Chronic Intestinal Inflammatory Condition Generates IL-10-Producing Regulatory B Cell Subset Characterized by CD1d Upregulation

AbstractB cells possess a variety of immune functions that are involved in normal and abnormal immune responses, including autoimmune disorders. Through murine models of intestinal inflammation, we here demonstrate a B cell subset that is induced in gut-associated lymphoid tissues and is characterized by CD1d upregulation. This B cell subset appears under a chronic inflammatory environment, produces IL-10, and suppresses progression of intestinal inflammation by downregulating inflammatory cascades associated with IL-1 upregulation and STAT3 activation rather than by altering polarized T helper responses. This study indicates that B cells, by producing cytokines such as IL-10, can act as regulatory cells in immunologically mediated inflammatory reactions

Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Our previous studies have demonstrated that transduction of human dendritic cells (DC) with adenovirus encoding secondary lymphoid chemokine, CCL21, led to secretion of biologically active CCL21 without altering DC phenotype or viability. In addition, intratumoral injections of CCL21-transduced DC into established murine lung tumors resulted in complete regression and protective anti-tumor immunity. These results have provided the rationale to generate a clinical grade adenoviral vector encoding CCL-21 for <it>ex vivo </it>transduction of human DC in order to assess intratumoral administration in late stage human lung cancer.</p> <p>Methods</p> <p>In the current study, human monocyte-derived DC were differentiated by exposure to GM-CSF and IL-4 from cryopreserved mononuclear cells obtained from healthy volunteers. Transduction with clinical grade adenoviral vector encoding CCL21 (1167 viral particles per cell) resulted in secretion of CCL21 protein.</p> <p>Results</p> <p>CCL21 protein production from transduced DC was detected in supernatants (24–72 hours, 3.5–6.7 ng/4–5 × 10⁶cells). DC transduced with the clinical grade adenoviral vector were > 88% viable (n = 16), conserved their phenotype and maintained integral biological activities including dextran uptake, production of immunostimulatory cytokines/chemokines and antigen presentation. Furthermore, supernatant from CCL21-DC induced the chemotaxis of T2 cells <it>in vitro</it>.</p> <p>Conclusion</p> <p>Viable and biologically active clinical grade CCL21 gene-modified DC can be generated from cryopreserved PBMC.</p

Two Functionally Distinct Isoforms of TL1A (TNFSF15) Generated by Differential Ectodomain Shedding

Tumor necrosis factor–like cytokine 1A (TL1A) is expressed in endothelial cells and contributes to T-cell activation, via an extracellular fragment TL1AL72-L251, generated by ectodomain shedding. Fragments of TL1A, referred to as vascular endothelial growth inhibitor, were found to induce growth arrest and apoptosis in endothelial cells; however, the underlying mechanisms remained obscure. Here, we show that full-length TL1A is the major detectable gene product in both human umbilical vein endothelial cells and circulating endothelial progenitor cells. TL1A expression was significantly enhanced in senescent circulating endothelial progenitor cells, and knockdown of TL1A partially reverted senescence. TL1A overexpression induced premature senescence in both circulating endothelial progenitor cells and human umbilical vein endothelial cells. We also identified a novel extracellular fragment of TL1A, TL1AV84-L251, resulting from differential ectodomain shedding, which induced growth arrest and apoptosis in human umbilical vein endothelial cells. These findings suggest that TL1A is involved in the regulation of endothelial cell senescence, via a novel fragment produced by differential ectodomain shedding

TL1A Selectively Enhances IL-12/IL-18-Induced NK Cell Cytotoxicity against NK-Resistant Tumor Targets

# The Author(s) 2010. This article is published with open access at Springerlink.com Introduction TL1A (TNFSF15) augments IFN-γ production by IL-12/IL-18 responsive human T cells. Its ligand, death domain receptor 3 (DR3), is induced by activation on T and NK cells. Although IL-12/IL-18 induces DR3 expression on most NK cells, addition of TL1A minimally increases IFN-

