scholarly journals Regulation of Gastrointestinal Immunity by Metabolites

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 167
Author(s):  
Bon-Hee Gu ◽  
Myunghoo Kim ◽  
Cheol-Heui Yun
Keyword(s):  
Gastrointestinal Tract ◽  
Immune Cell ◽  
Intestinal Immunity ◽  
Control Of Gene Expression ◽  
Surface Receptors ◽  
Functional Activities ◽  
Cell Functions ◽  
Dietary Antigens ◽  
Molecular Regulatory Mechanisms ◽  
Microbial Enzymatic Activities

The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. The maintenance of homeostasis at the gastrointestinal tract requires stringent regulation of immune responses against various environmental conditions. Dietary components can be converted into gut metabolites with unique functional activities through host as well as microbial enzymatic activities. Accumulating evidence demonstrates that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and are further integrated into the immune response of distal mucosal tissue. Metabolites, especially those derived from the microbiota, regulate immune cell functions in various ways, including the recognition and activation of cell surface receptors, the control of gene expression by epigenetic regulation, and the integration of cellular metabolism. These mucosal immune regulations are key to understanding the mechanisms underlying the development of gastrointestinal disorders. Here, we review recent advancements in our understanding of the role of gut metabolites in the regulation of gastrointestinal immunity, highlighting the cellular and molecular regulatory mechanisms by macronutrient-derived metabolites.

scholarly journals Regulation of Gastrointestinal Immunity by Metabolites

2020 ◽  
Author(s):  
Bon-Hee Gu ◽  
Myunghoo Kim ◽  
Cheol-Heui Yun
Keyword(s):  
Gastrointestinal Tract ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Intestinal Immunity ◽  
Surface Receptors ◽  
Functional Activities ◽  
Cell Functions ◽  
Dietary Antigens ◽  
Molecular Regulatory Mechanisms ◽  
Microbial Enzymatic Activities

The gastrointestinal tract contains multiple types of immune cells that maintain the balance between tolerance and activation at the first line of host defense facing non-self antigens, including dietary antigens, commensal bacteria, and sometimes unexpected pathogens. Maintaining homeostasis at the gastrointestinal tract requires stringent regulation of the immune responses against various environmental conditions. Diet can be converted into gut metabolites which have unique functional activities through host as well as microbial enzymatic activities. Accumulating evidences demonstrate that gastrointestinal metabolites have significant impacts on the regulation of intestinal immunity and further integrate immune response of distal mucosal tissue. Metabolites, especially derived from microbiota, regulate immune cell functions by various ways including recognition and activation of cell surface receptors, controlling of gene expression by epigenetic regulation and integration of cellular metabolism. These mucosal immune regulations are key to understand underlying mechanism for the development of gastrointestinal disorders. Here, we review the recent advancement of our understanding on the role of gut metabolites in the regulation of gastrointestinal immunity with highlighting the cellular and molecular regulatory mechanisms by macronutrients-derived metabolites.

scholarly journals DDRE-09. DEVELOPING IDO-PROTACS TO IMPROVE IMMUNOTHERAPEUTIC EFFICACY IN PATIENTS WITH GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii63-ii63
Author(s):  
Lakshmi Bollu ◽  
Derek Wainwright ◽  
Lijie Zhai ◽  
Erik Ladomersky ◽  
Kristen Lauing ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Time Course ◽  
Immune Cell ◽  
Enzyme Inhibitors ◽  
Tumor Development ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Specific Protein ◽  
Cell Functions

Abstract INTRODUCTION Indoleamine 2,3-dioxygenase 1 (IDO; IDO1) is a rate-limiting enzyme that metabolizes the essential amino acid tryptophan into kynurenine. Recent work by our group has revealed that IDO promotes tumor development and suppresses immune cell functions independent of its enzyme activity. Moreover, pharmacologic IDO enzyme inhibitors that currently serve as the only class of drugs available for targeting immunosuppressive IDO activity, fail to improve the survival of patients with GBM. Here, we developed IDO-Proteolysis Targeting Chimeras (IDO-PROTACs). PROTACs bind to a specific protein and recruit an E3 ubiquitin ligase that enhance proteasome-mediated degradation of the target protein. METHODS A library of ≥100 IDO-PROTACs were developed by joining BMS986205 (IDO binder) with a linker group to various E3-ligase ligands. Western blot analysis of PROTAC-induced IDO degradation was tested in vitro among multiple human and mouse GBM cell lines including U87, GBM6, GBM43 and GL261 along a time course ranging between 1–96 hours of treatment and at varying concentrations. The mechanism of IDO protein degradation was investigated using pharmacologic ligands that inhibit or compete with the proteasome-mediated protein degradation pathway. RESULTS Primary screening identified several IDO-PROTACs with IDO protein degradation potential. Secondary screening showed that our lead compound has a DC50 value of ~0.5µM with an ability to degrade IDO in all GBM cells analyzed, and an initial activity within 12 hours of treatment that extended for up to 96 hours. Mutating the CRBN-binding ligand, pretreatment with the ubiquitin proteasome system inhibitors MG132 or MLN4924 or using unmodified parental compound all inhibited IDO protein degradation. CONCLUSIONS This study developed an initial IDO-PROTAC technology that upon further optimization, can neutralize both IDO enzyme and non-enzyme immunosuppressive effects. When combined with other forms of immunotherapy, IDO-PROTACs have the potential to substantially enhance immunotherapeutic efficacy in patients with GBM.

