The reduction of the metabolyc syndrome in Navarra-Spain (RESMENA-S) study; a multidisciplinary strategy based on chrononutrition and nutritional education, together with dietetic and psychological control

Introduction: The high prevalence of metabolic syndrome (MS) in Spain requires additional efforts for prevention and treatment. Objective: The study RESMENA-S aims to improve clinical criteria and biomarkers associated with MS though an integral therapy approach. Methods: The study is a randomized prospective parallel design in which is expected to participate a total of 100 individuals. The RESMENA-S group (n = 50) is a personalized weight loss (30% energy restriction) diet, with a macronutrient distribution (carbohydrate / fat / protein) of 40/30/30, high meal frequency (7 / day), low glycemic index/load and high antioxidant capacity as well as a high adherence to the Mediterranean diet. The control group (n = 50) is assigned to a diet with the same energy restriction and based on the American Heart Association pattern. Both experimental groups are under dietary and psychological control during 8 weeks. Likewise, for an additional period of 16 weeks of self-control, is expected that volunteers will follow the same pattern but with no dietary advice. Results: Anthropometrical data and body composition determinations as well as blood and urine samples are being collected at the beginning and end of each phase. This project is registered at www.clinicaltrials.gov with the number NCT01087086 and count with the Research Ethics Committee of the University of Navarra approval (065/2009). Conclusions: Intervention trials to promote the adoption of dietary patterns and healthy lifestyle are of great importance to identify the outcomes and nutritional mechanisms that might explain the link between obesity, metabolic syndrome and associated complications

Overall avidity declines in TCR repertoires during latent CMV but not EBV infection.

The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown. To address these issues, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCRαβ clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. The parameters involved during the long-term persistence of virus-specific T cell clonotypes were further evaluated by gene expression profiling, phenotype and functional analyses. Within CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression. These findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data further suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct

High Peptide Dose Vaccination Promotes the Early Selection of Tumor Antigen-Specific CD8 T-Cells of Enhanced Functional Competence.

CD8 T-cell response efficiency critically depends on the TCR binding strength to peptide-MHC, i.e., the TCR binding avidity. A current challenge in onco-immunology lies in the evaluation of vaccine protocols selecting for tumor-specific T-cells of highest avidity, offering maximal immune protection against tumor cells and clinical benefit. Here, we investigated the impact of peptide and CpG/adjuvant doses on the quality of vaccine-induced CD8 T-cells in relation to binding avidity and functional responses in treated melanoma patients. Using TCR-pMHC binding avidity measurements combined to phenotype and functional assays, we performed a comprehensive study on representative tumor antigen-specific CD8 T-cell clones (n = 454) from seven patients vaccinated with different doses of Melan-A/ELA peptide (0.1 mg vs. 0.5 mg) and CpG-B adjuvant (1-1.3 mg vs. 2.6 mg). Vaccination with high peptide dose favored the early and strong in vivo expansion and differentiation of Melan-A-specific CD8 T-cells. Consistently, T-cell clones generated from those patients showed increased TCR binding avidity (i.e., slow off-rates and CD8 binding independency) readily after 4 monthly vaccine injections (4v). In contrast, the use of low peptide or high CpG-B doses required 8 monthly vaccine injections (8v) for the enrichment of anti-tumor T-cells with high TCR binding avidity and low CD8 binding dependency. Importantly, the CD8 binding-independent vaccine-induced CD8 T-cells displayed enhanced functional avidity, reaching a plateau of maximal function. Thus, T-cell functional potency following peptide/CpG/IFA vaccination may not be further improved beyond a certain TCR binding avidity limit. Our results also indicate that while high peptide dose vaccination induced the early selection of Melan-A-specific CD8 T-cells of increased functional competence, continued serial vaccinations also promoted such high-avidity T-cells. Overall, the systematic assessment of T-cell binding avidity may contribute to optimize vaccine design for improving clinical efficacy

MicroRNA-155 Expression Is Enhanced by T-cell Receptor Stimulation Strength and Correlates with Improved Tumor Control in Melanoma.

microRNAs are short noncoding RNAs that regulate protein expression posttranscriptionally. We previously showed that miR-155 promotes effector CD8 <sup>+</sup> T-cell responses. However, little is known about the regulation of miR-155 expression. Here, we report that antigen affinity and dose determine miR-155 expression in CD8 <sup>+</sup> T cells. In B16 tumors expressing a low-affinity antigen ligand, tumor-specific infiltrating CD8 <sup>+</sup> T cells showed variable miR-155 expression, whereby high miR-155 expression was associated with more cytokine-producing cells and tumor control. Moreover, anti-PD-1 treatment led to both increased miR-155 expression and tumor control by specific CD8 <sup>+</sup> T cells. In addition, miR-155 overexpression enhanced exhausted CD8 <sup>+</sup> T-cell persistence in the LCMV cl13 chronic viral infection model. In agreement with these observations in mouse models, miR-155 expression in human effector memory CD8 <sup>+</sup> T cells positively correlated with their frequencies in tumor-infiltrated lymph nodes of melanoma patients. Low miR-155 target gene signature in tumors was associated with prolonged overall survival in melanoma patients. Altogether, these results raise the possibility that high miR-155 expression in CD8 <sup>+</sup> tumor-infiltrating T cells may be a surrogate marker of the relative potency of in situ antigen-specific CD8 <sup>+</sup> T-cell responses

Autologous Dendritic Cells Prolong Allograft Survival Through Tmem176b-Dependent Antigen Cross-Presentation

