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Results for “Immune microenvironment”

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PubMed1996

The central nervous system as an immunocompetent organ: role of glial cells in antigen presentation.

The central nervous system has the capacity to initiate and regulate immune responses by allowing restricted entry of peripheral immune cells and providing a microenvironment that is conducive to the activation of immune effector cells. In this commentary, we discuss the ability of two glial cell types, astrocytes and microglia, to function as APCs. In particular, we focus on the phenotypic and functional distinctions between astrocytes and microglia that may contribute to their differing abilities to effectively present Ag to CD4+ cells.

Animals↗
PubMed2003

Lymphotoxin/light, lymphoid microenvironments and autoimmune disease.

Much of the efficiency of the immune system is attributed to the high degree of spatial and temporal organization in the secondary lymphoid organs. Signalling through the lymphotoxin (LT) pathway is a crucial element in the maintenance of this organized microenvironment. The effect of altering lymphoid microenvironments on immune responses remains relatively unexplored. Inhibitors of the LT and LIGHT pathways have been shown to reduce disease in a wide range of autoimmune models. This approach has provided a tool to probe the effect of manipulation of the microenvironment on both normal and pathological immune responses.

Animals↗
PubMed2000

Neuropeptide regulation of immunity. The immunosuppressive activity of alpha-melanocyte-stimulating hormone (alpha-MSH).

The ocular microenvironment is an extreme example of regional immunity. Within its microenvironment, expression of delayed type hypersensitivity (DTH) is suppressed. This immunosuppression is mediated in part by the constitutive expression of alpha-MSH. Previously we have found that alpha-MSH suppresses the production of IFN-gamma by activated effector T cells. Recently we have found that alpha-MSH can mediate induction of TGF-beta-producing T cells that act as regulatory T cells. This has encouraged us to further examine the potential for alpha-MSH to suppress T cell-mediated inflammation (autoimmune disease) and to regulate lymphokine production by effector T cells. When alpha-MSH was injected i.v. into mice at the time of peak retinal inflammation, the severity of experimental autoimmune uveitis (EAU) was significantly suppressed. Effector T cells activated in vitro in the presence of alpha-MSH proliferated and produced IL-4 and enhanced levels of TGF-beta while their IFN-gamma and IL-10 production was suppressed. The alpha-MSH-treated T cells functioned as regulatory T cells by suppressing in vitro IFN-gamma production by other inflammatory T cells. This regulatory activity was the function of alpha-MSH-treated CD4+ CD25+ T cells. Therefore, alpha-MSH mediates immunosuppression by inducing a differential expression of lymphokine production and by inducing activation of regulatory functions in T cells. This implies that alpha-MSH may take part in regional mechanisms of immunosuppression and possibly peripheral tolerance. Thus, alpha-MSH can be used to suppress autoimmune disease and possibly reestablish tolerance to autoantigens.

Animals↗
PubMed2025

Natural, safety immunomodulatory derivatives of lactobacillus biofilms promote diabetic wound healing by metabolically regulating macrophage phenotype and alleviating local inflammation.

