Alcohol Facilitates CD1d Loading, Subsequent Activation of NKT Cells, and Reduces the Incidence of Diabetes in NOD Mice

Background: Ethanol ('alcohol') is a partly hydrophobic detergent that may affect the accessibility of glycolipids thereby influencing immunological effects of these molecules. Methods: The study included cellular in vitro tests using α-galactosylceramide (αGalCer), and in vivo NOD mice experiments detecting diabetes incidence and performing behavioural and bacterial analyses. Results: Alcohol in concentrations from 0.6% to 2.5% increased IL-2 production from NKT cells stimulated with αGalCer by 60% (p<0.05). CD1d expressed on HeLa cells contained significantly increasing amounts of αGalCer with increasing concentrations of alcohol, suggesting that alcohol facilitated the passive loading of αGalCer to CD1d. NOD mice were found to tolerate 5% ethanol in their drinking water without signs of impairment in liver function. Giving this treatment, the diabetes incidence declined significantly. Higher numbers of CD3+CD49b+ NKT cells were found in spleen and liver of the alcohol treated compared to the control mice (p<0.05), whereas the amount of CD4+Foxp3+ regulator T cells did not differ. Increased concentrations of IFN-γ were detected in 24-hour blood samples of alcohol treated mice. Behavioural studies showed no change in attitude of the ethanol-consuming mice, and bacterial composition of caecum samples was not affected by alcohol, disqualifying these as protective mechanisms. Conclusion: Alcohol facilitates the uptake of glycolipids and the stimulation of NKT cells, which are known to counteract Type 1 diabetes development. We propose that this is the acting mechanism by which treatment with alcohol reduces the incidence of diabetes in NOD mice. This is corroborated by epidemiology showing beneficial effect of alcohol to reduce the severity of atherosclerosis and related diseases

The prognostic role of tumor associated macrophages in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis

Head and neck squamous cell carcinoma (HNSCC) is an immunogenic cancer type, and tumor associated macrophages (TAMs) are a major component of the tumor microenvironment (TME). In this systematic review and meta-analysis, studies assessing tumor infiltration with CD68+, iNOS+, HLA-DR+, CD11b+, CD163+, CD206+, and CD204+TAMs were included, and correlation to survival hazard was studied. A low number of CD68+TAMs correlated to better overall survival (OS) in multivariate analysis (HR 1.36 95 %CI (1.07–1.72) P = .01). CD68+TAMs did not correlate to disease free survival (DFS), disease specific survival (DSS), progression free survival (PFS), or recurrence free survival (RFS). A low number of CD163+TAMs correlated to better OS in uni- and multivariate analysis (resp. HR 2.65 95 %CI (1.57–4.46) P = .01 and HR 2.42 95 %CI (1.72–3.41) P < .001). A low number of CD163+TAMs also correlated to better DFS and PFS, whereas a low number of CD204+TAMs only correlated to PFS. While IHC analysis of pan macrophage marker CD68 and M2-like marker CD163 both show prognostic utility in OS, CD163 is a stronger prognosticator, as indicated by multivariate meta-analysis. CD163+TAMs also correlate to DFS and PFS; outcomes that are more relevant to patients, thus showing promising results for future clinical implementation

Changes in Natural Foxp3⁺Treg but Not Mucosally-Imprinted CD62L^negCD38⁺Foxp3⁺Treg in the Circulation of Celiac Disease Patients

<div><p>Background</p><p>Celiac disease (CD) is an intestinal inflammation driven by gluten-reactive CD4⁺ T cells. Due to lack of selective markers it has not been determined whether defects in inducible regulatory T cell (Treg) differentiation are associated with CD. This is of importance as changes in numbers of induced Treg could be indicative of defects in mucosal tolerance development in CD. Recently, we have shown that, after encounter of retinoic acid during differentiation, circulating gut-imprinted T cells express CD62L^negCD38⁺. Using this new phenotype, we now determined whether alterations occur in the frequency of natural CD62L⁺Foxp3⁺ Treg or mucosally-imprinted CD62L^negCD38⁺Foxp3⁺ Treg in peripheral blood of CD patients. In particular, we compared pediatric CD, aiming to select for disease at onset, with adult CD.</p><p>Methods</p><p>Cell surface markers, intracellular Foxp3 and Helios were determined by flow cytometry. Foxp3 expression was also detected by immunohistochemistry in duodenal tissue of CD patients.</p><p>Results</p><p>In children, the percentages of peripheral blood CD4⁺Foxp3⁺ Treg were comparable between CD patients and healthy age-matched controls. Differentiation between natural and mucosally-imprinted Treg on the basis of CD62L and CD38 did not uncover differences in Foxp3. In adult patients on gluten-free diet and in refractory CD increased percentages of circulating natural CD62L⁺Foxp3⁺ Treg, but normal mucosally-imprinted CD62L^negCD38⁺Foxp3⁺ Treg frequencies were observed.</p><p>Conclusions</p><p>Our data exclude that significant numeric deficiency of mucosally-imprinted or natural Foxp3⁺ Treg explains exuberant effector responses in CD. Changes in natural Foxp3⁺ Treg occur in a subset of adult patients on a gluten-free diet and in refractory CD patients.</p></div

Distribution of CD62L/CD38 subsets within CD4⁺ peripheral blood lymphocytes; changes with age.

