Modulation of Intestinal Dendritic Cells by Manipulation of Enteric Bacteria in Intestinal Inflammation

Inflammatory bowel disease (IBD) involves dysregulated immune responses to intestinal microbiota. Intestinal dendritic cells (DC) play a pivotal role in bacterial recognition, tolerance induction, T cell homing and differentiation. We hypothesized that alterations in human colonic DC are central to the inflammatory process, lymphocyte homing, and therapeutic responses in patients with IBD. Colonic CD11c+ cells have been shown to be activated in IBD but CD11c- cells have not been characterised. We identified, in ulcerative colitis (UC), a CD11c- population that had morphological features of DC, expressed MHC class II and Natural Killer cell marker CD56, expressed less activation markers and produced less cytokine, and were weakly stimulatory. Few were plasmacytoid DC. Their number increased in UC and Crohn’s disease (CD) but decreased after inflammation resolved. We explored function and homing properties of colonic CD11c+ DC, and their relationship with intestinal microbiota in IBD. In acute UC, IL-10+ and IL-12p40+ CD11c+ DC increased, and fewer CD11c+ DC expressed the homing molecule α-E (CD103). In active CD, IL-12p40+ DC increased and the ratio of pro:anti-inflammatory bacteria, namely bacteroides:bifidobacteria, correlated positively with IL-12p40+ DC; IL-6+ DC also increased and correlated with increased C-reactive protein, but negatively with antiinflammatory Faecalibacterium praustnitzii. In IBD probiotics and corticosteroids may work, in part, by modulating DC function. In UC patients treated with the probiotic mixture VSL#3, TLR-2+ DC and IL-12p40+ DC decreased while IL-10+ DC increased. In patients on corticosteroids similar changes were seen. Such effects were however not seen in patients on placebo. In conclusion, intestinal inflammation in IBD is associated with novel human colonic cells that share features of DC and NK cells. Intestinal DC function is influenced by composition of the commensal microbiota. Probiotics and corticosteroids are associated with altered “favourable” DC function; these effects may contribute to therapeutic benefit in patients with IBD

Publisher Correction: Crohn's disease

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Does CSR image matter to hypermarket’s consumers in Malaysia? perspective from persuasion knowledge model

It is commonly accepted that positive corporate social responsibility (CSR) image brings desirable outcomes, for instance, brand loyalty, improved brand image, enhanced store image, as well as increased visit intention; suggesting there are various direct outcomes of CSR image. Underpinned by the Persuasion Knowledge Model (PKM), this paper proposes that these outcomes are presented in a sequential manner, where there is a core mechanism that relates CSR image to store image and brand awareness, and in turn associate with consumers’ visit intention. A quantitative research methodology has been used where a structured questionnaire was distributed to consumers in selected states in Malaysia using the mall intercept method. Structural equation modelling was applied to examine the proposed model. The discoveries of the current study offer the observed evidence for the correlation between perceived CSR image and hypermarket visit intention, mediated by overall store image and brand awareness. The study emphasises a prominent role of CSR schemes, bringing together the overall hypermarket store image and the hypermarket brand awareness, which will enable hypermarket management to further boost visit intention from consumers

Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease

Genes that showed greater than four-fold upregulation in IBD. (XLSX 28 kb

Safety and potential efficacy of cyclooxygenase-2 inhibitors in coronavirus disease 2019

Objectives While the safety of non‐steroidal anti‐inflammatory drugs in COVID‐19 has been questioned, they may be beneficial given the hyper‐inflammatory immune response associated with severe disease. We aimed to assess the safety and potential efficacy of cyclooxygenase‐2 (COX‐2) selective inhibitors in high‐risk patients. Methods Retrospective study of patients with COVID‐19 pneumonia and aged ≥ 50 years who were admitted to hospital. Adverse outcomes analysed included supplemental oxygen use, intensive care unit admission, mechanical ventilation and mortality, with the primary endpoint a composite of any of these. Plasma levels of inflammatory cytokines and chemokines were measured in a subset. Results Twenty‐two of 168 (13.1%) in the cohort received COX‐2 inhibitors [median duration 3 days, interquartile range (IQR) 3–4.25]. Median age was 61 (IQR 55–67.75), 44.6% were female, and 72.6% had at least one comorbidity. A lower proportion of patients receiving COX‐2 inhibitors met the primary endpoint: 4 (18.2%) versus 57 (39.0%), P = 0.062. This difference was less pronounced after adjusting for baseline difference in age, gender and comorbidities in a multivariate logistic regression model [adjusted odds ratio (AOR) 0.45, 95% CI 0.14–1.46]. The level of interleukin‐6 declined after treatment in five of six (83.3%) treatment group patients [compared to 15 of 28 (53.6%) in the control group] with a greater reduction in absolute IL‐6 levels (P‐value = 0.025). Conclusion Treatment with COX‐2 inhibitors was not associated with an increase in adverse outcomes. Its potential for therapeutic use as an immune modulator warrants further evaluation in a large randomised controlled trial

