from the stromal fraction corresponding to the AF. As a dietary control, nuclei were prepared from the UF of an age-matched normal chow-fed mouse. Single cell/nucleus transcriptome libraries were sequenced using short-read NGS. Results: A total of 32,949 cells were recovered by snRNA-seq. Fractionation lost recovery of certain cell types, including epithelial, mesothelial, and B cells. Fractionation barely enriched Ads in the AF at 12.4%, comparable to the Ads (11.2%) in the UF. Macrophages (Mφs), rather than Ads, accounted for 54.6% of the AF. The Mφs were clustered into six subtypes by Seurat independent of dietary conditions or fractionation. However, certain cytokines were more highly expressed in Mφs from fractions than those from UF. In support of this, functional annotation-driven unsupervised clustering, ASURAT, mapped three Mφ subtypes in the libraries from fractions that differed from those from the UF, where there were four other subtypes. Conclusion: The current study suggests that the conventional fractionation could bias the transcriptome and a nuclear library from unfractionated frozen fat would represent a naïve comprehensive transcriptome that better reflects the pathophysiology of obesity, which should be important for understanding cell function. Disclosure Y. Onogi: None. T. Wada: None. S. Fujisaka: None. T. Sasaoka: None. K. Iida: None. Y. Okada: None. M. Kadowaki: None. S. Saito: None. K. Tobe: None. Funding JST Moonshot R&D (JPMJMS2021)
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