Ethyl Pyruvate Induces Tolerogenic Dendritic Cells

Dendritic cells (DC) are professional antigen presenting cells that have a key role in shaping the immune response. Tolerogenic DC (tolDC) have immuno-regulatory properties and they are a promising prospective therapy for multiple sclerosis and other autoimmune diseases. Ethyl pyruvate (EP) is a redox analog of dimethyl fumarate (Tecfidera), a drug for multiple sclerosis treatment. We have recently shown that EP ameliorates experimental autoimmune encephalomyelitis, a multiple sclerosis murine model. Here, we expanded our study to its tolerogenic effects on DC. Phenotypic analysis has shown that DC obtained from mice or humans reduce expression of molecules required for T cell activation such as CD86, CD83, and HLA-DR under the influence of EP, while CD11c expression and viability of DC are not affected. Furthermore, EP-treated DC restrain proliferation and modulate cytokine production of allogeneic lymphocytes. These results demonstrate that EP has the ability to direct DC toward tolDC

Increased Natural Killer Cells Are Associated with Alcohol Liver Fibrosis and with T Cell and Cytotoxic Subpopulations Change

Natural killer (NK) cells play a therapeutic role in liver fibrosis (LF). We aimed to analyze NK cells in heavy drinkers without cirrhosis or decompensated liver disease and establish correlations with other related subpopulations. Data on sociodemographic characteristics, alcohol consumption, laboratory parameters, and immunophenotyping of NK (CD16 + /CD56 +), T (CD3 +), B (CD19 +), NKT (CD16 + /CD56 + /CD3 +), and cytotoxic (CD3 - CD8 +) cells were collected. Fibrosis-4 (FIB-4) scores were used to compare patients without (FIB-4 3.25) advanced LF (ALF). We included 136 patients (76% male) with a mean age of 49 years who had a 15-year alcohol use disorder (AUD) and alcohol consumption of 164 g/day. Patients with ALF (n = 25) presented significantly lower absolute total lymphocyte, T cell, B cell, and NKT cell numbers than patients without LF (n = 50; p < 0.01). However, the NK cells count was similar (208 ± 109 cells/µL vs. 170 ± 105 cells/µL) in both groups. The T cells percentage was lower (80.3 ± 5.6% vs. 77 ± 7%; p = 0.03) and the NK cells percentage was higher (9.7 ± 5% vs. 13 ± 6%; p = 0.02) in patients with ALF than in those without LF. The percentages of NK cells and T cells were inversely correlated in patients without (r = -0.65, p < 0.01) and with ALF (r = −0.64; p < 0.01). Additionally, the NK cells and CD3 - CD8 + cell percentages were positively correlated in patients without (r = 0.87, p < 0.01) and with (r = 0.92; p < 0.01) ALF. Conclusions: Heavy drinkers without decompensated liver disease showed an increase in NK cells related to T cells lymphopenia and an increase in cytotoxic populations. The interaction of NK cells with other subpopulations may modify alcohol-related liver disease progression

Regulatory role of vitamin D in T-cell reactivity against myelin peptides in relapsing-remitting multiple sclerosis patients

Background: Low levels of plasma 25-hydroxyvitaminD (25(OH)D) are associated with a higher incidence of multiple sclerosis (MS) due to the immune suppressive properties of vitamin D. The aim of this study was to determine the correlation between plasma 25(OH)D concentrations and clinical and immunological variables in a cohort of multiple sclerosis patients. Methods: Plasma 25(OH)D concentrations were evaluated in summer and winter in 15 primary progressive MS (PPMS) patients, 40 relapsing- remitting MS (RRMS) patients and 40 controls (HC). Protocol variables included demographic and clinical data, radiological findings and immunological variables (oligoclonal bands, HLADR15 and T-lymphocyte proliferation to a definite mix of 7 myelin peptides). Results: During the winter, plasma concentrations were significantly lower in RRMS patients compared to HC, whereas no differences were found in summer. No relationships were found between plasma 25(OH)D concentrations and clinical or radiological variables. RRMS patients with a positive T-cell proliferation to a mix of myelin peptides (n = 31) had lower 25(OH)D concentrations. Conclusions: 25(OH)D is an immunomodulatory molecule that might have a regulatory role in T-cell proliferation to myelin peptides in RRMS patients

Comparative transcriptomic profile of tolerogenic dendritic cells differentiated with vitamin D3, dexamethasone and rapamycin

Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes

Ethyl Pyruvate Induces Tolerogenic Dendritic Cells.

