scholarly journals BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Cristian Alfredo Segura-Cerda ◽  
Brenda Marquina-Castillo ◽  
Vasti Lozano-Ordaz ◽  
Dulce Mata-Espinosa ◽  
Jorge Alberto Barrios-Payán ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Lymphocytes ◽  
Inflammatory Cytokines ◽  
B Lymphocyte ◽  
Acute Infection ◽  
T And B Lymphocytes ◽  
Middle Income ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Abstract Comorbidity between Tuberculosis (TB) and type 2 diabetes (T2D) is one of the greatest contributors to the spread of Mycobacterium tuberculosis (M. tuberculosis) in low- and middle-income countries. T2D compromises key steps of immune responses against M. tuberculosis and it might affect the protection afforded by vaccine candidates against TB. We compared the protection and immune response afforded by the BCGΔBCG1419c vaccine candidate versus that of wild-type BCG in mice with T2D. Vaccination with both BCGΔBCG1419c, BCG or infection with M. tuberculosis reduced weight loss, hyperglycemia, and insulin resistance during T2D progression, suggesting that metabolic changes affecting these parameters were affected by mycobacteria. For control of acute TB, and compared with non-vaccinated controls, BCG showed a dominant T CD4+ response whereas BCGΔBCG1419c showed a dominant T CD8+/B lymphocyte response. Moreover, BCG maintained an increased response in lung cells via IFN-γ, TNF-α, and IL-4, while BCGΔBCG1419c increased IFN-γ but reduced IL-4 production. As for chronic TB, and compared with non-vaccinated controls, both BCG strains had a predominant presence of T CD4+ lymphocytes. In counterpart, BCGΔBCG1419c led to increased presence of dendritic cells and an increased production of IL-1 β. Overall, while BCG effectively reduced pneumonia in acute infection, it failed to reduce it in chronic infection, whereas we hypothesize that increased production of IL-1 β induced by BCGΔBCG1419c contributed to reduced pneumonia and alveolitis in chronic TB. Our results show that BCG and BCGΔBCG1419c protect T2D mice against TB via different participation of T and B lymphocytes, dendritic cells, and pro-inflammatory cytokines.

scholarly journals Author Correction: BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Cristian Alfredo Segura-Cerda ◽  
Brenda Marquina-Castillo ◽  
Vasti Lozano-Ordaz ◽  
Dulce Mata-Espinosa ◽  
Jorge Alberto Barrios-Payán ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Lymphocytes ◽  
Inflammatory Cytokines ◽  
T And B Lymphocytes ◽  
Diabetic Mice ◽  
Type 2 Diabetic ◽  
Pro Inflammatory Cytokines

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Apoptotic Cells for the Prevention of Cytokine Release Syndrome (CRS) in CAR T-Cell Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1626-1626
Author(s):  
Dror Mevorach ◽  
Veronique Amor ◽  
Yehudith Shabat
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
Apoptotic Cells ◽  
Car T ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Abstract Background: Chimeric antigen receptor (CAR)-modified T cells with specificity against CD19 have demonstrated dramatic promise against highly refractory hematologic malignancies. Clinical responses with complete remission rates as high as 90% have been reported in children and adults with relapsed/refractory acute lymphoblastic leukemia (ALL). However, very significant toxicity has been observed and as many as 30% in average developing severe forms of CRS and possibly related neurotoxicity. CRS is occurring due to large secretion of pro-inflammatory cytokines, mainly from macrophages/monocytes, and resembles macrophage-activating syndrome and hemophagocytosis in response to CAR T-secreting IFN-g and possibly additional cytokines. To better understand the mechanisms leading to CRS and to treat or prevent it, we have developed in vitro and in vivo models of CRS with and without CAR-modified T cells. Early apoptotic cells that have been successfully tested for the prevention of acute GVHD, including in 7 ALL patients, were tested in these models for their effect on cytokines and CAR T cell cytotoxicity. Methods: CD19-expressing HeLa cells were used alone or with co-incubation with human macrophages for in vitro experiments and intraperitoneal experiments. Raji was used in vivo for leukemia induction. LPS and IFN-γ were used to trigger additional cytokine release. CD19-specific CAR-modified cells were used (ProMab) for anti-tumor effect against CD19-bearing cells. Cytotoxicity assay was examined in vivo using 7-AAD with flow cytometry and in vitro by survival curves and analysis of tumor load in bone marrow and liver. CRS occurred spontaneously or in response to LPS and IFN-γ. Mouse IL-10, IL-1β, IL-2, IP-10, IL-4, IL-5, IL-6, IFNα, IL-9, IL-13, IFN-γ, IL-12p70, GM-CSF, TNF-α, MIP-1α, MIP-1β, IL-17A, IL-15/IL-15R, and IL-7, as well as 32 human cytokines were evaluated by Luminex technology using the MAPIX system analyzer (Mereck Millipore) and MILLIPLEX Analyst software (Merek Millipore). Mouse IL-6Rα, MIG (CXCL9), and TGF-β1 were evaluated by Quantikine ELISA (R&D systems). Bone marrow and liver were evaluated using flow cytometry and immunohistochemistry. The IFN-γ effect was evaluated by STAT1 phosphorylation and biological products. Human macrophages and dendritic cells were generated from monocytes. Early apoptotic cells were produced as shown in GVHD clinical trial; at least 50% of cells were annexin V-positive and less than 5% were PI-positive. Results: Apoptotic cells had no negative effect in vitro or in vivo on CAR-modified T cells with specificity against CD19. There were comparable E/T ratios for CAR T in the presence or absence of apoptotic cells in vitro, and comparable survival curves in vivo. On the other hand, significant downregulation (p<0.01) of pro-inflammatory cytokines, including IL-6, IP-10, TNF-a, MIP-1α, MIP-1β, was documented. IFN-γ was not downregulated, but its effect on macrophages and dendritic cells was inhibited at the level of phosphorylated STAT1 and IFN-γ-induced expression of CXCL10 and CXCL9 was reduced. Conclusion: CRS evolves from several factors, including tumor biology, interaction with monocytes/macrophages/dendritic cells, and as a response to the CAR T cell effect and expansion. Apoptotic cells decrease pro-inflammatory cytokines that originate from innate immunity and inhibit the IFN-γ effect on monocyte/macrophages/ dendritic cells without harming IFN-γ levels or CAR-T cytotoxicity. Disclosures Mevorach: Enlivex: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Amor:Enlivex: Employment. Shabat:Enlivex: Employment.