<p>Peripheral blood from pediatric CD patients was stained for flow cytometric analysis. (<b>a</b>) Representative gating strategy for analysis of CD62L/CD38 subsets within the CD4⁺ T cell population. Two representative CD62L/CD38 analyses of peripheral blood CD4⁺ T cells in CD patients aged 1 and 5 years old. (<b>b</b>) The percentages of cells in each of the four CD62L/CD38 T-cell subsets were calculated (Kruskal-Wallis test). CD, celiac disease.</p

Demographic features of pediatric celiac disease (CD) and controls.

<p>CD, celiac disease.</p

No differences in numbers of circulating Treg cells or mucosally-imprinted Treg cells between pediatric CD patients and controls.

<p>(<b>a</b>) The percentage of CD62L^negCD38⁺ mucosally-imprinted T cells were observed within the peripheral blood CD4⁺ T cell population of CD patients (n = 36) and controls (n = 20). (<b>b</b>) The percentage of CCR9⁺ cells within the CD62L^negCD38⁺CD4⁺ T cell subset in pediatric CD patients (n = 34) and controls (n = 9). (<b>c</b>) Percentages of naive (CD45RA⁺) cells within CD62L^negCD38⁺CD4⁺ T cell in pediatric CD patients (n = 19) and controls (n = 9).(<b>d</b>) WBC counts per liter peripheral blood for pediatric CD patients (n = 36) and controls (n = 20). (<b>e</b>) The frequency of total Foxp3⁺ cells (gated on CD4⁺ lymphocytes) in pediatric CD patients (n = 36) and controls (n = 20). (<b>f</b>) The percentage of mucosally-imprinted Foxp3⁺CD62L^negCD38⁺ cells in pediatric CD patients (n = 36) and in controls (n = 20). * Statistically significant (<i>P</i><0.05), n.s. not significant (Mann-Whitney <i>U</i> test). CD, celiac disease.</p

Increased numbers of circulating natural Treg cells in adult RCD and treated CD compared to controls.

<p>Peripheral blood was obtained from adult patients with RCD (n = 14), CD patients responding to a GFD (treated CD, n = 13) and healthy controls (n = 14). (<b>a</b>) The percentages of Foxp3 cells within the total CD3⁺CD4⁺ T cells and within the different CD4⁺CD62L/CD38 T cells were determined. (<b>a</b>) Percentage of Foxp3⁺ cells within the total CD4⁺ T-cell gate (<b>b</b>) The percentage of Foxp3⁺ T cells in the CD62L⁺CD38⁺ and CD62L⁺CD38^neg subset. (<b>c</b>) The percentage of Foxp3⁺ in the mucosally-imprinted CD62L^negCD38⁺ T cells or in the CD62L^negCD38^neg T-cells in patient groups and controls. (<b>d</b>) Lymphocytes of 4 RCD patients were gated on CD3⁺CD4⁺ T cells and Foxp3 and Helios positivity were analyzed. The large majority of the Foxp3⁺ cells co-expressed Helios. (<b>e</b>) Representative dot-plots of Foxp3 and Helios expression (left panel) and isotype controls (right panel) are shown. Data analyzed Mann-Whitney <i>U</i> test. CD, celiac disease; RCD, refractory celiac disease.</p

No increase of IL-15 plasma levels in CD patients.

<p>The IL-15 concentration in plasma was determined in pediatric controls (n = 8), pediatric CD (n = 6), adult controls (n = 5), adult treated CD (n = 13) and RCD patients (n = 13) by enzyme-linked immunosorbent assay. Dashed line represents the detection limit. CD, celiac disease. Data are representative for three independent measurements.</p

Demographic features of adult celiac disease (CD) patients and controls.

<p>CD, celiac disease; EmA, anti-endomysial antibodies; tTG anti-tissue transglutaminase antibodies; RCD, refractory celiac disease; EATL, enteropathy-associated T cell lymphoma; GFD, gluten free diet. All patients were tested for anti-tissue transglutaminase and anti-endomysial antibodies. * This patient was positive for anti-tissue transglutaminase antibodies.</p

A química medicinal na próxima década Brazilian medicinal chemistry in the next decade

<abstract language="eng">Medicinal chemistry is multi, trans and inter disciplinary on its essence. It has a great deal of challenging Brazilian chemists in the next decade. The pharmacy school is essentially attached and has an important role in the development on the field that is still in domain of big pharmaceutical industries. This work shows the challenges to face and directions to jointly follow for a myriad of researchers throughout the country. The unnamed science has to work out through specific objectives in order to diminish the problems associated with human being health. A brief history is presented where the main goal is to devise chemistry, as a natural science, and many other interfaced disciplines