INTRODUCTION: Long-term inflammatory microenvironment further impairs the healing process of diabetic wounds. Many studies have shown that Lactobacillus can regulate immune function and promote injured tissue repair. However, the immunomodulatory function and safety of Lactobacillus biofilm (LB) on wounds need further investigation. OBJECTIVES: In this present research, we proposed a "bacteria-free biofilm derivative therapy" and successfully extracted Lactobacillus biofilm derivatives (LBDs) by ultrasonic separation and filtration technology for the natural and safe treatment of diabetic wounds. METHODS: The study first cultured Lactobacillus anaerobically and extracted LBDs using ultrasound separation combined with filtration technology. LBDs were characterized via scanning electron microscopy, Concanavalin A fluorescence staining, and protein gel electrophoresis. In vivo diabetic wound model, wound closure rates were dynamically monitored, and tissue sections were analyzed using hematoxylin-eosin and immunofluorescence staining to evaluate LBDs' healing effects. An in vitro macrophage inflammation model was established, employing immunofluorescence, flow cytometry, and Western blotting techniques to explore the molecular mechanisms underlying LBDs' effects on macrophage phenotypes. Furthermore, whole-genome sequencing and proteomics of LBDs-treated macrophages were performed to further elucidate the intrinsic molecular mechanisms through which LBDs regulate macrophage phenotypes. RESULTS: LBDs were effectively extracted utilizing ultrasonic separation coupled with filtration technology. Studies revealed that LBDs modulate the systemic metabolic reprogramming in wound-site macrophages, suppress JAK-STAT1 signaling pathway, alleviate the local inflammatory microenvironment, promote neovascularization and ultimately accelerate wound healing. CONCLUSION: The LBDs retains most bioactive components of the LB. As a natural, safe and immunomodulatory agent, LBDs promote diabetic wound healing by metabolically reprogramming macrophage phenotypes and improving the local immune microenvironment, offering promising potential for regenerative applications in diabetic wound management.

Wound Healing↗
PubMed1997

Cytokine-in-adjuvant steering of the immune response phenotype to HIV-1 vaccine constructs: granulocyte-macrophage colony-stimulating factor and TNF-alpha synergize with IL-12 to enhance induction of cytotoxic T lymphocytes.

To enhance and steer immune responses to synthetic peptide vaccines toward selected functional types and to understand the cooperative action of cytokines in fine-tuning the immune response, we attempted to influence the in vivo cytokine environment by delivering cytokines directly to the microenvironment in which the immune response is initiated. Here we study the effects of IL-2, IL-4, IL-7, IL-1beta, IL-12, IFN-gamma, TNF-alpha, and granulocyte-macrophage CSF (GM-CSF) incorporated with peptide in adjuvant on a variety of responses elicited: CTL, T cell proliferation, cytokine production and message, and Ab isotype. We show GM-CSF to be the single most effective cytokine for enhancing both cellular and humoral immunity to two previously characterized HIV-1 MN vaccine constructs. Novel synergies were also detected. GM-CSF synergized with IL-12 for CTL induction in BALB/c mice concomitant with suppression of Th2 cytokines IL-4 and IL-10. TNF-alpha also synergized with IL-12, but by a different mechanism, inducing IFN-gamma production in BALB/c mice and thus shifting the response to a Th1 phenotype. The results presented here suggest that in addition to IL-2, optimum induction of CD8+ CTL in vivo requires a combination of cytokines, including GM-CSF (probably acting to enhance Ag presentation and CD4+ cell help) and IL-12 (steering the Th response toward Th1 cytokines).

AIDS Vaccines↗
PubMed2005

Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone.

Cell-mediated immunity (CMI) is key to defense against intracellular pathogens such as Chlamydia trachomatis and viruses that infect the lower female genital tract, but little is known about CMI at this site. Recent studies indicate that there are immunological microenvironments within the female genital tract, and that immune functions are affected by hormones as well as infections and inflammatory processes. To determine the distribution of mediators of CMI within the lower female genital tract, we have enumerated and characterized T-lymphocyte subsets and natural killer and antigen presenting cells (APCs; macrophages and dendritic cells) in the introitus, vagina, ectocervix, endocervix and cervical transformation zone (TZ) from healthy women, and have examined the effects of the menstrual cycle, menopause and inflammation on these parameters. In women without inflammation, T cells and APCs were most prevalent in the cervical TZ and surrounding tissue. Intraepithelial lymphocytes were predominantly CD8+ T cell+; most CD8+ cells in the TZ and endocervix, and a proportion of cells in the ectocervix, expressed T-cell internal antigen-1, a marker of cytotoxic potential. In contrast, the normal vaginal mucosa contained few T cells and APCs. Cervicitis and vaginitis cases had increased numbers of intraepithelial CD8+ and CD4+ lymphocytes and APCs. The menstrual cycle and menopause had no apparent effect on cellular localization or abundance in any of the lower genital tract tissues. These data indicate that the cervix, especially the TZ, is the major inductive and effector site for CMI in the lower female genital tract. Because CD4+ T cells and APCs are primary host cells for human immunodeficiency virus type 1 (HIV-1), these data also provide further evidence that the cervix is a primary infection site of HIV-1, and that inflammation increases the risk of HIV transmission.

