scholarly journals A modified porous silicon microparticle promotes mucosal delivery of SARS-CoV-2 antigen and induction of potent and durable systemic and mucosal T helper 1 skewed protective immunity

2021 ◽  
Author(s):  
Awadalkareem Adam ◽  
Qing Shi ◽  
Binbin Wang ◽  
Jing Zou ◽  
Junhua Mai ◽  
...  
Keyword(s):  
Porous Silicon ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
T Helper ◽  
T Helper 1 ◽  
Viral Loads ◽  
Mucosal Vaccination ◽  
Mucosal Delivery ◽  
Th Cell

Development of optimal SARS-CoV-2 vaccines to induce potent, long-lasting immunity and provide cross-reactive protection against emerging variants remains a high priority. Here, we report that a modified porous silicon microparticle (mPSM)-adjuvanted SARS-CoV-2 receptor-binding domain (RBD) vaccine activated dendritic cells and generated more potent and durable SARS-CoV-2-specific systemic humoral and type 1 helper T (Th) cell-mediated immune responses than alum-formulated RBD following parenteral vaccination, and protected mice from SARS-CoV-2 and Beta variant infection. mPSM facilitated the uptake of SARS-CoV-2 RBD antigens by nasal and airway epithelial cells. Parenteral and intranasal prime and boost vaccinations with mPSM-RBD elicited potent systemic and lung resident memory T and B cells and SARS-CoV-2 specific IgA responses, and markedly diminished viral loads and inflammation in the lung following SARS-CoV-2 Delta variant infection. Our results suggest that mPSM can serve as potent adjuvant for SARS-CoV-2 subunit vaccine which is effective for systemic and mucosal vaccination.

A Commitment to Lineage

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-22-SCI-22
Author(s):  
Laurie H. Glimcher ◽  
Vanja Lazarevic ◽  
Joerg Ermann ◽  
Wendy Garrett
Keyword(s):  
Colorectal Cancer ◽  
Immune System ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Inflammatory Diseases ◽  
Rectal Adenocarcinoma ◽  
Adaptive Immune System ◽  
T Helper ◽  
T Helper 1

Abstract Abstract SCI-22 The transcription factor T-bet, isolated in our laboratory a decade ago, is a master regulator of Type 1 immunity in cells of both the adaptive and innate immune system. In adaptive immunity, T-bet instigates genetic programs in T helper 1 (Th1) cells and is required for production of the hallmark Th1 cytokine IFNg. It simultaneously represses the differentiation of T helper 2 cells and the profibrotic cytokines IL-13 and TGFb. We have recently determined that T-bet is also a repressor of the Th17 genetic program and have established the molecular mechanisms that underpin that function. T-bet also controls the optimal differentiation and function of the cytolytic CD8 cell, and is required for the development of the natural killer T cell. T-bet deficient animals are largely protected from autoimmune/inflammatory diseases such as multiple sclerosis, systemic lupus, type 1 diabetes and inflammatory arthritis, but are susceptible to type 2 driven diseases such as asthma and scleroderma. An exception to this overall rule is our recent discovery that in the absence of an adaptive immune system, the majority of mice lacking T-bet develop a spontaneous ulcerative colitis that progresses to colonic dysplasia and rectal adenocarcinoma. This colitis and inflammation associated colorectal cancer are MyD88 independent, driven by colitogenic flora and ameliorated by treatment with TNF blockade, antibiotics, and transfer of T regulatory cells. This phenotype maps to the T-bet deficient dendritic cell that drives this pro-inflammatory program; selective over-expression of T-bet in DCs was sufficient to reduce colonic inflammation and prevent the progression to neoplasia. The molecular pathogenesis of TRUC colitis and colitis-associated colorectal (caCRC) shares several key features with human caCRC. This model of colitis and colitis-associated colorectal cancer provides opportunities to further understand host-microbial relationships in inflammation and neoplasia and test preventative and therapeutic strategies pre-clinically. The function and mechanism of action of T-bet in the pathogenesis of immune system driven diseases will be discussed. Disclosures: Glimcher: Merck: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells

