transforming-growth-factor-beta and Gastritis

Eosinophilic esophagitis (EoE) is an allergen-mediated disease and elimination diets have proven to be effective to obtain clinical and histological remission. However, the effect of elimination diets on specific EoE transcripts and their clinical correlates is relatively unknown. The main aim of the study was to evaluate the effect of dietary treatment (four-food elimination diet [FFED]) with or without addition of amino acid-based formula (AAF) on a variety of pro-/anti-inflammatory, epithelial/barrier function and remodeling/fibrosis-related markers of disease activity and clinical correlates (eosinophils, symptoms, and endoscopic signs) in adult EoE patients.. We conducted an analysis of biopsy samples and data collected during a randomized controlled trial with an elimination diet in adult patients with active EoE (≥15 eosinophils [eos] per high-power field [hpf]). Demographics, symptoms (SDI-score), endoscopic signs (EREFS) and peak eosinophil counts/hpf were recorded at baseline and after 6 weeks of treatment. Transcripts of 10 indicated genes were measured (qPCR) and compared to clinical correlates at baseline and after treatment.. Forty patients (pooled FFED + FFED + AAF) (60% male, age 34.5 (interquartile range [IQR] 29-42.8 years) completed the diet. Peak eosinophil counts/hpf, symptoms and endoscopic signs were significantly decreased after 6 weeks dietary treatment. DSG-1 levels were significantly upregulated from baseline to week 6, whereas IL-13, CAPN-14, IL-5, IL-10, CCL-26, POSTN, TSLP, CPA-3, and TGF-β were significantly downregulated after 6 weeks of diet (all; <0.01). Prior to treatment, upregulation of CAPN-14 and lower levels of DSG-1 were associated with clinical fibrotic phenotypes, whereas upregulation of IL-10 was linked to food impaction phenotypes.. These findings strongly suggest that elimination diets, besides a clinical and histological response, are associated with a broad transcriptional response at the level of the esophageal epithelium.

Topics: Allergens; Amino Acids; Anti-Inflammatory Agents; Diet; Enteritis; Eosinophilia; Eosinophilic Esophagitis; Female; Gastritis; Gene Expression; Humans; Interleukin-10; Interleukin-13; Interleukin-5; Male; Prospective Studies; Transforming Growth Factor beta

Helicobacter pylori is planted in the human stomach and is the most common cause of chronic gastritis, which produced specific local and systemic humoral immunity, while the associations of these immune responses and H. pylori in the development of chronic gastritis remain unclear.. This study analyzed histology, the number of Th22 and regulatory T (Treg) cells, and the levels of inflammation- and gastritis-related indicators between 22 H. pylori-infected and 24 non-H. pylori-infected chronic gastritis patients by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR, and flow cytometry analysis.. This study found that the pathological damage degree of gastric mucosa in H. pylori infection patients was more serious. In the H. pylori-infected patient serum, the gastrin, G-17, interleukins (IL)-22, transforming growth factor (TGF)-β, tumor necrosis factor (TNF)-α, IL-4, and IL-17A levels were notably raised, while the interferon (IFN)-γ level was inhibited, and in gastric mucosa, and except IFN-γ, the IL-22, forkhead box P3 (Foxp3), TNF-α, IL-4, and IL-17A mRNA levels were raised too. The receiver operating characteristic curve analysis indicates serum IL-22, TGF-β, TNF-α, IL-4, and IL-17A are suitable for differential diagnosis of H. pylori infection. In addition, in the peripheral blood, the percentages of the IL-22. Treg and Th22 cells were positively associated with the degree of H. pylori infection and the severity of gastritis. In summary, this study provides an experimental basis for the study of the eradication of H. pylori and the biological mechanism of chronic gastritis.

Topics: Forkhead Transcription Factors; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Interferon-gamma; Interleukin-17; Interleukin-4; RNA, Messenger; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori-infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines-interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32-in H pylori-infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori-infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.