Adult↗
PubMed2026

Integrated analysis reveals the impact of obesity on triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited therapeutic options. While the prevalence of overweight/obese (OW/OB) women continues to rise, the impact of obesity on molecular features of TNBC remains incompletely understood. We investigated clinicopathological and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using our original multi-omics database of TNBC (N = 465) for associations with patient body mass index (BMI). Multi-omics profiling revealed that OW/OB patients exhibited worse survival as well as elevated inflammation of tumor microenvironment, higher expression of immune checkpoints, and dysregulated lipid metabolism. Our in vivo experiments demonstrated that tumors in obese mice displayed faster growth rates, a higher proportion of PD-1+CD8+ T cells and enhanced responsiveness to anti-PD-1 treatment. In addition, we analyzed data from four independent clinical trials and discovered that OW/OB patients demonstrated higher pathological complete response rates and longer progression-free survival following anti-PD-1-based immunotherapy. In conclusion, our study systematically revealed that obesity is associated with coordinated immune-metabolic remodeling in TNBC, characterized by checkpoint enrichment and lipid dysregulation, which may help explain the enhanced anti-PD-1 responsiveness and should be taken into account in the field of precision medicine.

Immunity↗
PubMed2005

Tumor-immune memory T cells from the bone marrow exert GvL without GvH reactivity in advanced metastasized cancer.

The bone marrow has been shown to represent a unique microenvironment where T cell immune responses against tumor associated antigens can be initiated and tumor-immune memory T cells are enriched. In the present study the graft versus leukemia (GvL) reactivity of bone marrow derived tumor-immune memory T cells was analyzed in an allogeneic minor histocompatibility different murine GvL tumor model with late stage disease. A single adoptive cell transfer of B10.D2 donor immune bone marrow cells (iBM) into sub-lethally irradiated late stage ESb-MP tumor-bearing DBA/2 mice led to a complete tumor remission and to significant life prolongation. Even though the frequency of bone marrow resident T cells is only around 2%, the GvL reactivity of iBM was superior to immune cells from the spleen (iSPL) or to those from the peritoneal cavity (iPEC) of the same immunized donors. iPEC exerted mostly unwanted graft versus host (GvH) reactivity, while iSPL exerted GvL and GvH reactivity. Bone marrow cells from naive donor mice or T cell depleted iBM cells were completely devoid of GvL reactivity. The low number of tumor-immune memory T cells thus conferred the GvL reactivity of iBM cells.

Animals↗
PubMed2002

Immunopathogenesis of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by inflammation that results from the interaction between the various components of the mucosal immune system and the microenvironment. These components-lu}inal antigens, intestinal epithelial cells (IEC), lymphocytes, and cells of the innate and adaptive immune system and their secreted mediators (cytokines and chemokines)-contribute to the cascade of events that ends in intestinal and systemic damage in a genetically predisposed host. The origin of IBD is as yet unknown, but the beginning of the third millennium has brought several new insights into the immune aberrations in IBD. The progress achieved last year in each component of IBD pathogenesis will be reviewed. In each section, an attempt to develop correlations between experimental findings and human disease is made.

Journal Article↗
PubMed2026

Malignant epithelial states drive immune dysfunction in ampulla of Vater carcinoma.