The Role of T cell PPAR γ in mice with experimental inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptor γ (PPAR γ) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD.</p> <p>Methods</p> <p>PPAR γ flfl; CD4 Cre⁺(CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays.</p> <p>Results</p> <p>The deficiency of PPAR γ in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8⁺T cells than WT mice and fewer CD4⁺FoxP3⁺regulatory T cells (Treg) and IL10⁺CD4⁺T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1β, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR γ in T cells.</p> <p>Conclusions</p> <p>The expression of PPAR γ in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive sites.</p

Constitutive TL1A (TNFSF15) Expression on Lymphoid or Myeloid Cells Leads to Mild Intestinal Inflammation and Fibrosis

TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, a subset of Crohn's disease (CD) patients with the risk TL1A haplotype is associated with elevated TL1A expression and a more severe disease course. To investigate the in vivo role of elevated TL1A expression, we generated two transgenic (Tg) murine models with constitutive Tl1a expression in either lymphoid or myeloid cells. Compared to wildtype (WT) mice, constitutive expression of Tl1a in either lymphoid or myeloid cells showed mild patchy inflammation in the small intestine, which was more prominent in the ileum. In addition, mice with constitutive Tl1a expression exhibited enhanced intestinal and colonic fibrosis compared to WT littermates. The percentage of T cells expressing the gut homing chemokine receptors CCR9 and CCR10 was higher in the Tl1a Tg mice compared to WT littermates. Sustained expression of Tl1A in T cells also lead to increased Foxp3+ Treg cells. T cells or antigen presenting cells (APC) with constitutive expression of Tl1a were found to have a more activated phenotype and mucosal mononuclear cells exhibit enhanced Th1 cytokine activity. These results indicated an important role of TL1A in mucosal T cells and APC function and showed that up-regulation of TL1A expression can promote mucosal inflammation and gut fibrosis

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn\u27s disease.

BACKGROUND:Small bowel stricture is one of the most common complications in patients with Crohn\u27s disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD.METHODS:Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available.RESULTS:A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation.CONCLUSIONS:In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD

