Beneficial effects of estrogen treatment in the HLA-B27 transgenic rat model of inflammatory bowel disease

A well-established model of bowel inflammation is the HLA-B27 transgenic rat that exhibits a spontaneous disease phenotype resulting in chronic diarrhea caused by immune cell activation. Estrogens have previously been shown to modulate the immune system, and both estrogen receptors (ERα and ERβ) are present in the intestine and cells of the immune system. Therefore, the ability of estrogen to ameliorate disease progression in the HLA-B27 transgenic rat was determined. HLA-B27 transgenic rats with chronic diarrhea were treated with 17α-ethynyl-17β-estradiol (EE) for 5 days. EE treatment dramatically improved stool scores after only 3 days. Histological scores of the degree of ulceration, inflammatory cell infiltration, fibrosis, and lesion depth of the colon were also improved by EE treatment. Because neutrophil infiltration into the colon is involved in the development and propagation of disease, myeloperoxidase (MPO) activity was measured. MPO levels were reduced by 80% by EE treatment. Cotreatment with the pure ER antagonist ICI-182780 (ICI) blocked the effects of EE on stool character, MPO activity, and histology scores, strongly suggesting that the activity of EE is mediated through ER. Mast cell proteases can promote neutrophil infiltration, and gene expression analysis demonstrated that mast cell protease 1, 3, and 4 mRNA were all decreased in colons from estrogen-treated rats. In addition, a direct effect of estrogen on bone marrow-derived mast cell activity was demonstrated, suggesting that ER-mediated inactivation of mast cells may contribute to the improvement in the clinical sign and histological scores in this model.

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Mast Cell Activation Disorder: A Rare Cause of Chronic Diarrhea and Abdominal Pain

The American Journal of Gastroenterology ◽

10.14309/00000434-201610001-02116 ◽

2016 ◽

Vol 111 ◽

pp. S1010

Author(s):

Jeffrey Bank ◽

Abdul Haseeb ◽

Kathryn Peterson

Keyword(s):

Mast Cell ◽

Abdominal Pain ◽

Cell Activation ◽

Chronic Diarrhea ◽

Mast Cell Activation

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Immunomodulation of Epithelium

Canadian Journal of Gastroenterology ◽

10.1155/1996/937461 ◽

1996 ◽

Vol 10 (4) ◽

pp. 243-248 ◽

Cited By ~ 1

Author(s):

Mary H Perdue

Keyword(s):

Mast Cell ◽

Immune Cells ◽

Cell Activation ◽

Immune Cell ◽

Regulatory System ◽

Mast Cell Activation ◽

Immune Cell Activation ◽

Inflammatory Conditions ◽

Close Proximity ◽

Antigenic Material

Many studies have provided evidence that the immune system is a key regulatory system of intestinal function. The interaction of immune cells with the gut epithelium plays an important role in host defence, acting to eliminate pathogens, antigens and other noxious material from the lumen of the gastrointestinal tract. During inflammatory conditions of the gut, the mucosa becomes packed with immune cells in close proximity to the enterocytes. Mediators released from these cells have profound effects on epithelial functions. The two main functions of the intestinal epithelium are to transport nutrients, ions and water, and to act as a barrier to prevent unimpeded uptake of antigenic material and microbes from the lumen. Both these functions are altered by immune reactions in response to various stimuli. Topics discussed include mast cells and epithelial function; mast cell-nerve interaction; mast cell activation; neutrophils, eosinophils and macrophages; T cells; and prostaglandins and immune cell activation.

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LncRNAs Target Ferroptosis-Related Genes and Impair Activation of CD4+ T Cell in Gastric Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.797339 ◽

2021 ◽

Vol 9 ◽

Author(s):

Fuwen Yao ◽

Yongqiang Zhan ◽

Zuhui Pu ◽

Ying Lu ◽

Jiao Chen ◽

...

Keyword(s):