BACKGROUND: Ampulla of Vater (AoV) carcinoma is a rare malignancy arising at the junction of intestinal and pancreatobiliary epithelium. Its heterogeneous clinical behavior and histological diversity have hindered therapeutic advances, and the cellular basis of this heterogeneity remains unclear. We aimed to construct a single-cell transcriptomic atlas of AoV carcinoma, with a focus on identifying epithelial subtypes and their interactions with the tumor microenvironment (TME). METHODS: We performed single-cell RNA sequencing on eight primary AoV tumors and four matched normal tissues. Comprehensive clustering and transcriptomic analyses identified cell-type composition, epithelial heterogeneity, and tumor-immune interactions. Findings were validated using deconvolution of bulk RNA-seq data from 62 AoV carcinoma patients. Results Malignant epithelial cells were categorized into four distinct subtypes: Int-Wnt, PB-KRAS, Int-Hypoxia, and Cycling stage. PB-KRAS cells exhibited stem-like transcriptional programs and high genomic instability. Deconvolution analysis of bulk RNA-seq data from the independent AoV cohort revealed that enrichment of the PB-KRAS subtype correlated with tumor recurrence and poor survival. Our immune profiling analysis discovered a significant association between PB-KRAS subtype and GZMK+ CD8+ T cells, which are in a pre-dysfunctional state, alongside SPP1+ macrophages exhibiting immunosuppressive traits. Spatial transcriptome data further supports the immunosuppressive natures of TME around PB-KRAS subtype malignant epithelial cells in AoV carcinoma. CONCLUSIONS: Our study presents a single-cell atlas of AoV carcinoma, highlighting the molecular diversity of malignant epithelium and its association with the immune microenvironment. The PB-KRAS subtype emerges as a stem-like, immunosuppressive tumor state associated with poor prognosis, providing insights for future therapeutic targeting.

Ampulla of Vater carcinoma↗
PubMed2006

Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth.

Controlling metastases remains a critical problem in cancer biology. Within the peritoneal cavity, omental tissue is a common site for metastatic disease arising from intraperitoneal tumors; however, it is unknown why this tissue is so favorable for metastatic tumor growth. Using five different tumor cell lines in three different strains of mice, we found that the omentum was a major site of metastases growth for intraperitoneal tumors. Furthermore, initial attachment and subsequent growth were limited to specific sites within the omentum, consisting of organized aggregates of immune cells. These immune aggregates contained a complex network of capillaries exhibiting a high vascular density, which appear to contribute to the survival of metastatic cells. We found that the vasculature within these aggregates contained CD105+ vessels and vascular sprouts, both indicators of active angiogenesis. A subset of mesothelial cells situated atop the immune aggregates was found to be hypoxic, and a similar proportion was observed to secrete vascular endothelial growth factor-A. These data provide a physiological mechanism by which metastatic tumor cells preferentially grow at sites rich in proangiogenic vessels, apparently stimulated by angiogenic factors produced by mesothelial cells. These sites provide metastatic cells with a microenvironment highly conducive to survival and subsequent growth.

Animals↗
PubMed2003

Patterns of CD4/CD8 T-cell ratio in dialysis effluents predict the long-term outcome of peritonitis in patients undergoing peritoneal dialysis.

