scholarly journals Attenuation of Dupuytren’s fibrosis via targeting of the STAT1 modulated IL-13Rα1 response

2020 ◽  
Vol 6 (28) ◽  
pp. eaaz8272 ◽  
Author(s):  
Moeed Akbar ◽  
Emma Garcia-Melchor ◽  
Sabarinadh Chilaka ◽  
Kevin J. Little ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Complex Disease ◽  
Human Model ◽  
Therapeutic Approaches ◽  
Fibrotic Disease ◽  
Common Complex Disease ◽  
Inflammatory Processes ◽  
Fibrotic Disorders ◽  
Fibrotic Disorder

Fibrotic disorders represent common complex disease pathologies that are therapeutically challenging. Inflammation is associated with numerous fibrotic pathogeneses; however, its role in the multifaceted mechanisms of fibrosis remains unclear. IL-13 is implicated in aberrant responses involved in fibrotic disease, and we aimed to understand its role in the inflammatory processes of a common fibrotic disorder, Dupuytren’s disease. We demonstrated T-cells produced IFN-g, which induced IL-13 secretion from mast cells and up-regulated IL-13Ra1 on fibroblasts, rendering them more reactive to IL-13. Consequently, diseased myofibroblasts demonstrated enhanced fibroproliferative effects upon IL-13 stimulation. We established IFN-g and IL-13 responses involved STAT dependent pathways, and STAT targeting (tofacitinib) could inhibit IL-13 production from mast cells, IL-13Ra1 up-regulation in fibroblasts and fibroproliferative effects of IL-13 on diseased myofibroblasts. Accordingly, utilizing Dupuytren’s as an accessible human model of fibrosis, we propose targeting STAT pathways may offer previously unidentified therapeutic approaches in the management of fibrotic disease.

scholarly journals Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials

2020 ◽  
Vol 2 (5) ◽  
pp. 531-550
Author(s):  
Alessandro Siani
Keyword(s):  
Clinical Trials ◽  
Clinical Data ◽  
Pathological Condition ◽  
Systematic Search ◽  
Therapeutic Approaches ◽  
Cellular Mechanisms ◽  
Systematic Analysis ◽  
Prognostic Outcome ◽  
Fibrotic Disorders ◽  
Fibrotic Disorder

Abstract The term “fibrosis” refers to a spectrum of connective tissue disorders characterized by the excessive accumulation of extracellular matrix leading to organ dysfunction and, ultimately, failure. Fibrosis affects millions of patients worldwide and often manifests itself as a late-stage pathological condition associated with poor prognostic outcome. Although the aetiology and clinical course vary widely depending on the affected organ, fibrotic degeneration of different tissues is underpinned by similar molecular and cellular mechanisms, most notably the persistence and dysregulated activity of myofibroblasts. A systematic search of clinical trials was conducted using PubMed and Cochrane to qualitatively evaluate the effectiveness of different therapeutic approaches to the pharmacological targeting of myofibroblasts in patients affected by fibrotic disorders. The systematic search and screening returned 54 eligible clinical trials, 38 of which reported an improvement of the patients’ symptoms following treatment. The majority of the eligible articles focused on fibrotic degeneration of the respiratory system, skin, liver, and kidneys. The evaluation of clinical data unearthed commonalities between strategies that successfully ameliorated symptoms in patients affected by the same fibrotic disorder. However, none of the treatments evaluated in this study could improve symptoms across a range of fibrotic pathologies. These results indicate that, although no “one size fits all” treatment for fibrosis has yet been identified, the systematic analysis of clinical data can be used to inform the development of therapeutical strategies tailored to suit the diverse aetiology of each fibrotic condition.

scholarly journals Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2385
Author(s):  
Ethan Strattan ◽  
Gerhard Carl Hildebrandt
Keyword(s):  
Wound Healing ◽  
Mast Cell ◽  
Mast Cells ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Fibrotic Disease ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease.

scholarly journals Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke-Tao Jin ◽  
Bo Chen ◽  
Yu-Yao Liu ◽  
H uan-Rong Lan ◽  
Jie-Ping Yan
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
Immune Responses ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Therapeutic Approaches ◽  
Great Ability ◽  
Car T Cells ◽  
Car T

AbstractColorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. The immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. MAbs demonstrate the great ability to completely recognize cancer cell-surface receptors and blockade proliferative or inhibitory pathways. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Both of these approaches have beneficial anti-tumor effects on CRC. Herein, we review the different mAbs against various pathways and their applications in clinical trials, the different types of CAR-T cells, various specific CAR-T cells against TAAs, and their clinical use in CRC treatment.

scholarly journals Limosilactobacillus fermentum CECT5716: Mechanisms and Therapeutic Insights

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 1016
Author(s):  
María Jesús Rodríguez-Sojo ◽  
Antonio Jesús Ruiz-Malagón ◽  
María Elena Rodríguez-Cabezas ◽  
Julio Gálvez ◽  
Alba Rodríguez-Nogales
Keyword(s):  
Competitive Exclusion ◽  
Intestinal Barrier ◽  
Mechanisms Of Action ◽  
Intestinal Barrier Function ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Host Health ◽  
Inflammatory Processes ◽  
Immunomodulatory Properties ◽  
Immunological Alterations

Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches.