1997 ◽  
Vol 185 (5) ◽  
pp. 817-824 ◽  
Author(s):  
Susanne J. Szabo ◽  
Anand S. Dighe ◽  
Ueli Gubler ◽  
Kenneth M. Murphy
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Selective Loss ◽  
Th Cell ◽  
Subunit Expression ◽  
Ifn Γ

The developmental commitment to a T helper 1 (Th1)- or Th2-type response can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells results from a selective loss of IL-12 receptor (IL-12R) β2 subunit expression. To determine the basis for this selective loss, we examined IL-12R β2 subunit expression during Th cell development in response to T cell treatment with different cytokines. IL-12R β2 is not expressed by naive resting CD4+ T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN-γ were found to significantly modify IL-12 receptor β2 expression after T cell activation. IL-4 inhibited IL-12R β2 expression leading to the loss of IL-12 signaling, providing an important point of regulation to promote commitment to the Th2 pathway. IFN-γ treatment of early developing Th2 cells maintained IL-12R β2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN-γ production. Thus, IFN-γ may prevent early Th cells from premature commitment to the Th2 pathway. Controlling the expression of the IL-12R β2 subunit could be an important therapeutic target for the redirection of ongoing Th cell responses.

High T-helper-1 cytokines but low T-helper-3 cytokines, inflammatory cytokines and chemokines in children with high risk of developing type 1 diabetes

2007 ◽  
Vol 23 (6) ◽  
pp. 462-471 ◽  
Author(s):  
Katerina Stechova ◽  
Kristyna Bohmova ◽  
Zuzana Vrabelova ◽  
Annelie Sepa ◽  
Gabriela Stadlerova ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
High Risk ◽  
Inflammatory Cytokines ◽  
T Helper ◽  
T Helper 1 ◽  
Cytokines And Chemokines

scholarly journals Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells.

1988 ◽  
Vol 168 (2) ◽  
pp. 543-558 ◽  
Author(s):  
R Fernandez-Botran ◽  
V M Sanders ◽  
T R Mosmann ◽  
E S Vitetta
Keyword(s):  
Proliferative Response ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Ifn Gamma ◽  
T Helper 2 ◽  
Regulatory Interactions ◽  
Th Cell ◽  
Th1 And Th2

Murine Th1 and Th2 subsets differ not only in the lymphokines they produce, but also functionally. It is not clear what factors influence the preferential activation of one subset versus the other and what regulatory interactions exist between them. The purpose of this study was to examine the effect of lymphokines produced by clones of Th1 cells (IL-2 and IFN-gamma), Th2 cells (IL-4), and APC (IL-1) on the proliferative response of Th1 and Th2 cells after antigenic stimulation. Activation of both types of clones in the presence of antigen and APC resulted in the acquisition of responsiveness to the proliferative effects of both IL-2 and IL-4, although Th2 cells were more responsive to IL-4 than Th1 cells. Responsiveness of Th1 and Th2 cells to both lymphokines decreased with time after initial antigenic activation; Th1 cells lost their responsiveness to IL-4 more rapidly and to IL-2 more slowly than Th2 cells. IFN-gamma partially inhibited the IL-2 and IL-4-mediated proliferation of Th2, but not Th1 cells. Although the presence of IL-1 was not required for the response of Th1 or Th2 cells to IL-4, its presence resulted in a synergistic effect with IL-2 or IL-4 in Th2 but not in Th1 cells. Both subsets responded to a mixture of IL-2 and IL-4 in synergistic fashion. Delayed addition and wash-out experiments indicated that both IL-2 and IL-4 had to be present simultaneously in order for synergy to occur. These results suggest that Th cell subsets might regulate each other via the lymphokines that they secrete and that the pathways of IL-2 and IL-4 mediated proliferation are interrelated.

scholarly journals A Recessively Inherited Risk Locus on Chromosome 13q22-31 Conferring Susceptibility to Schizophrenia