Interventions to reduce Staphylococcus aureus in the management of eczema

© 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Background Staphylococcus aureus (S. aureus) can cause secondary infection in eczema, and may promote inflammation in eczema that does not look infected. There is no standard intervention to reduce S. aureus burden in eczema. It is unclear whether antimicrobial treatments help eczema or promote bacterial resistance. This is an update of a 2008 Cochrane Review. Objectives To assess the effects of interventions to reduce S. aureus for treating eczema. Search methods We updated our searches of the following databases to October 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We searched five trials registers and three sets of conference proceedings. We checked references of trials and reviews for further relevant studies. We contacted pharmaceutical companies regarding ongoing and unpublished trials. Selection criteria Randomised controlled trials of products intended to reduce S. aureus on the skin in people diagnosed with atopic eczema by a medical practitioner. Eligible comparators were a similar treatment regimen without the anti-staphylococcal agent. Data collection and analysis We used standard methodological procedures expected by Cochrane. Our key outcomes were participant-or assessor-rated global improvement in symptoms/signs, quality of life (QOL), severe adverse events requiring withdrawal, minor adverse events, and emergence of antibiotic-resistant micro-organisms. Main results We included 41 studies (1753 analysed participants) covering 10 treatment categories. Studies were conducted mainly in secondary care in Western Europe; North America; the Far East; and elsewhere. Twelve studies recruited children; four, adults; 19, both; and six, unclear. Fifty-nine per cent of the studies reported the mean age of participants (range: 1.1 to 34.6 years). Eczema severity ranged from mild to severe. Many studies did not report our primary outcomes. Treatment durations ranged from 10 minutes to 3 months; total study durations ranged from 15 weeks to 27 months. We considered 33 studies at high risk of bias in at least one domain. We present results for three key comparisons. All time point measurements were taken from baseline. We classed outcomes as short-term when treatment duration was less than four weeks, and long-term when treatment was given for more than four weeks. Fourteen studies evaluated topical steroid/antibiotic combinations compared to topical steroids alone (infective status: infected (two studies), not infected (four studies), unspecified (eight studies)). Topical steroid/antibiotic combinations may lead to slightly greater global improvement in good or excellent signs/symptoms than topical steroid alone at 6 to 28 days follow-up (risk ratio (RR) 1.10, 95% confidence interval (CI) 1.00 to 1.21; 224 participants; 3 studies, low-quality evidence). There is probably little or no difference between groups for QOL in children, at 14 days follow-up (mean difference (MD)-0.18, 95% CI-0.40 to 0.04; 42 participants; 1 study, moderate-quality evidence). The subsequent results for this comparison were based on very low-quality evidence, meaning we are uncertain of their validity: severe adverse events were rare (follow-up: between 6 to 28 days): both groups reported flare of dermatitis, worsening of the condition, and folliculitis (325 participants; 4 studies). There were fewer minor adverse events (e.g. flare, stinging, itch, folliculitis) in the combination group at 14 days follow-up (218 participants; 2 studies). One study reported antibiotic resistance in children at three months follow-up, with similar results between the groups (65 participants; 1 study). Four studies evaluated oral antibiotics compared to placebo (infective status: infected eczema (two studies), uninfected (one study), one study’s participants had colonisation but no clinical infection). Oral antibiotics may make no difference in terms of good or excellent global improvement in infants and children at 14 to 28 days follow-up compared to placebo (RR 0.80; 95% CI 0.18 to 3.50; 75 participants; 2 studies, low-quality evidence). There is probably little or no difference between groups for QOL (in infants and children) at 14 days follow-up (MD 0.11, 95% CI-0.10 to 0.32, 45 participants, 1 study, moderate-quality evidence). The subsequent results for this comparison were based on very low-quality evidence, meaning we are uncertain of their validity: adverse events requiring treatment withdrawal between 14 to 28 days follow-up were very rare, but included eczema worsening (both groups), loose stools (antibiotic group), and Henoch-Schönlein purpura (placebo group) (4 studies, 199 participants). Minor adverse events, including nausea, vomiting, diarrhoea, and stomach and joint pains, at 28 days follow-up were also rare and generally low in both groups (1 study, 68 infants and children). Antibiotic resistance at 14 days was reported as similar in both groups (2 studies, 98 infants and children). Of five studies evaluating bleach baths compared to placebo (water) or bath emollient (infective status: uninfected (two studies), unspecified (three studies)), one reported global improvement and showed that bleach baths may make no difference when compared with placebo at one month follow-up (RR 0.78, 95% CI 0.37 to 1.63; 36 participants; low-quality evidence). One study showed there is probably little or no difference in QOL at 28 days follow-up when comparing bleach baths to placebo (MD 0.90, 95% CI-1.32 to 3.12) (80 infants and children; moderate-quality evidence). We are uncertain if the groups differ in the likelihood of treatment withdrawals due to adverse events at two months follow-up (only one dropout reported due to worsening itch (placebo group)) as the quality of evidence was very low (1 study, 42 participants). One study reported that five participants in each group experienced burning/stinging or dry skin at two months follow-up, so there may be no difference in minor adverse events between groups (RR 1.00, 95% CI 0.35 to 2.87, 36 participants, low-quality evidence). Very low-quality evidence means we are also uncertain if antibiotic resistance at four weeks follow-up is different between groups (1 study, 80 participants ≤ 18 years). Authors' conclusions We found insufficient evidence on the effects of anti-staphylococcal treatments for treating people with infected or uninfected eczema. Low-quality evidence, due to risk of bias, imprecise effect estimates and heterogeneity, made pooling of results difficult. Topical steroid/ antibiotic combinations may be associated with possible small improvements in good or excellent signs/symptoms compared with topical steroid alone. High-quality trials evaluating efficacy, QOL, and antibiotic resistance are required