scholarly journals Modulation of ACE-2 mRNA by inflammatory cytokines in human thyroid cells: a pilot study

Endocrine ◽  
2021 ◽  
Author(s):  
Francesca Coperchini ◽  
Gianluca Ricci ◽  
Laura Croce ◽  
Marco Denegri ◽  
Rubina Ruggiero ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Combination Treatment ◽  
Primary Cultures ◽  
Human Thyroid ◽  
Thyroid Cell ◽  
Mrna Levels ◽  
Thyroid Cells ◽  
Tnf Α ◽  
Ifn Γ ◽  
Pro Inflammatory Cytokines

Abstract Introduction Angiotensin-converting-enzyme-2 (ACE-2) was demonstrated to be the receptor for cellular entry of SARS-CoV-2. ACE-2 mRNA was identified in several human tissues and recently also in thyroid cells in vitro. Purpose Aim of the present study was to investigate the effect of pro-inflammatory cytokines on the ACE-2 mRNA levels in human thyroid cells in primary cultures. Methods Primary thyroid cell cultures were treated with IFN-γ and TNF-α alone or in combination for 24 h. ACE-2 mRNA levels were measured by RT-PCR. As a control, the levels of IFN-γ inducible chemokine (CXCL10) were measured in the respective cell culture supernatants. Results The mean levels of ACE-2 mRNA increased after treatment with IFN-γ and TNF-α in all the thyroid cell preparations, while the combination treatment did not consistently synergically increase ACE-2-mRNA. At difference, CXCL10 was consistently increased by IFN-γ and synergically further increased by the combination treatment with IFN-γ + TNF-α, with respect to IFN-γ alone. Conclusions The results of the present study show that IFN-γ and, to a lesser extent TNF-α consistently increase ACE-2 mRNA levels in NHT primary cultures. More interestingly, the combined stimulation (proven to be effective according to the synergic effect registered for CXCL10) produces different responses in terms of ACE-2 mRNA modulation. These results would suggest that elevated levels of pro-inflammatory cytokines could facilitate the entering of the virus in cells by further increasing ACE-2 expression and/or account for the different degree of severity of SARS-COV-2 infection. This hypothesis deserves to be confirmed by further specific studies.

Glial Cells and Pro-inflammatory Cytokines as Shared Neurobiological Bases for Chronic Pain and Psychiatric Disorders

2020 ◽  
pp. 27-49
Author(s):  
Judith A. Strong ◽  
Sang Won Jeon ◽  
Jun-Ming Zhang ◽  
Yong-Ku Kim
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Psychiatric Disorders ◽  
Inflammatory Cytokines ◽  
Glial Cells ◽  
Neuronal Excitability ◽  
Pro Inflammatory Cytokines