Topics: Adult; Aged; Carcinoma; Female; Gastric Mucosa; Gastritis; Gene Expression; Helicobacter Infections; Helicobacter pylori; Humans; Interferon-gamma; Interleukins; Male; Middle Aged; RNA, Messenger; Stomach Neoplasms; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

Strategies to boost the numbers and functions of regulatory T cells (Tregs) are currently being tested as means to treat autoimmunity. While Tregs have been shown to be effective in this role, strategies to manipulate Tregs to effectively suppress later stages of ongoing diseases need to be established. In this study, we evaluated the ability of TGF-β-induced Tregs (iTregs) specific for the major self-antigen in autoimmune gastritis to suppress established autoimmune gastritis in mice. When transferred into mice during later stages of disease, iTregs demethylated the Foxp3 promoter, maintained Foxp3 expression, and suppressed effector T cell proliferation. More importantly, these iTregs were effective at stopping disease progression. Untreated mice had high numbers of endogenous Tregs (enTregs) but these were unable to stop disease progression. In contrast, iTregs, were found in relatively low numbers in treated mice, yet were effective at stopping disease progression, suggesting qualitative differences in suppressor functions. We identified several inhibitory receptors (LAG-3, PD-1, GARP, and TNFR2), cytokines (TGF-β1 and IL12p35), and transcription factors (IRF4 and Tbet) expressed at higher levels by iTregs compared to enTregs isolated form mice with ongoing disease, which likely accounts for superior suppressor ability in this disease model. These data support efforts to use iTregs in therapies to treat establish autoimmunity, and show that iTregs are more effective than enTregs at suppressing inflammation in this disease model.

Topics: Animals; Autoantigens; Autoimmunity; Costimulatory and Inhibitory T-Cell Receptors; Cytokines; Flow Cytometry; Gastritis; In Vitro Techniques; Mice; Mice, Transgenic; Real-Time Polymerase Chain Reaction; Statistics, Nonparametric; T-Lymphocytes, Regulatory; Transcription Factors; Transforming Growth Factor beta

We evaluated allergy/hypersensitivity clinical markers and their correlation with Helicobactor pylori infection in children and adults to analyze how early acquisition of H. pylori could modulate allergic disorder expression.. H. pylori presence was assessed by the rapid urease test and histology of antrum biopsies in 165 patients. Skin tests, serum IgE, and two clinical allergy questionnaires were performed. Allergy severity was operationally defined using a combined score. Findings were correlated with H. pylori status and cytotoxin-associated gene A presence in pediatric and adult patients. Transforming growth factor β (TGF-β) levels were measured by an enzyme-linked immunosorbent assay in serum and gastric biopsies of H. pylori (+) patients.. H. pylori (-) children had more positive skin tests to a higher number of antigens than H. pylori (+) children (P<0.05). Operationally defined allergy inversely correlates with H. pylori infection in children, but not in adults. The percentage of H. pylori infection was lower in children with severe allergy (32.3%) compared with children with mild allergy (43.4%) or no allergy (64.3%) (P<0.05). Colonization with virulent strains (cytotoxin-associated gene A+) showed a nonsignificant inverse correlation with severity of allergies in pediatric patients. H. pylori-infected children, but not adults, without allergy markers showed increased levels of TGF-β compared with allergic children both in serum and gastric mucosa (P<0.05).. There was a strong inverse correlation between allergy markers and H. pylori infection in pediatric patients associated with elevated levels of TGF-β locally and systemically. H. pylori-associated chronic gastritis might downregulate clinical allergy expression.

Topics: Adolescent; Adult; Age Factors; Child; Cytokines; Female; Gastric Mucosa; Gastritis; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Hypersensitivity; Immunoglobulin E; Male; Middle Aged; Pyloric Antrum; Skin Tests; Transforming Growth Factor beta; Young Adult

The ability to regulate ongoing inflammation using regulatory T cells (Tregs) is under intense investigation. Strategies to induce and expand Ag-specific Tregs are being developed, and whether various types of Tregs are suppressive in the inflammatory conditions associated with ongoing disease needs to be determined. In this study, we report that TGF-β-induced Tregs (iTregs) and expanded Tregs specific for a major self-Ag in autoimmune gastritis suppress inflammation and associated pathology when administered late in the process of ongoing disease. Transferred iTregs localized to the stomach, maintained Foxp3 and suppressor functions, and engaged several distinct mechanisms to alleviate disease progression. In addition to suppressing the production of inflammatory cytokines in the stomach and preventing the destruction of parietal cells, we show that iTregs secrete numerous chemokines and regulate both iTreg and effector T cell trafficking into the stomach. These data support efforts to use iTregs in therapies to treat autoimmunity and inflammatory diseases and provide novel insight into the biological mechanisms of iTreg-mediated immune suppression.