Use of thiopurines in inflammatory bowel disease : an update

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.Peer reviewe

Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir

A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19

COVID-19 severity is associated with cytokine levels and lymphopenia, but the role of immune cell subsets is not well understood. Here the authors immunophenotype whole blood samples from 54 COVID-19 patients and find that the immature neutrophil-to-VD2 T-cell ratio is associated with severe COVID-19

Association of SARS-CoV-2 clades with clinical, inflammatory and virologic outcomes: An observational study

BACKGROUND: Host determinants of severe coronavirus disease 2019 include advanced age, comorbidities and male sex. Virologic factors may also be important in determining clinical outcome and transmission rates, but limited patient-level data is available. METHODS: We conducted an observational cohort study at seven public hospitals in Singapore. Clinical and laboratory data were collected and compared between individuals infected with different SARS-CoV-2 clades. Firth's logistic regression was used to examine the association between SARS-CoV-2 clade and development of hypoxia, and quasi-Poisson regression to compare transmission rates. Plasma samples were tested for immune mediator levels and the kinetics of viral replication in cell culture were compared. FINDINGS: 319 patients with PCR-confirmed SARS-CoV-2 infection had clinical and virologic data available for analysis. 29 (9%) were infected with clade S, 90 (28%) with clade L/V, 96 (30%) with clade G (containing D614G variant), and 104 (33%) with other clades 'O' were assigned to lineage B.6. After adjusting for age and other covariates, infections with clade S (adjusted odds ratio (aOR) 0·030 (95% confidence intervals (CI): 0·0002-0·29)) or clade O (B·6) (aOR 0·26 (95% CI 0·064-0·93)) were associated with lower odds of developing hypoxia requiring supplemental oxygen compared with clade L/V. Patients infected with clade L/V had more pronounced systemic inflammation with higher concentrations of pro-inflammatory cytokines, chemokines and growth factors. No significant difference in the severity of clade G infections was observed (aOR 0·95 (95% CI: 0·35-2·52). Though viral loads were significantly higher, there was no evidence of increased transmissibility of clade G, and replicative fitness in cell culture was similar for all clades. INTERPRETATION: Infection with clades L/V was associated with increased severity and more systemic release of pro-inflammatory cytokines. Infection with clade G was not associated with changes in severity, and despite higher viral loads there was no evidence of increased transmissibility

Antibody response of heterologous vs homologous mRNA vaccine boosters against the SARS-CoV-2 Omicron variant: interim results from the PRIBIVAC study, A Randomized Clinical Trial

Abstract Background Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity has raised the need for booster vaccinations. However, which combination of COVID-19 vaccines offers the strongest immune response against Omicron variant is unknown. Methods This randomized, subject-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. 100 BNT162b2-vaccinated individuals were enrolled and randomized 1: 1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; ‘BBB’) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ‘BBM’). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and VOCs at Day 28. Results 51 participants were allocated to BBB and 49 to BBM; 50 and 48 respectively were analyzed for safety and immunogenicity outcomes. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22,382  IU/mL 95% CI, 18,210 to 27,517) vs BBM (29,751  IU/mL 95% CI, 25,281 to 35,011, p = 0.034) as was the median level of neutralizing antibodies: BBB 99.0% (IQR 97.9 to 99.3%) vs BBM 99.3% (IQR 98.8 to 99.5%, p = 0.021). On sub-group analysis, significant differences in mean spike antibody titer and live Omicron neutralization titer was only observed in older adults. Median surrogate neutralizing antibody level against all VOCs was also significantly higher with BBM in older adults, and against Omicron was BBB 72.8% (IQR 54.0 to 84.7%) vs BBM 84.3% (IQR 78.1 to 88.7%, p = 0.0073). Both vaccines were well tolerated. Conclusions Heterologous mRNA-1273 booster vaccination induced a stronger neutralizing response against the Omicron variant in older individuals compared with homologous BNT123b2. </jats:sec