Gastric Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

T Cell Activation ◽

Cell Activation ◽

Immune Cell ◽

Cell Activity ◽

Cell Receptor ◽

Cell Infiltration ◽

Poor Overall Survival

Gastric cancer (GC) is a malignant disease of the digestive tract and a life-threatening disease worldwide. Ferroptosis, an iron-dependent cell death caused by lipid peroxidation, is reported to be highly correlated with gastric tumorigenesis and immune cell activity. However, the underlying relationship between ferroptosis and the tumor microenvironment in GC and potential intervention strategies have not been unveiled. In this study, we profiled the transcriptome and prognosis data of ferroptosis-related genes (FRGs) in GC samples of the TCGA-STAD dataset. The infiltrating immune cells in GC were estimated using the CIBERSORT and XCELL algorithms. We found that the high expression of the hub FRGs (MYB, PSAT1, TP53, and LONP1) was positively correlated with poor overall survival in GC patients. The results were validated in an external GC cohort (GSE62254). Further immune cell infiltration analysis revealed that CD4+ T cells were the major infiltrated cells in the tumor microenvironment of GC. Moreover, the hub FRGs were significantly positively correlated with activated CD4+ T cell infiltration, especially Th cells. The gene features in the high-FRG score group were enriched in cell division, DNA repair, protein folding, T cell receptor, Wnt and NIK/NF-kappaB signaling pathways, indicating that the hub FRGs may mediate CD4+ T cell activation by these pathways. In addition, an upstream transcriptional regulation network of the hub FRGs by lncRNAs was also developed. Three lncRNAs (A2M-AS1, C2orf27A, and ZNF667-AS1) were identified to be related to the expression of the hub FRGs. Collectively, these results showed that lncRNA A2M-AS1, C2orf27A, and ZNF667-AS1 may target the hub FRGs and impair CD4+ T cell activation, which finally leads to poor prognosis of GC. Effective interventions for the above lncRNAs and the hub FRGs can help promote CD4+ T cell activation in GC patients and improve the efficacy of immunotherapy. These findings provide a novel idea of GC immunotherapy and hold promise for future clinical application.

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Quercetin Attenuates Trauma-Induced Heterotopic Ossification by Tuning Immune Cell Infiltration and Related Inflammatory Insult

Frontiers in Immunology ◽

10.3389/fimmu.2021.649285 ◽

2021 ◽

Vol 12 ◽

Author(s):

Juehong Li ◽

Ziyang Sun ◽

Gang Luo ◽

Shuo Wang ◽

Haomin Cui ◽

...

Keyword(s):

Mast Cell ◽

Heterotopic Ossification ◽

Cell Activation ◽

Immune Cell ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Mast Cell Activation ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Dependent Manner

Heterotopic ossification (HO) is one of the most intractable disorders following musculoskeletal injury and is characterized by the ectopic presence of bone tissue in the soft tissue leading to severe loss of function in the extremities. Recent studies have indicated that immune cell infiltration and inflammation are involved in aberrant bone formation. In this study, we found increased monocyte/macrophage and mast cell accumulation during early HO progression. Macrophage depletion by clodronate liposomes and mast cell stabilization by cromolyn sodium significantly impeded HO formation. Therefore, we proposed that the dietary phytochemical quercetin could also suppress immune cell recruitment and related inflammatory responses to prevent HO. As expected, quercetin inhibited the monocyte-to-macrophage transition, macrophage polarization, and mast cell activation in vitro in a dose-dependent manner. Using a murine burn/tenotomy model, we also demonstrated that quercetin attenuated inflammatory responses and HO in vivo. Furthermore, elevated SIRT1 and decreased acetylated NFκB p65 expression were responsible for the mechanism of quercetin, and the beneficial effects of quercetin were reversed by the SIRT1 antagonist EX527 and mimicked by the SIRT agonist SRT1720. The findings in this study suggest that targeting monocyte/macrophage and mast cell activities may represent an attractive approach for therapeutic intervention of HO and that quercetin may serve as a promising therapeutic candidate for the treatment of trauma-induced HO by modulating SIRT1/NFκB signaling.

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Lifting the innate immune barriers to antitumor immunity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000695 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000695 ◽

Cited By ~ 5

Author(s):

Carla V Rothlin ◽

Sourav Ghosh

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Immune System ◽

T Cell ◽

Time Course ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Cell Activity ◽

Innate Immune ◽

Cell Functions

The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

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Nanoengineering of Immune Cell Function

MRS Proceedings ◽

10.1557/proc-1209-yy03-01 ◽

2009 ◽

Vol 1209 ◽

Cited By ~ 3

Author(s):

Keyue Shen ◽

Michael C Milone ◽

Michael L. Dustin ◽

Lance Cameron Kam

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Immune Cell ◽

Cell Communication ◽

Cell Therapies ◽

Nano Scale

AbstractT lymphocytes are a key regulatory component of the adaptive immune system. Understanding how the micro- and nano-scale details of the extracellular environment influence T cell activation may have wide impact on the use of T cells for therapeutic purposes. In this article, we examine how the micro- and nano-scale presentation of ligands to cell surface receptors, including microscale organization and nanoscale mobility, influences the activation of T cells. We extend these studies to include the role of cell-generated forces, and the rigidity of the microenvironment, on T cell activation. These approaches enable delivery of defined signals to T cells, a step toward understanding the cell-cell communication in the immune system, and developing micro/nano- and material- engineered systems for tailoring immune responses for adoptive T cell therapies.