scholarly journals Emerging Evidence for Pleiotropism of Eosinophils

2021 ◽  
Vol 22 (13) ◽  
pp. 7075
Author(s):  
José M. Rodrigo-Muñoz ◽  
Marta Gil-Martínez ◽  
Beatriz Sastre ◽  
Victoria del Pozo
Keyword(s):  
Gastrointestinal Tract ◽  
Immune Defense ◽  
Extracellular Dna ◽  
Regulatory Cells ◽  
Viral Pathogens ◽  
Effective Response ◽  
Surface Receptors ◽  
Gm Csf ◽  
Variable Surface ◽  
Macrophage Colony

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.

scholarly journals Gut symbiotic microbes imprint intestinal immune cells with the innate receptor SLAMF4 which contributes to gut immune protection against enteric pathogens

Gut ◽  
2017 ◽  
Vol 67 (5) ◽  
pp. 847-859 ◽  
Author(s):  
Allison Cabinian ◽  
Daniel Sinsimer ◽  
May Tang ◽  
Youngsoon Jang ◽  
Bongkum Choi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Immune Cells ◽  
Immune Cell ◽  
Lymphocyte Activation ◽  
Premature Death ◽  
Enteric Pathogens ◽  
Immune Protection ◽  
Intestinal Immunity ◽  
Cell Responses ◽  
And Function

BackgroundInteractions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field.AimWe have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is.MethodsExpression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFPtg bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium.ResultsSLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC)TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death.ConclusionsSLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.

Dietary phosphatidylinositol protects C57BL/6 mice from concanavalin A-induced liver injury by modulating immune cell functions

2013 ◽  
Vol 57 (9) ◽  
pp. 1671-1679 ◽  
Author(s):  
Masashi Inafuku ◽  
Koji Nagao ◽  
Ayako Inafuku ◽  
Teruyoshi Yanagita ◽  
Naoyuki Taira ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Immune Cell ◽  
Cell Functions

A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3099-3099
Author(s):  
Jin Li ◽  
Nong Xu ◽  
Tianshu Liu ◽  
Jianjin Huang ◽  
Yongmei Yin ◽  
...  
Keyword(s):  
Disease Control ◽  
Solid Tumors ◽  
Immune Cell ◽  
Target Lesion ◽  
Advanced Solid Tumors ◽  
Cell Functions ◽  
Potential Clinical Benefit ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