This chapter reviews the roles of cytokines and glial cells in chronic pain and in psychiatric disorders, especially depression. One important role of cytokines is in communicating between activated glia and neurons, at all levels of the nervous system. This process of neuroinflammation plays important roles in pain and depression. Cytokines may also directly regulate neuronal excitability. Many cytokines have been implicated in both pain and psychiatric disorders, including interleukin-1β‎ (IL-1β‎), tumor necrosis factor-α‎, and IL-6. More generally, an imbalance between type 1, pro-inflammatory cytokines and type 2, anti-inflammatory cytokines has been implicated in both pain and psychiatric disorders. Activation of the sympathetic nervous system can contribute to both pain and psychiatric disorders, in part through its actions on inflammation and the cytokine profile.

scholarly journals Macrophage-associated pro-inflammatory state in human islets from obese individuals

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Wei He ◽  
Ting Yuan ◽  
Kathrin Maedler
Keyword(s):  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Human Islets ◽  
Macrophage Phenotype ◽  
Inflammatory State ◽  
Obese Control ◽  
Inflammatory Macrophages ◽  
Inflammatory Macrophage ◽  
Pro Inflammatory Cytokines

AbstractObesity is associated with inflammatory macrophages in insulin responsive tissues and the resulting inflammatory response is a major contributor to insulin resistance. In insulin-producing pancreatic islets, the intra-islet accumulation of macrophages is observed in patients of type 2 diabetes (T2D), but such has not been investigated in obese individuals. Here, we show that pro-inflammatory cytokines (IL-1β, IL-6, and TNF), anti-inflammatory cytokines (IL-10 and TGF-β) and macrophage polarization markers (CD11c, CD163, and NOS2) were expressed in isolated human islets from non-diabetic donors. Clodronate-mediated depletion of resident macrophages revealed expression of IL1B and IL10 mostly from macrophages, while IL6, TNF, and TGFB1 came largely from a non-macrophage origin in human islets. NOS2 expression came exclusively from non-macrophage cells in non-obese individuals, while it originated also from macrophages in obese donors. Macrophage marker expression of CD68, CD163, and ITGAX was unchanged in islets of non-obese control and obese cohorts. In contrast, IL1B and NOS2 were significantly increased in islets from obese, compared to non-obese individuals, implying a more inflammatory macrophage phenotype in islets in obesity. Our study shows elevated macrophage-associated inflammation in human islets in obesity, which could be an initiating factor to the pro-inflammatory intra-islet milieu and contribute to the higher susceptibility to T2D in obese individuals.

scholarly journals Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

2020 ◽  
Author(s):  
Bruna Lima Correa ◽  
Nadia El Harane ◽  
Ingrid Gomez ◽  
Hocine Rachid Hocine ◽  
José Vilar ◽  
...  
Keyword(s):  
Immune Response ◽  
Extracellular Vesicles ◽  
Inflammatory Cytokines ◽  
Nk Cell ◽  
Inflammatory Monocytes ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Aims The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation. Methods and results Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages. Conclusions EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.

scholarly journals Bioactive Compounds from Polygala tenuifolia and Their Inhibitory Effects on Lipopolysaccharide-Stimulated Pro-inflammatory Cytokine Production in Bone Marrow-Derived Dendritic Cells

Plants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1240
Author(s):  
Le Ba Vinh ◽  
Myungsook Heo ◽  
Nguyen Viet Phong ◽  
Irshad Ali ◽  
Young Sang Koh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Inflammatory Cytokines ◽  
2D Nmr ◽  
Inhibitory Effects ◽  
Triterpenoid Saponins ◽  
Traditional Chinese Herbal Medicine ◽  
Polygala Tenuifolia ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The roots of Polygala tenuifolia Wild (Polygalaceae), which is among the most important components of traditional Chinese herbal medicine, have been widely used for over 1000 years to treat a variety of diseases. In the current investigation of secondary metabolites with anti-inflammatory properties from Korean medicinal plants, a phytochemical constituent study led to the isolation of 15 compounds (1–15) from the roots of P. tenuifolia via a combination of chromatographic methods. Their structures were determined by means of spectroscopic data such as nuclear magnetic resonance (NMR), 1D- and 2D-NMR, and liquid chromatography-mass spectrometry (LC-MS). As the obtained results, the isolated compounds were divided into two groups—phenolic glycosides (1–9) and triterpenoid saponins (10–15). The anti-inflammatory effects of crude extracts, fractions, and isolated compounds were investigated on the production of the pro-inflammatory cytokines interleukin (IL)-12 p40, IL-6, and tumour necrosis factor-α in lipopolysaccharide-stimulated bone marrow-derived dendritic cells. The IC50 values, ranging from 0.08 ± 0.01 to 21.05 ± 0.40 μM, indicated potent inhibitory effects of the isolated compounds on the production of all three pro-inflammatory cytokines. In particular, compounds 3–12, 14, and 15 showed promising anti-inflammatory activity. These results suggest that phenolic and triterpenoid saponins from P. tenuifolia may be excellent anti-inflammatory agents.

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