Topics: Animals; Autoantigens; Autoimmune Diseases; Cell Movement; Chemokines; Forkhead Transcription Factors; Gastric Mucosa; Gastritis; Mice; Mice, Inbred BALB C; Mice, Transgenic; Stomach; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

To detect the expression levels of transcription factors and associated cytokines of Th17 and Treg cells in peripheral blood mononuclear cells (PBMC) of patients with gastric cancer, and explore the possible pathological mechanism of these cells involved in the development of gastric cancer.. The mRNA levels of RORgammat, FoxP3 in PBMC were determined by quantitative real-time PCR (QRT-PCR) from 57 patients with gastric cancer, 31 patients with benign gastric illness and 40 healthy people. The concentration of IL-17, IL-23, TGF-beta, IL-10 in plasma were detected by enzyme linked immunosorbent assay (ELISA).. Compared with healthy volunteers, patients with gastric cancer showed higher levels of RORgammat and FoxP3 in PBMC (P < 0.05). The ratio of FoxP3/RORgammat in gastric cancer group was higher than that in the volunteer group and benign gastric illness group (P < 0.05). The ratio of FoxP3/RORgammat was higher in advanced disease than early disease (P < 0.05). The expressions of IL-17, IL-23, TGF-beta and IL-10 were higher in patients with gastric cancer than that in healthy volunteers (P < 0.05). In addition, The expression of TGF-beta and IL-10 were significantly increased in the advanced disease group than that in the early group (P < 0.05), but IL-17 and IL-23 was not significantly changed between the two groups (P > 0.05).. There are higher levels of Th17 and Treg cells in gastric cancer patients, and it also shows a persistent predominant tendency of Treg cells and a reduced tendency of Th17 cells in advanced disease. Detecting the expression of Th17/Treg transcription factor and related cytokines would contribute to the diagnosis and prediction of the disease development and prognosis.

Topics: Adult; Aged; Female; Forkhead Transcription Factors; Gastritis; Humans; Interleukin-10; Interleukin-17; Interleukin-23; Male; Middle Aged; Neoplasm Staging; Nuclear Receptor Subfamily 1, Group F, Member 3; RNA, Messenger; Stomach Neoplasms; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Naïve antigen-specific CD4(+) T cells (TxA23) induce autoimmune gastritis when transferred into BALB/c nu/nu mice. Transfer of in vitro pre-differentiated Th1 or Th17 TxA23 effector T cells into BALB/c nu/nu recipients induces distinct histological patterns of disease. We have previously shown that co-transfer of polyclonal naturally occurring Treg (nTreg) suppressed development of Th1-, but not Th17-mediated disease. Therefore, we analysed the suppressive capacity of different types of Treg to suppress Th1- and Th17-mediated autoimmune gastritis. We compared nTreg with polyclonal TGFbeta-induced WT Treg (iTreg) or TGFbeta-induced antigen-specific TxA23 iTreg in co-transfer experiments with Th1 or Th17 TxA23 effector T cells. 6 weeks after transfer in vitro pre-differentiated TxA23 Th1 and Th17 effector cells induced destructive gastritis. Th1-mediated disease was prevented by co-transfer of nTreg and also antigen-specific iTreg, whereas WT iTreg did not show an effect. However, Th17-mediated disease was only suppressed by antigen-specific iTreg. Pre-activation of nTreg in vitro prior to transfer did not increase their suppressive activity in Th17-mediated gastritis. Thus, antigen-specific iTreg are potent suppressors of autoimmune gastritis induced by both, fully differentiated Th1 and Th17 effector cells.