BACKGROUND: The peritoneal immune compartment is a microenvironment with a particular T-cell repertoire and susceptible to local inflammation. To clarify the role of T lymphocytes in peritoneal immunity, the changes in T-cell subpopulations in peritoneal dialysis effluents (PDEs), and their influence on the response to the treatment of peritonitis and on its prognosis were studied in patients undergoing long-term, continuous ambulatory peritoneal dialysis (CAPD). METHODS: A cohort of 36 patients treated with CAPD and who had histories of peritonitis were divided into a group with rapid and a group with delayed response to antibiotics, and were followed for 3 years. CD4/CD8 T-cell ratios, T-cell cytokine mRNA expression patterns and transforming growth factor-beta1 (TGF-beta1) concentrations were examined in PDE during bouts of peritonitis. The change in 4 h D/P creatinine during the peritoneal equilibration test (PET) between year 0 and year 3 was expressed as deltaD/P creatinine. RESULTS: The serial changes in T-cell subsets in PDE during peritonitis showed two patterns: (i) pattern 1, manifest as a progressive increase in the CD4/CD8 ratio, and associated with a rapid response to treatment; and (ii) pattern 2, manifest as a progressive decrease in the CD4/CD8 ratio, and associated with a delayed response to treatment. The major T-cell phenotypes in PDE during peritonitis were Th1-CD4(+) and Tc2-CD8(+), determined by cloning techniques, RT-PCR and double immunofluorescence staining. TGF-beta1 in the effluent was undetectable in pattern 1 after 7-8 days, but remained detectable at 2 weeks in pattern 2. Pattern 2 patients had a significantly greater decrease (deltaD/P creatinine: -0.198+/-0.086) in solute transport than pattern 1 patients (deltaD/P creatinine: -0.036+/-0.077, P<0.05). CONCLUSIONS: These results suggest that a progressive decrease of the CD4/CD8 ratio in PDE correlates with a persistent expression of TGF-beta1, and plays a pathogenetic role in the evolution of peritonitis, PET deterioration and peritoneal fibrosis. Therefore, patterns of CD4/CD8 T-cell ratio in PDE may predict clinical outcomes of peritonitis in CAPD patients.

Adult↗
PubMed2003

Portal to the interior: viral pathogenesis and natural compounds that restore mucosal immunity and modulate inflammation.

Most antigens, particularly viruses, enter the body through the mucosal epithelia where they are carried by afferent lymphatics to regional lymph nodes for presentation to the immune system. Although they share immunological similarities, immune processes that protect the mucosa are distinct from innate and acquired immunity. The barrier formed by the intestinal mucosa is the most studied, with its microenvironment having a marked influence on both local and systemic immune responses. A healthy microenvironment and resilient neighboring tissue provide protection against inflammation known to dampen mucosal immunity, promote carcinogenesis, contribute to systemic inflammatory processes, and result in autoimmune diseases. Numerous natural substances improve this microenvironment and thereby enhance immunity against microbial infections. Since mucosal immunity forms the first line of defense against many commonly transmitted pathogens, restoring and maintaining mucosal immunity is critical for disease prevention and intervention. This article discusses the nature of mucosal immunity and its relationship to viral infections and other conditions, and reviews natural compounds that help restore mucosal immunity.

Dietary Supplements↗
PubMed1998

Regulation of adhesion and migration in the germinal center microenvironment.

T cell dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell homing to the GC and interaction with FDC critically depend on integrin-mediated adhesion. We have recently indentified the c-met-encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signalling pathway regulating B cell adhesion (van der Voort et al., 1997, J. Exp. Med. 185, 2121-2131). The c-Met protein is expressed on B cells localized in the dark zone of the GC (centroblasts) and is induced by CD40 plus BCR ligation. Stimulation of c-Met with HGF/SF, which is produced at high levels by tonsillar stromal cells and FDC, leads to receptor phosphorylation and to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Interestingly, these responses to HGF/SF are promoted by heparan-sulfate proteoglycan forms of CD44 (CD44-HS). Like c-Met, CD44-HS is induced on B cells by CD40 ligation. It efficiently binds HGF/SF and strongly promotes signalling through c-Met. We conclude that integrin regulation during antigen specific B cell differentiation involves cross-talk between the HGF/SF-c-Met pathway and CD44-HS.

Animals↗
PubMed2002

The bloodsucking arthropod bite as possible cofactor in the transmission of human herpesvirus-8 infection and in the expression of Kaposi's sarcoma disease.

