Angelica gigas extract ameliorates allergic rhinitis in an ovalbumin-induced mouse model by inhibiting Th2 cell activation

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.

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Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001615 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001615

Author(s):

Rachel A Woolaver ◽

Xiaoguang Wang ◽

Alexandra L Krinsky ◽

Brittany C Waschke ◽

Samantha M Y Chen ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

Immune Responses ◽

Single Cell ◽

T Cell Activation ◽

Antitumor Immunity ◽

Cell Activation ◽

Tcr Repertoire ◽

Underlying Mechanisms ◽

Personalized Cancer

BackgroundAntitumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences.MethodsWe developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous antitumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor-infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes.ResultsWe discovered that genetically identical wild-type recipient mice responded heterogeneously to the same squamous cell carcinoma tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous antitumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRα/TCRβ sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing versus growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status.ConclusionsWe reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous antitumor immune responses in different hosts. We suggest that antitumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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Upregulated Expression of Toll-Like Receptor 7 in Peripheral Blood Basophils of Patients With Allergic Rhinitis

American Journal of Rhinology and Allergy ◽

10.1177/1945892421993034 ◽

2021 ◽

pp. 194589242199303

Author(s):

Lihong Wang ◽

Mengmeng Zhan ◽

Junling Wang ◽

Dong Chen ◽

Nan Zhao ◽

...

Keyword(s):

Allergic Rhinitis ◽

Mrna Levels ◽

Toll Like Receptor ◽

Cell Functions ◽

Th2 Cell ◽

Hla Dr ◽

Ku812 Cells ◽

Th1 Cytokine ◽

Der P1 ◽

Blood Granulocyte

Background Recently, it has been reported that Toll-like receptor 7 (TLR7) agonists can improve allergic rhinitis (AR) symptoms by up-regulation of Th1 cytokine release and suppression of Th2 cell functions. However, little is known of the expression of TLR7 in basophils of AR. Objective To explore the expression of TLR7 in basophils of AR, and influence of allergens on TLR7 expression. Methods The expression levels of TLR7 in basophils of patients with AR were determined by flow cytometry, and the influence of allergens on TLR7 expression was examined by real time (q) PCR. Results The percentages of TLR7+CCR3+ cells ( P < 0.001 and P = 0.011), TLR7+CD123+HLA-DR− cells ( P = 0 .016 and P = 0.042) and TLR7+CCR3+CD123+HLA-DR− cells ( P = 0.046 and P = 0.035) in blood granulocyte and mononucleated cell populations of the patients with AR were increased, respectively compared with HC subjects. TLR7 MFI on CCR3+ cells ( P = 0.050 and P = 0.043), CD123+HLA-DR− cells ( P < 0.001 and P = 0.002) and CCR3+CD123+HLA-DR− cells ( P < 0.001 and P = 0.003) were enhanced compared with HC subjects. Allergens Der p1 and OVA provoked upregulation of TLR7 expression at both protein and mRNA levels and IL-13 production in KU812 cells. House Dust Mite extract (HDME), Artemisia sieversiana wild allergen extract (ASWE), IL-31, IL-33, IL-37, and TSLP provoked elevation of IL-6 release from KU812 cells following 2 h incubation period. Conclusions The percentage of TLR7+ basophils and TLR7 expression intensity in a single basophil are both increased in the blood of patients with AR, indicating that basophils likely contribute to the pathogenesis of AR via TLR7.

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Fetal Sex Affects Uterine Natural Killer Cell Activation and Spiral Artery Angiogenesis in a Transgenic Mouse Model of Intrauterine Growth Restriction

Placenta ◽

10.1016/j.placenta.2017.07.164 ◽

2017 ◽

Vol 57 ◽

pp. 274

Author(s):

Jessica Hebert ◽

Terry Morgan

Keyword(s):

Natural Killer Cell ◽

Mouse Model ◽

Natural Killer ◽

Transgenic Mouse ◽

Intrauterine Growth Restriction ◽

Cell Activation ◽

Killer Cell ◽

Transgenic Mouse Model ◽

Spiral Artery ◽

Intrauterine Growth

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Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Blood ◽

10.1182/blood-2012-01-406827 ◽

2012 ◽

Vol 120 (5) ◽

pp. 1005-1014 ◽

Cited By ~ 18

Author(s):

Veronica Marrella ◽

Pietro L. Poliani ◽

Elena Fontana ◽

Anna Casati ◽

Virginia Maina ◽

...

Keyword(s):

T Cell ◽

Mouse Model ◽

T Cell Activation ◽

Cell Activation ◽

Severe Combined Immunodeficiency ◽

Cell Receptor ◽

Omenn Syndrome ◽

Activated T Cells ◽

Therapeutic Implications ◽

Autoimmune Regulator

Abstract Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3ε monoclonal antibody (mAb) treatment in RAG2−/− mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3ε mAb administration in the RAG2R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2R229Q progenitors into RAG2−/− animals previously conditioned with anti-CD3ε mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3ε mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity.

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