Topics: Adoptive Transfer; Animals; Antigens; Autoimmune Diseases; Cell Differentiation; Gastritis; Immune Tolerance; Interleukin-17; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Nude; Stomach; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th1 Cells; Thymus Gland; Transforming Growth Factor beta

CD4(+) T cells from the TCR transgenic TxA23 mouse recognize a peptide from the H/K-ATPase alpha-chain. When TxA23 CD4(+) thymocytes are differentiated into Th1, Th2, and Th17 lines, all three subpopulations induced autoimmune gastritis (AIG) upon transfer into nu/nu recipients. The induction of AIG by naive T cells or by Th1 or Th2 cell lines could be prevented by the cotransfer of polyclonal Foxp3(+) T regulatory cells (nTreg), whereas Th17-induced AIG was resistant to suppression. We compared the capacity of different types of Treg to suppress Th17-mediated AIG. Cotransfer of either nTreg or polyclonal TGFbeta-induced Treg (iTreg) did not prevent AIG, while cotransfer of TGFbeta-induced Ag-specific TxA23 iTreg completely prevented the development of disease. Ag-specific iTreg were able to suppress Th17-mediated disease when injected 6 days after the Th17 effectors. The implications of these results for the use of Treg for the cellular biotherapy of autoimmune disease are discussed.

Topics: Adoptive Transfer; Animals; Autoimmune Diseases; Cells, Cultured; Epitopes, T-Lymphocyte; Female; Gastritis; Interleukin-17; Mice; Mice, Inbred BALB C; Mice, Nude; Mice, Transgenic; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Several strategies are being designed to test the therapeutic potential of Ag-specific regulatory T cells to prevent or treat autoimmune diseases. In this study, we demonstrate that naive CD4+ Foxp3- T cells specific for a naturally expressed autoantigen (H+/K+ ATPase) can be converted to Foxp3+ T regulatory cells (Tregs) when stimulated in presence of TGFbeta. TGFbeta-induced Tregs (iTregs) have all the characteristics of naturally generated regulatory T cells in vitro, and more importantly, are effective at preventing organ-specific autoimmunity in a murine model of autoimmune gastritis. H+/K+ ATPase specific iTregs were able to inhibit the initial priming and proliferation of autoreactive T cells, and appear to do so by acting on H+/K+ ATPase presenting dendritic cells (DC). DC exposed to iTregs in vivo were reduced in their ability to stimulate proliferation and cytokine production by H+/K+ ATPase specific T cells. iTregs specifically reduced CD80 and CD86 expression on the surface of H+/K+ ATPase presenting DC in vitro. These studies reveal the therapeutic potential of Ag specific iTregs to prevent autoimmunity, and provide a mechanism by which this population of regulatory T cells, and perhaps others, mediate their suppressive effects in vivo.

Topics: Animals; Autoantigens; Autoimmunity; B7-1 Antigen; B7-2 Antigen; CD4 Lymphocyte Count; Cells, Cultured; Dendritic Cells; Diabetes Mellitus, Type 1; Female; Forkhead Transcription Factors; Gastritis; Lymph Nodes; Lymphocyte Activation; Mice; Organ Specificity; Phenotype; T-Lymphocytes, Regulatory; Time Factors; Transforming Growth Factor beta

Downregulation of TGF-beta receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-beta1 types I/II receptors, is now implicated in carcinogenesis, especially gastrointestinal carcinogenesis.. We generated transgenic mice, called pS2-dnRII or ITF-dnRII, of which the dominant negative mutant of the TGF-beta type II receptor was expressed under the control of tissue-specific promoters, the pS2 promoter for stomach and ITF for intestine. They were either infected with H.pylori (ATCC 43504 strain, CagA+ and VacA+) or administered with azoxymethane to determine the significance of loss of TGF-beta signalling in gastrointestinal carcinogenesis.. Gastric adenocarcinoma developed in pS2-dnRII mice, whereas only chronic active gastritis was noted in wild-type littermates after 36 weeks of H.pylori infection. Mice lacking in TGF-beta signalling specifically in the stomach showed a significantly higher proliferation cell nuclear antigen-labelling index when infected with H.pylori than wild-type littermates (P < 0.01). Development of colonic aberrant crypt foci was provoked in mice by intraperitoneal injections of azoxymethane, and ITF-dnRII mice showed significantly higher incidences of ACF and colon cancers than wild-type littermates.. Maintaining normal TGF-beta signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.