Based on a review of the literature on human herpesvirus-8 (HHV8) and Kaposi's sarcoma (KS) and on the distribution of KS in Italy (Veneto region particularly), we hypothesize that the bite of bloodsucking arthropods is a cofactor in the seroconversion to HHV8 positivity and probably in the pathogenesis of KS. The bloodsucking arthropod releases with saliva powerful antihaemostatics and immunomodulators which may favour the replication and the establishment of the pathogen. Transmission would depend on the close contact of the child with a seropositive mother (or relatives) whose infective saliva is used to relieve itching and scratching at the arthropod bite's sites. During any deregulation of the immune system (e.g. ageing), local immune responses to new insect bites may induce virus activation which could prelude KS insurgence. The pathogen is not directly transmitted by the arthropod which merely prepares the cutaneous microenvironment for the virus. We have therefore introduced a new category of medically important arthropods, "promoter arthropods", besides those already defined as biological or mechanical vectors. Promoter arthropods are species able to induce in the host long-lasting, immediate or delayed-type hypersensitivity responses as well as local immunosuppression due to substances injected with their saliva. The striking variability of ORF-K1 gene of HHV8 could be due to the adaptation of the virus to the specific microenvironments resulting from the immune response to the salivary antigens characteristic of the bloodsucking arthropod species prevalent in each geographical area. It is worth noting that other viruses (especially Hepatitis B Virus) may exploit the same non-sexual transmission route.

Animals↗
PubMed2006

Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer.

Transforming growth factor-beta (TGFbeta) signalling regulates cancer through mechanisms that function either within the tumour cell itself or through host-tumour cell interactions. Studies of tumour-cell-autonomous TGFbeta effects show clearly that TGFbeta signalling has a mechanistic role in tumour suppression and tumour promotion. In addition, factors in the tumour microenvironment, such as fibroblasts, immune cells and the extracellular matrix, influence the ability of TGFbeta to promote or suppress carcinoma progression and metastasis. The complex nature of TGFbeta signalling and crosstalk in the tumour microenvironment presents a unique challenge, and an opportunity to develop therapeutic intervention strategies for targeting cancer.

Animals↗
PubMed1999

Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens.

The cloning of cancer Ags recognized by T cells has provided potentially new tools to enhance immunity against metastatic cancer. The biological monitoring of effective immunization has, however, remained a dilemma. We describe here a sensitive molecular quantitation methodology that allows analysis of in vivo immune response to vaccination. Metastatic melanoma patients were immunized with a synthetically modified peptide epitope (209-2M) from the melanoma self-Ag gp100. Using serial gene expression analysis, we report functional evidence of vaccine-induced CTL reactivity in fresh cells obtained directly from the peripheral blood of postimmunized patients. Further, we demonstrate in vivo localization of vaccine-induced immune response within the tumor microenvironment. The results of these molecular assays provide direct evidence that peptide immunization in humans can result in tumor-specific CTL that localize to metastatic sites.

Biopsy, Needle↗
PubMedDate not supplied

Secretion of tumor-promoting and immune suppressive cytokines by cell lines of head and neck squamous cell carcinoma.

BACKGROUND: Cytokine profiles of permanent cell lines of head and neck squamous cell carcinoma (HNSCC) were analyzed to define the cytokine levels secreted in the absence of immune cells. MATERIALS AND METHODS: Cytokine profiles of IL-4, IL-6, IL-8 and IL-10 were analyzed in the supematants of 4 different permanent HNSCC cell lines using the Bio-Plex human cytokine assay system. RESULTS: In HNSCC, IL-6 and IL-8 are involved in oncogenic processes, while IL-4 and IL-10 suppress proper immune responses in the tumor microenvironment. Our data indicate that, in the absence of tumor-infiltrating immune cells, HNSCC secretes high levels of the proto-oncogenic cytokines IL-6 and IL-8, but no significant levels of the immune suppressors IL-4 and IL-10. CONCLUSION: The data strongly suggest that the intercellular crosstalk between cells of HNSCC and tumor-infiltrating immune cells in vivo is required to stimulate an increased production of immune suppressive mediators in head and neck cancer.

Carcinoma, Squamous Cell↗