2020 ◽  
Author(s):  
Tariq Mahmood ◽  
Mohammed E El-Asrag ◽  
James A Poulter ◽  
Alastair G Cardno ◽  
Anneka Tomlinson ◽  
...  
Keyword(s):  
Homozygosity Mapping ◽  
Risk Haplotype ◽  
Structural Variants ◽  
T Helper ◽  
Protein Coding ◽  
Th Cell ◽  
The Family ◽  
Homozygous Region ◽  
A Minor

Abstract We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia.

scholarly journals Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs

2016 ◽  
Vol 9 (3) ◽  
pp. 318-329 ◽  
Author(s):  
Nader Alaridah ◽  
Nataliya Lutay ◽  
Erik Tenland ◽  
Anna Rönnholm ◽  
Oskar Hallgren ◽  
...  
Keyword(s):  
G Protein ◽  
Airway Epithelial Cells ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Airway Epithelial ◽  
Mucosal Vaccination ◽  
Mapk Signalling Pathway ◽  
The Impact ◽  
G Protein Coupled ◽  
Rac1 Expression

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

scholarly journals Role of Dexamethasone on immune dysregulation mediated through Th1/Th2 cytokine balance in mice challenged with type 1 diabetes and allergic asthma

2019 ◽  
Vol 10 (4) ◽  
pp. 3042-3054
Author(s):  
Ravikumar N ◽  
Kavitha CH N
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
T Helper ◽  
Dexamethasone Treatment ◽  
T Helper 1 ◽  
Sterile Saline ◽  
Cytokine Balance

Dysregulated equilibrium between T helper 1 (Th1) and T helper 2 (Th2) immune responses has been implicated in the pathogenesis of type 1 diabetes (T1D) and asthma. Conflicting evidence exist explaining the association between T1D and asthma and is still a point of debate. In the present study, our objective was to investigate the influence of associated T1Dco morbid condition on the induction of experimental asthma in mice and also to evaluate the efficacy of Dexamethasone (0.5 mg/kg, s.c.ly) in these mice. Type 1 diabetes was induced by a single intravenous injection of alloxan (80 mg/kg) in Balb/c mice. Following diabetes induction, mice were sensitized with an intraperitoneal injection of 50 µg ovalbumin (Ova) emulsified in 2.5 mg aluminum hydroxide on days 3 and 8. From day 13 to day 15, animals were challenged intranasally with 100 µg Ova in 25 µl of sterile saline. Dexamethasone treatment was initiated on sensitization day and continued once in 2 days thereafter until day 15. Control animals received only saline without Ova. On day 16, mice were subjected to nasal hyperresponsiveness (NHR) immediately after the Ova challenge. Bronchioalveolar lavage fluid (BALF), blood, and lungs were collected 1h post completion of NHR for further analysis. Alloxan diabetic mice showed significantly lower levels of eosinophils in BALF and blood with the corresponding decrease in inflammatory cells around airways in hematoxylin & eosin-stained lung sections, but with no change in NHR than in non-diabetics after Ova sensitization and challenge. Dexamethasone treatment showed a significant reduction of airway inflammation and related Th2 immune responses, with a lesser magnitude of efficacy in diabetic asthma mice than in non-diabetic asthma mice. The presence of T1D featured a unique, yet the intermediary stage of asthma induction and also presented an altered magnitude of Dexamethasone efficacy compared to the absence of T1D in the murine model of Ova induced asthma.

scholarly journals Assessment of the infectious threshold of SARS-CoV-2 in primary airway epithelial cells

2021 ◽  
Author(s):  
Manel ESSAIDI-LAZIOSI ◽  
Francisco Javier Perez Rodriguez ◽  
Pascale Sattonnet Roche ◽  
Nicolas Hulo ◽  
Frederique Jacquerioz ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Lines ◽  
Virus Isolation ◽  
Airway Epithelial Cells ◽  
Clinical Samples ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Viral Loads ◽  
Human Airway ◽  
Human Airway Epithelia

Comparison of virus isolation success from clinical samples across a range of viral loads inoculated in parallel on Vero E6 and human airway epithelia (HAE) showed lower success of virus isolation in HAE, suggesting an overestimation of actual infectiousness in humans using Vero E6 cell lines, commonly considered as reference.

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