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The pLysRS-Ap4A Pathway in Mast Cells Regulates the Switch from Host Defense to a Pathological State

International Journal of Molecular Sciences ◽

10.3390/ijms22115620 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5620

Author(s):

Sharmila Govindaraj ◽

Lakshmi Bhargavi Paruchuru ◽

Ehud Razin

Keyword(s):

Mast Cell ◽

Immune System ◽

Mast Cells ◽

Host Defense ◽

Cell Activation ◽

Adaptive Immune System ◽

Allergic Diseases ◽

Mast Cell Activation ◽

Pathological State ◽

Adaptive Immune

The innate and adaptive immune systems play an essential role in host defense against pathogens. Various signal transduction pathways monitor and balance the immune system since an imbalance may promote pathological states such as allergy, inflammation, and cancer. Mast cells have a central role in the regulation of the innate/adaptive immune system and are involved in the pathogenesis of many inflammatory and allergic diseases by releasing inflammatory mediators such as histamines, proteases, chemotactic factors, and cytokines. Although various signaling pathways are associated with mast cell activation, our discovery and characterization of the pLysRS-Ap4A signaling pathway in these cells provided an additional important step towards a full understanding of the intracellular mechanisms involved in mast cell activation. In the present review, we will discuss in depth this signaling pathway’s contribution to host defense and the pathological state.

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469 A phase 1 first in human study of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.469 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A498-A498

Author(s):

Leah DiMascio ◽

Dipti Thakkar ◽

Siyu Guan ◽

Eric Rowinsky ◽

Jordi Rodon ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cell ◽

Tumor Microenvironment ◽

T Cell Activation ◽

Cell Activation ◽

Immune Cell ◽

Phase 1 ◽

Human Study ◽

Cell Activity ◽

Myeloid Cells

BackgroundV-domain Ig suppressor of T cell Activation (VISTA), an immune checkpoint regulator predominantly expressed on myeloid cells, represents a promising therapeutic target due to its role in suppressing pro-inflammatory, anti-tumor responses within the tumor microenvironment (TME). Based on VISTA’s broad expression across immune cell subtypes, HMBD-002 has been designed as a non-depleting, IgG4 monoclonal antibody with high affinity and specificity to VISTA across species (human, cynomolgus monkey, and rodent) that has the ability to block a predicted counter-structure binding site. In preclinical studies, HMBD-002 significantly inhibited tumor growth, both as a monotherapy and in combination with pembrolizumab, while decreasing infiltration of suppressive myeloid cells within the TME and increasing T cell activity. While rapid serum clearance and immune toxicities (e.g. cytokine release syndrome) have been reported for IgG1 antibodies, these were not observed preclinically with HMBD-002. In addition to VISTA expression on pro-inflammatory immune cells, examination of VISTA expression across cancer types has revealed that several malignancies, particularly human samples of triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), express high levels of VISTA, thereby providing a rationale for exploring these indications in clinical studies.MethodsThis Phase 1, first in human study is being conducted in two parts and will evaluate multiple doses and schedules of intravenously (IV) administered HMBD-002, with or without pembrolizumab, in patients with advanced solid tumors. Part 1 (dose escalation) seeks to identify the maximum tolerated dose (MTD), or the maximum tested dose, of HMBD-002 as a monotherapy, and separately, in combination with pembrolizumab to define the recommend doses for subsequent disease directed studies (i.e., recommended phase 2 dose [RP2D]). Part 2 (dose expansion) will assess the anti-cancer activity of HMBD-002 as a monotherapy at the RP2D in previously treated patients with TNBC, and NSCLC, and in combination with pembrolizumab in patients with TNBC, NSCLC, and other VISTA-expressing malignancies. The size of the disease-directed cohorts will be determined based on an interim futility analysis conducted upon enrollment of 15 patients. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints will be monitored and reported. Correlative studies will assess pre- and post-treatment markers of immune activity in the periphery and the tumor microenvironment.AcknowledgementsThis work was funded in part by the Cancer Prevention and Research Institute of Texas (CPRIT).Ethics ApprovalThe study was approved by each participating Institution’s Institutional Review Board.

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Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽

10.12688/f1000research.8132.2 ◽

2016 ◽

Vol 5 ◽

pp. 251

Author(s):

Binh Phong ◽

Lawrence P. Kane

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Signaling Pathways ◽

Cell Activation ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Allergic Diseases ◽

Mast Cell Activation ◽

High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

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