Topics: Animals; Azoxymethane; Carcinogens; Carcinoma; Colonic Neoplasms; Disease Susceptibility; Gastritis; Helicobacter Infections; Helicobacter pylori; Mice; Mice, Transgenic; Receptors, Transforming Growth Factor beta; Signal Transduction; Stomach Neoplasms; Transforming Growth Factor beta

The host immune response to Helicobacter pylori infection might be of importance with regard to the outcome of infection by this organism, e.g., to explain why only a proportion of infected subjects develop peptic ulcers. In this study we have analyzed the local response of different cytokines-i.e., the proinflammatory interleukin-1beta, (IL-1beta), IL-6, tumor necrosis factor alpha, and IL-8; the immunoregulatory gamma interferon (IFN-gamma); and IL-4; and the anti-inflammatory transforming growth factor beta (TGF-beta)-in antral biopsy specimens from H. pylori-infected duodenal ulcer (DU) patients and asymptomatic (AS) carriers (i.e., with chronic gastritis only). For comparison, biopsy specimens from uninfected healthy individuals were also analyzed. An immunohistochemical technique was used to allow quantification of the cytokine responses as well as identification of the cell types associated with the cytokine expression. We found that the levels of all of the studied cytokines except IL-4 were increased in the H. pylori-infected subjects compared to the levels in the healthy individuals. Our results indicate that the antral cytokine response is of the Th1 type since IFN-gamma, but not IL-4, was up-regulated both in H. pylori-infected DU patients and in AS carriers. However, there were no significant differences in either proinflammatory or immunoregulatory cytokine levels when H. pylori-infected subjects with and without peptic ulcers were compared. Some of the cytokines, particularly IL-1beta and TGF-beta, were also found in the gastric mucosae of healthy, uninfected subjects. We also showed that the gastric epithelium contributes substantially to the antral cytokine response of the proinflammatory cytokines IL-1beta and IL-6 in addition to IL-8.

Topics: Adult; Aged; Chronic Disease; Cytokines; Duodenal Ulcer; Female; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Interferon-gamma; Interleukins; Intestinal Mucosa; Male; Middle Aged; Pyloric Antrum; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Transforming growth factor beta-1 (TGF beta 1) is known to inhibit the growth of many epithelial cell types in culture. Consequently, it is important to determine whether it has any tumor suppressor activity in vitro. Fifteen heterozygous and eight wild type TGF beta 1-deficient mice were examined to determine if there was a difference in lifespan or lesion development due to the loss of one TGF beta 1 allele. Mice were killed when there was evidence of neoplasia or severe illness. There was no significant difference in the lifespan of the two groups. Hyperplastic lesions in the glandular mucosa were seen in 10 TGF beta 1 (+/-) mice. These lesions were localized to the lesser curvature of the stomach, extending from the limiting ridge to the pylorus. Seven of the 10 glandular hyperplastic lesions in the TGF beta 1 (+/-) mice had features similar to human gastritis cystica profunda. Associated with the glandular invasion of the muscularis were a mixed inflammatory infiltration of the surrounding muscular wall and mucosa with chronic vasculitis in the tissues adjacent to these lesions. In contrast to the distinct genotypic differences in lesion incidence observed in the glandular stomach, there was no significant difference in lesion incidence in other organs. The increased incidence of the hyperplastic lesions in the TGF beta 1 (+/-) mice is highly suggestive that allelic loss of TGF beta 1 plays an important role in the genesis of these lesions. However, allelic loss of TGF beta 1 does not cause alterations in the incidence of neoplasia.

Topics: Alleles; Animals; Gastric Mucosa; Gastritis; Genotype; Heterozygote; Hybridization, Genetic; Hyperplasia; Mice; Mice, Inbred Strains; Stomach; Transforming Growth Factor beta