International audienceThe administration of autologous (recipient-derived) tolerogenic dendritic cells (ATDCs) is under clinical evaluation. However, the molecular mechanisms by which these cells prolong graft survival in a donor-specific manner is unknown. Here, we tested mouse ATDCs for their therapeutic potential in a skin transplantation model. ATDC injection in combination with anti-CD3 treatment induced the accumulation of CD8+CD11c+ T cells and significantly prolonged allograft survival. TMEM176B is an intracellular protein expressed in ATDCs and initially identified in allograft tolerance. We show that Tmem176b[−/−] ATDCs completely failed to trigger both phenomena but recovered their effect when loaded with donor peptides before injection. These results strongly suggested that ATDCs require TMEM176B to cross-present antigens in a tolerogenic fashion. In agreement with this, Tmem176b[−/−] ATDCs specifically failed to cross-present male antigens or ovalbumin to CD8+ T cells. Finally, we observed that a Tmem176b-dependent cation current controls phagosomal pH, a critical parameter in cross-presentation. Thus, ATDCs require TMEM176B to cross-present donor antigens to induce donor-specific CD8+CD11c+ T cells with regulatory properties and prolong graft survival

A new dietary strategy for long-term treatment of the metabolic syndrome is compared with the American Heart Association (AHA) guidelines: the MEtabolic Syndrome REduction in NAvarra (RESMENA) project

The long-term effects of dietary strategies designed to combat the metabolic syndrome (MetS) remain unknown. The present study evaluated the effectiveness of a new dietary strategy based on macronutrient distribution, antioxidant capacity and meal frequency (MEtabolic Syndrome REduction in NAvarra (RESMENA) diet) for the treatment of the MetS when compared with the American Heart Association guidelines, used as Control. Subjects with the MetS (fifty-two men and forty-one women, age 49 (se 1) years, BMI 36·11 (se 0·5) kg/m) were randomly assigned to one of two dietary groups. After a 2-month nutritional-learning intervention period, during which a nutritional assessment was made for the participants every 15 d, a 4-month self-control period began. No significant differences were found between the groups concerning anthropometry, but only the RESMENA group exhibited a significant decrease in body weight ( - 1·7%; P= 0·018), BMI ( - 1·7%; P= 0·019), waist circumference ( - 1·8%; P= 0·021), waist:hip ratio ( - 1·4%; P= 0·035) and android fat mass ( - 6·9%; P= 0·008). The RESMENA group exhibited a significant decrease in alanine aminotransferase and aspartate aminotransferase (AST) concentrations ( - 26·8%; P= 0·008 and - 14·0%; P= 0·018, respectively), while the Control group exhibited a significant increase in glucose (7·9%; P= 0·011), AST (11·3%; P= 0·045) and uric acid (9·0%; P< 0·001) concentrations. LDL-cholesterol (LDL-C) concentrations were increased (Control group: 34·4%; P< 0·001 and RESMENA group: 33·8%; P< 0·001), but interestingly so were the LDL-C:apoB ratio (Control group: 28·7%; P< 0·001, RESMENA group: 17·1%; P= 0·009) and HDL-cholesterol concentrations (Control group: 21·1%; P< 0·001, RESMENA group: 8·7; P= 0·001). Fibre was the dietary component that most contributed to the improvement of anthropometry, while body-weight loss explained changes in some biochemical markers. In conclusion, the RESMENA diet is a good long-term dietary treatment for the MetS

A new dietary strategy for long-term treatment of the metabolic syndrome is compared with the American Heart Association (AHA) guidelines: the MEtabolic Syndrome REduction in NAvarra (RESMENA) project

The long-term effects of dietary strategies designed to combat the metabolic syndrome (MetS) remain unknown. The present study evaluated the effectiveness of a new dietary strategy based on macronutrient distribution, antioxidant capacity and meal frequency (MEtabolic Syndrome REduction in NAvarra (RESMENA) diet) for the treatment of the MetS when compared with the American Heart Association guidelines, used as Control. Subjects with the MetS (fifty-two men and forty-one women, age 49 (se 1) years, BMI 36·11 (se 0·5) kg/m) were randomly assigned to one of two dietary groups. After a 2-month nutritional-learning intervention period, during which a nutritional assessment was made for the participants every 15 d, a 4-month self-control period began. No significant differences were found between the groups concerning anthropometry, but only the RESMENA group exhibited a significant decrease in body weight ( - 1·7%; P= 0·018), BMI ( - 1·7%; P= 0·019), waist circumference ( - 1·8%; P= 0·021), waist:hip ratio ( - 1·4%; P= 0·035) and android fat mass ( - 6·9%; P= 0·008). The RESMENA group exhibited a significant decrease in alanine aminotransferase and aspartate aminotransferase (AST) concentrations ( - 26·8%; P= 0·008 and - 14·0%; P= 0·018, respectively), while the Control group exhibited a significant increase in glucose (7·9%; P= 0·011), AST (11·3%; P= 0·045) and uric acid (9·0%; P< 0·001) concentrations. LDL-cholesterol (LDL-C) concentrations were increased (Control group: 34·4%; P< 0·001 and RESMENA group: 33·8%; P< 0·001), but interestingly so were the LDL-C:apoB ratio (Control group: 28·7%; P< 0·001, RESMENA group: 17·1%; P= 0·009) and HDL-cholesterol concentrations (Control group: 21·1%; P< 0·001, RESMENA group: 8·7; P= 0·001). Fibre was the dietary component that most contributed to the improvement of anthropometry, while body-weight loss explained changes in some biochemical markers. In conclusion, the RESMENA diet is a good long-term dietary treatment for the MetS