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The prevalence of fragrances in various hygiene products contributes to their sensorial allure. However, fragrances can induce sensitization in the skin or respiratory system, and the mechanisms involved in this process are incompletely understood. This study investigated the intricate mechanisms underlying the fragrance's effects on sensitization response, focusing on the interplay between CYP450 enzymes, a class of drug‐metabolizing enzymes, and the adaptive immune system. Specifically, we assessed the expression of CYP450 enzymes and cytokine profiles in culture of BEAS‐2B and mature dendritic cells (mDC) alone or in co‐culture stimulated with 2 mM of a common fragrance, cinnamyl alcohol (CA) for 20 h. CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2A13 were analyzed by RT‐PCR and IL‐10, IL‐12p70, IL‐18, IL‐33, and thymic stromal lymphopoietin (TSLP) by Cytometric Bead Array (CBA). Through RT–PCR analysis, we observed that CA increased CYP1A2 and CYP1B1 expression in BEAS‐2B, with a further increased in BEAS‐2B‐mDC co‐culture. Additionally, exposure to CA increased IL‐12p70 levels in mDC rather than in BEAS‐2B‐mDC co‐culture. In regards to IL‐18, level was higher in BEAS‐2B than in BEAS‐2B‐mDC co‐culture. A positive correlation between the levels of IL‐10 and CYP1B1 was found in mDC‐CA‐exposed and between IL‐12p70 and CYP1A1 was found in BEAS‐2B after CA exposure. However, IL‐12p70 and CYP1A2 as well as IL‐18, IL‐33, and CYP1A1 levels were negative, correlated mainly in co‐culture control. These correlations highlight potential immunomodulatory interactions and complex regulatory relationships. Overall, exposure to CA enhances CYP450 expression, suggesting that CA can influence immune responses by degrading ligands on xenosensitive transcription factors. This study investigated mechanisms underlying the fragrance's effects on sensitization response through CYP450 enzymes and immune system. We quantified CYP450 enzymes and cytokines in BEAS‐2B and mature dendritic cells (mDC) alone or in co‐culture stimulated with 2 mM of cinnamyl alcohol (CA) for 20 h. Positive correlations between IL‐10 and CYP1B1 in mDC‐CA‐exposed and IL‐12p70 and CYP1A1 in BEAS‐2B‐CA‐exposed were found. These correlations highlight potential immunomodulatory interactions and regulatory relationships, suggesting that CA could influence immune responses by degrading ligands on xenosensitive transcription factors. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are central to regulating innate and adaptive immune responses. Strategies that modify DC function provide new therapeutic opportunities in autoimmune diseases and transplantation. Current pharmacological approaches can alter DC phenotype to induce tolerogenic DC (tolDC), a maturation-resistant DC subset capable of directing a regulatory immune response that are being explored in current clinical trials. The classical phenotypic characterization of tolDC is limited to cell-surface marker expression and anti-inflammatory cytokine production, although these are not specific. TolDC may be better defined using gene signatures, but there is no consensus definition regarding genotypic markers. We address this shortcoming by analyzing available transcriptomic data to yield an independent set of differentially expressed genes that characterize human tolDC. We validate this transcriptomic signature and also explore gene differences according to the method of tolDC generation. As well as establishing a novel characterization of tolDC, we interrogated its translational utility in vivo , demonstrating this geneset was enriched in the liver, a known tolerogenic organ. Our gene signature will potentially provide greater understanding regarding transcriptional regulators of tolerance and allow researchers to standardize identification of tolDC used for cellular therapy in clinical trials. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are the guardians of the immune system since they are located in the majority of peripheral tissues. In addition, they are crucial for the induction of an effective immune response based on their unique capacity to stimulate naive T cells. During co-evolution, the human pathogen herpes simplex virus type 1 (HSV-1) has evolved several immune evasion mechanisms in order to subvert the host's immune system especially by targeting DC biology and function. Here we demonstrate that HSV-1 infection influences the IL-6 receptor (IL6R) expression both on protein and mRNA levels in/on human monocyte-derived mature DCs (mDCs). Surprisingly, reduced IL6R expression levels were also observed on uninfected bystander mDCs. Mechanistically, we clearly show that HSV-1-derived non-infectious light (L-) particles are sufficient to trigger IL6R regulation on uninfected bystander mDCs. These L-particles lack the viral DNA-loaded capsid and are predominantly produced during infection of mDCs. Our results show that the deletion of the HSV-1 tegument protein vhs partially rescued the reduced IL6R surface expression levels on/in bystander mDCs. Using a neutralizing antibody, which perturbs the transfer of L-particles to bystander mDCs, was sufficient to rescue the modulation of IL6R surface expression on uninfected bystander mDCs. This study provides evidence that L-particles transfer specific viral proteins to uninfected bystander mDCs, thereby negatively interfering with their IL6R expression levels, however, to a lesser extend compared to H-particles. Due to their immune-modulatory capacity, L-particles represent an elaborated approach of HSV-1-mediated immune evasion. [ABSTRACT FROM AUTHOR]