Dendritic cells (DC) are professional antigen presenting cells that have a key role in shaping the immune response. Tolerogenic DC (tolDC) have immuno-regulatory properties and they are a promising prospective therapy for multiple sclerosis and other autoimmune diseases. Ethyl pyruvate (EP) is a redox analog of dimethyl fumarate (Tecfidera), a drug for multiple sclerosis treatment. We have recently shown that EP ameliorates experimental autoimmune encephalomyelitis, a multiple sclerosis murine model. Here, we expanded our study to its tolerogenic effects on DC. Phenotypic analysis has shown that DC obtained from mice or humans reduce expression of molecules required for T cell activation such as CD86, CD83, and HLA-DR under the influence of EP, while CD11c expression and viability of DC are not affected. Furthermore, EP-treated DC restrain proliferation and modulate cytokine production of allogeneic lymphocytes. These results demonstrate that EP has the ability to direct DC toward tolDC

Assessing Blood-Based Biomarkers to Define a Therapeutic Window for Natalizumab

Natalizumab is a monoclonal antibody that binds CD49d. Although it is one of the most effective treatments for Relapsing-Remitting Multiple Sclerosis (RRMS), a dosing regimen has not been optimized for safety and efficacy in individual patients. We aimed to identify biomarkers to monitor Natalizumab treatment and to establish a personalized dose utilizing an ongoing longitudinal study in 29 RRMS patients under Natalizumab with standard interval dose (SD) of 300 mg/4 wks or extended interval dose (EID) of 300 mg/6 wks. Blood samples were analyzed by flow cytometry to determine CD49d saturation and expression in several T and B lymphocytes subpopulations. Each patient was analyzed at two different timepoints separated by 3 Natalizumab administrations. Natalizumab and sVCAM-1 levels in serum were also analyzed using ELISA. To determine the reproducibility of various markers, two different timepoints were compared and no significant differences were observed for CD49d expression nor for saturation; SD patients had higher saturation levels (~80%) than EID patients (~60%). A positive correlation exists between CD49d saturation and Natalizumab serum levels. CD49d expression and saturation are stable parameters that could be used as biomarkers in the immunomonitoring of Natalizumab treatment. Moreover, Natalizumab and sVCAM-1 serum levels could be used to optimize an individual's dosing schedule

COVID-19 : Age, Interleukin-6, C-reactive protein, and lymphocytes as key clues from a multicentre retrospective study

Background: The SARS-CoV-2 infection has widely spread to become the greatest public health challenge to date, the COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. The Spanish case-fatality rate is 11.22%, far higher than those reported in Asia or by other European countries. A multicentre retrospective study of demographic, clinical, laboratory and immunological features of 584 Spanish COVID-19 hospitalized patients and their outcomes was performed. The use of renin-angiotensin system blockers was also analysed as a risk factor. Results: In this study, 27.4% of cases presented a mild course, 42.1% a moderate one and for 30.5% of cases, the course was severe. Ages ranged from 18 to 98 (average 63). Almost 60 % (59.8%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19, and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of angiotensin-converting enzyme inhibitors was associated with a better prognosis. The angiotensin II receptor blocker use was associated with a more severe course. Conclusions: Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and the clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for the hampering of immune system effectors. The adaptive immunity would become exhausted and a strong but ineffective and almost deleterious innate response would account for COVID-19 severity. Angiotensin-converting enzyme inhibitors used by hypertensive patients have a protective effect in regards to COVID-19 severity in our series. Conversely, patients on angiotensin II receptor blockers showed a severer disease