3099 Background: Phosphatidylinositol-3 kinase (PI3K) pathways are important elements of tumor survival and progression, and PIK3C genes are often mutated or overexpressed in many cancers. Additionally, PIK3D (PI3Kδ) modulates immune cell functions in tumors, elaborating another PI3Kδ inhibition feature with a potential clinical benefit. Linperlisib, an oral and highly selective PI3Kδ inhibitor, demonstrated potent anti-tumor activity in syngeneic animals from previous research. In this Phase 1b study, the safety, tolerability, and efficacy of linperlisib is under investigation for patients with advanced solid tumors. Methods: Linperlisib was given orally once daily (QD) in 28-day cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according to RECIST1.1 criteria. Results: As of December 28, 2020, 70 patients were enrolled in the Phase1b study, with advanced cancers, including colorectal (n = 22), breast (n = 8), lung (n = 8), kidney (n = 5), liver (n = 4), ovarian (n = 1), head and neck (n = 5), and esophageal (n = 1) cancers; sarcomas, (n = 4), small intestinal stromal tumor (n = 3), thymic (n = 2), gallbladder (n = 2), gastric (n = 4), and pancreatic (n = 1) carcinomas. The patients were heavily pretreated with an average of 4 previous lines of therapy. Among the 70 patients, the most common nonhematologic TEAEs (all grades/grade≥3) were proteinuria (37.14%/0%), elevated aspartate aminotransferase (20%/0%), nausea (20%/0%), oral mucositis (2.8%/2.8%), diarrhea (2.8%/2.8%). The most common hematological TEAEs were leukopenia (24.28%/0%) and neutropenia (17.14%/4.28%). There were no unexpected toxicities in this study. Of 42 patients evaluable for response, the overall response rate was 2.38%. Notably, the disease control rate (DCR) was 45.24% from monotherapy treatment. One patient with thymic carcinoma obtained a partial response (80.8% reduction of the target lesion), with a duration of response of more than 6 cycles. The treatment of this subject is continuing. A lung adenocarcinoma subject reached radiological stable disease associated with 13.7% reduction in the target lesion and disease control for approximately 6 months. Conclusions: In this study, the PI3K inhibitor, linperlisib exhibited a favorable safety profile as was previously seen in lymphoma patients. Monotherapy treatment with linperlisib was observed to impart a high DCR in advanced solid cancers of many types. Available data from linperlisib and other PI3K inhibitors suggests that linperlisib may limit tumor growth directly, but also by affecting the tumor immune microenvironment. With these promising indications of clinical tolerability and activity, further investigation of linperlisib alone or in key therapeutic combinations is warranted. Clinical trial information: NCT04049929.

scholarly journals Immune Cell-Derived Extracellular Vesicles – New Strategies in Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengxiang Yang ◽  
Yong Peng ◽  
Yuan Feng ◽  
Zhuoying Xu ◽  
Panfeng Feng ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Immune Cell ◽  
Bilayer Membrane ◽  
Innate Immune ◽  
Antitumor Effects ◽  
Comprehensive Overview ◽  
Surface Receptors ◽  
Effector Molecules ◽  
Therapeutic Modalities ◽  
Pass Through

Immune cell-derived extracellular vesicles (EVs) have increasingly become the focus of research due to their unique characteristics and bioinspired applications. They are lipid bilayer membrane nanosized vesicles harboring a range of immune cell-derived surface receptors and effector molecules from parental cells. Immune cell-derived EVs are important mediators of intercellular communication that regulate specific mechanisms of adaptive and innate immune responses. However, the mechanisms underlying the antitumor effects of EVs are still being explored. Importantly, immune cell-derived EVs have some unique features, including accessibility, storage, ability to pass through blood-brain and blood-tumor barriers, and loading of various effector molecules. Immune cell-derived EVs have been directly applied or engineered as potent antitumor vaccines or for the diagnosis of clinical diseases. More research applications involving genetic engineering, membrane engineering, and cargo delivery strategies have improved the treatment efficacy of EVs. Immune cell-derived EV-based therapies are expected to become a separate technique or to complement immunotherapy, radiotherapy, chemotherapy and other therapeutic modalities. This review aims to provide a comprehensive overview of the characteristics and functions of immune cell-derived EVs derived from adaptive (CD4+ T, CD8+ T and B cells) and innate immune cells (macrophages, NK cells, DCs, and neutrophils) and discuss emerging therapeutic opportunities and prospects in cancer treatment.

425 In-vitro regulation of immune cell functions by human IgE

1991 ◽  
Vol 87 (1) ◽  
pp. 246
Author(s):  
R PARHAR ◽  
P ERNST ◽  
F ALMOHANNA ◽  
A KWAASI ◽  
K SHETH ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Functions

scholarly journals Resolvins as Regulators of the Immune System

2010 ◽  
Vol 10 ◽  
pp. 818-831 ◽  
Author(s):  
Hiroyuki Seki ◽  
Takaharu Sasaki ◽  
Tomomi Ueda ◽  
Makoto Arita
Keyword(s):  
Immune System ◽  
Acute Inflammation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Bioactive Metabolites ◽  
Cell Functions ◽  
First Response ◽  
Beneficial Impact

Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of ω-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions bothin vitroandin vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.

Effects of dietary tryptophan supplementation in the acetic acid-induced colitis mouse model

2018 ◽  
Vol 9 (8) ◽  
pp. 4143-4152 ◽  
Author(s):  
Shuai Chen ◽  
Meiwei Wang ◽  
Lanmei Yin ◽  
Wenkai Ren ◽  
Peng Bin ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Acetic Acid ◽  
Gastrointestinal Tract ◽  
Mouse Model ◽  
Chronic Inflammation ◽  
Bowel Disease ◽  
Intestinal Immunity ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and is strongly associated with intestinal immunity and the microbiome.

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