Rationale: Tumor-infiltrating immune cells affect lung cancer outcome. However, the factors that influence the composition and function of the tumor immune environment remain poorly defined and need investigation, particularly in the era of immunotherapy.Objectives: To determine whether the tumoral immune environment is related to lung adenocarcinoma mutations.Methods: This retrospective cohort included 316 consecutive patients with lung adenocarcinoma (225 men; 258 smokers) studied from 2001 to 2005 in a single center. We investigated the association of densities of intratumoral mature dendritic cells (mDCs), CD8+ T cells, neutrophils, and macrophages with clinical and pathological variables and tumor cell mutation profiles obtained by next-generation sequencing.Measurements and Main Results: In 282 tumors, we found 460 mutations, mainly in TP53 (59%), KRAS (40%), STK11 (24%), and EGFR (14%). Intratumoral CD8+ T-cell density was high in smokers (P = 0.02) and TP53-mutated tumors (P = 0.02) and low in BRAF-mutated tumors (P = 0.005). Intratumoral mDC density was high with low pathological tumor stage (P = 0.01) and low with STK11 mutation (P = 0.004). Intratumoral neutrophil density was high and low with BRAF mutation (P = 0.04) and EGFR mutation (P = 0.02), respectively. Intratumoral macrophage density was low with EGFR mutation (P = 0.01). Intratumoral CD8+ T-cell and mDC densities remained strong independent markers of overall survival (P = 0.001 and P = 0.02, respectively).Conclusions: Intratumoral immune cell densities (mDCs, CD8+ T cells, neutrophils, macrophages) were significantly associated with molecular alterations in adenocarcinoma underlying the interactions between cancer cells and their microenvironment. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are potent and specialized antigen-presenting cells that play a crucial role in initiating and amplifying both the innate and adaptive immune responses. Tumor cells can escape from immune attack by secreting suppressive cytokines which solely or cooperatively impair the immune function and microrheological properties of DCs. However, the underlying mechanisms are not fully defined. Transforming growth factor-β1 (TGF-β1) has been identified as a major cytokine in the tumor microenvironment. To determine the effects of TGF-β1 on mature DCs (mDCs) from microrheological viewpoint, cells were treated with different concentrations of TGF-β1. The results showed that the impaired microrheological parameters, including osmotic fragility, electrophoretic mobility, deformability, membrane fluidity, F-actin organization and so on, as well as motilities of mDCs relied heavily on TGF-β1 concentration. Moreover, these changes were correlated with the expression levels of fascin1, cofilin1, phosphorylated cofilin1 and profilin, this could be one of the crucial aspects of immune escape mechanisms of tumors, hinting that the signal pathway of TGF-β1 should be blocked in appropriate way before performing DCs-based immunotherapy against cancer. It is clinically important to understand the biological behavior of DCs and immune escape mechanism of tumor as well as how to improve efficiency of the anti-tumor therapy based on DCs. [ABSTRACT FROM AUTHOR]

We report that methamphetamine (meth) may act as cofactor in human immunodeficiency virus (HIV)-1 pathogenesis by increasing dendritic cell (DC)-specific intercellular adhesion molecule-3 (ICAM-3) grabbing non-integrin (DC-SIGN) expression on DCs. Mature DCs (MDCs), obtained from normal subjects, cultured with meth show an up-regulation of DC-SIGN gene and protein expression as analyzed by real-time quantitative polymerase chain reaction and fluorescence-activated cell-sorting analyses, respectively. Furthermore, these meth-induced effects were reversed by a dopamine D1 receptor antagonist (SCH 23390) and small interfering RNA specific to the D1 receptor (D1R) demonstrating that meth-induced effects are mediated through these receptors. Furthermore, meth in synergy with the HIV-1 peptide gp120 up-regulates DC-SIGN gene expression by MDCs. These data are the first evidence that meth up-regulates the expression of DC-SIGN on MDCs. A better understanding of the role of DC-SIGN in HIV-1 infection may help to design novel therapeutic strategies against the progression of HIV-1 disease in the drug-using population. [ABSTRACT FROM AUTHOR]

Neoadjuvant radiation or chemoradiation is currently the treatment of choice for patients with locally advanced carcinoma of the rectum. To assess the effects of chemoradiation on tumour regression and on uninvolved mesorectal lymph nodes, a consecutive series of 76 patients receiving neoadjuvant chemoradiation and a stage-adapted control series of 57 patients without pretreatment were studied. Densities of cells positive for CD4 (T-helper cells), CD8 (cytotoxic T-cells), CD83 (mature dendritic cells), and CD57 (natural killer cells) were determined on immunostains. Tumour regression was graded, and presence or absence of extramural tumour was recorded. The densities of CD4+ T-lymphocytes and CD83+ dendritic cells in the paracortex of mesorectal lymph nodes were observed to be significantly reduced, as were the densities of CD57+ cells in the follicles; densities of CD8+ T-lymphocytes did not differ. Strong, moderate and poor tumour regression was observed in 29, 25, and 22 cases, respectively. For 12 patients, absence of extramural vital or regressing tumour was recorded, indicating pretherapeutic overstaging. The results bring to mind that neoadjuvant chemoradiation as a side effect may have a negative impact on anti-tumour immunity. Together with the drawback of overstaging the results argue for a careful selection of patients. [ABSTRACT FROM AUTHOR]