Mast cells and T-cell expansion

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2497-2498
Author(s):  
Susumu Nakae ◽  
Keisuke Oboki ◽  
Hirohisa Saito
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mast Cells ◽  
Cell Expansion ◽  
Memory T Cells ◽  
T Cell Expansion

IgE/antigen-FcϵRI crosslinking promotes antigen internalization and apoptosis in mouse mast cells. Dendritic cells uptake the apoptotic mast cells carrying internalized antigens, and thus can efficiently present the antigens to memory T cells.

scholarly journals Human Mucosal Mast Cells Capture HIV-1 and Mediate Viraltrans-Infection of CD4+T Cells

2015 ◽  
Vol 90 (6) ◽  
pp. 2928-2937 ◽  
Author(s):  
Ai-Ping Jiang ◽  
Jin-Feng Jiang ◽  
Ji-Fu Wei ◽  
Ming-Gao Guo ◽  
Yan Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Cell Surface ◽  
Bacterial Infections ◽  
Mucosal Mast Cells ◽  
Mucosal Tissues ◽  
Viral Particles ◽  
Molecular Patterns ◽  
Hiv 1

ABSTRACTThe gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4+T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viraltrans-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection.IMPORTANCEIn this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1trans-infection of CD4+T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination.

scholarly journals Genetic Vectors as a Tool in Association Studies: Definitions and Application for Study of Rheumatoid Arthritis

2015 ◽  
Vol 2015 ◽  
pp. 1-13
Author(s):  
Igor Sandalov ◽  
Leonid Padyukov
Keyword(s):  
Rheumatoid Arthritis ◽  
Complex Disease ◽  
Association Studies ◽  
Healthy Population ◽  
Common Complex Disease ◽  
New Approach ◽  
Functional Studies ◽  
Biological Interpretation ◽  
Genetic Vectors ◽  
Efficient Selection

To identify putative relations between different genetic factors in the human genome in the development of common complex disease, we mapped the genetic data to an ensemble of spin chains and analysed the data as a quantum system. Each SNP is considered as a spin with three states corresponding to possible genotypes. The combined genotype represents a multispin state, described by the product of individual-spin states. Each person is characterized by a single genetic vector (GV) and individuals with identical GVs comprise the GV group. This consolidation of genotypes into GVs provides integration of multiple genetic variants for a single statistical test and excludes ambiguity of biological interpretation known for allele and haplotype associations. We analyzed two independent cohorts, with 2633 rheumatoid arthritis cases and 2108 healthy controls, and data for 6 SNPs from the HTR2A locus plus shared epitope allele. We found that GVs based on selected markers are highly informative and overlap for 98.3% of the healthy population between two cohorts. Interestingly, some of the GV groups contain either only controls or only cases, thus demonstrating extreme susceptibility or protection features. By using this new approach we confirmed previously detected univariate associations and demonstrated the most efficient selection of SNPs for combined analyses for functional studies.

Generation of mucosal mast cells is stimulated in vitro by factors derived from T cells of helminth-infected rats

Nature ◽  
1982 ◽  
Vol 300 (5888) ◽  
pp. 188-190 ◽  
Author(s):  
David M. Haig ◽  
Thomas A. McKee ◽  
Ellen E. E. Jarrett ◽  
Richard Woodbury ◽  
Hugh R. P. Miller
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Mucosal Mast Cells

scholarly journals Human Mast Cells Release Metalloproteinase-9 on Contact with Activated T Cells: Juxtacrine Regulation by TNF-α

2001 ◽  
Vol 167 (7) ◽  
pp. 4008-4016 ◽  
Author(s):  
Dana Baram ◽  
Gayle G. Vaday ◽  
Pazit Salamon ◽  
Ilana Drucker ◽  
Rami Hershkoviz ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cells ◽  
Activated T Cells ◽  
Human Mast Cells ◽  
Tnf Α ◽  
Metalloproteinase 9
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