Soluble TREM-1 plasma levels are associated with acute kidney injury, acute atrial fibrillation and prolonged ICU stay after cardiac surgery- a proof-concept study.

Background: Cardiopulmonary bypass (CPB) during cardiac surgery leads to deleterious systemic inflammation. We hypothesized that TREM-1, a myeloid receptor shed after activation, drives systemic inflammation during CPB. Methods: Prospective observational bi-centric study. Blood analysis (flow cytometry and ELISA) before and at H2 and H24 after CPB. Inclusion of adult patients who underwent elective cardiac surgery with CPB. Results: TREM-1 expression on neutrophils decreased between H0 and H2 while soluble (s)TREM-1 plasma levels increased. sTREM-1 levels increased at H2 and at H24 (p < 0.001). IL-6, IL-8, G-CSF and TNF-α, but not IL-1ß, significantly increased at H2 compared to H0 (p < 0.001), but dropped at H24. Principal component analysis showed a close relationship between sTREM-1 and IL-8. Three patterns of patients were identified: Profile 1 with high baseline sTREM-1 levels and high increase and profile 2/3 with low/moderate baseline sTREM-1 levels and no/moderate increase overtime. Profile 1 patients developed more severe organ failure after CPB, with higher norepinephrine dose, higher SOFA score and more frequently acute kidney injury at both H24 and H48. Acute atrial fibrillation was also more frequent in profile 1 patients at H24 (80% vs. 19.4%, p = 0.001). After adjustment on age and duration of CPB, H0, H2 and H24 sTREM-1 levels remained associated with prolonged ICU and hospital length of stay. Conclusions: Baseline sTREM-1 levels as well as early kinetics after cardiac surgery identified patients at high risk of post-operative complications and prolonged length of stay.

High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes.

The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T-cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development.

Cellular immune responses induced with dose-sparing intradermal administration of HIV vaccine to HIV-uninfected volunteers in the ANRS VAC16 trial.

OBJECTIVE: The objective was to compare the safety and cellular immunogenicity of intradermal versus intramuscular immunization with an HIV-lipopeptide candidate vaccine (LIPO-4) in healthy volunteers. METHODOLOGY: A randomized, open-label trial with 24 weeks of follow-up was conducted in France at six HIV-vaccine trial sites. Sixty-eight healthy 21- to 55-year-old HIV-uninfected subjects were randomized to receive the LIPO-4 vaccine (four HIV lipopeptides linked to a T-helper-stimulating epitope of tetanus-toxin protein) at weeks 0, 4 and 12, either intradermally (0.1 ml, 100 microg of each peptide) or intramuscularly (0.5 ml, 500 microg of each peptide). Comparative safety of both routes was evaluated. CD8+ T-cell immune responses to HIV epitopes (ELISpot interferon-gamma assay) and tetanus toxin-specific CD4+ T-cell responses (lymphoproliferation) were assessed at baseline, two weeks after each injection, and at week 24. RESULTS AND CONCLUSION: No severe, serious or life-threatening adverse events were observed. Local pain was significantly more frequent after intramuscular injection, but local inflammatory reactions were more frequent after intradermal immunization. At weeks 2, 6, 14 and 24, the respective cumulative percentages of induced CD8+ T-cell responses to at least one HIV peptide were 9, 33, 39 and 52 (intradermal group) or 14, 20, 26 and 37 (intramuscular group), and induced tetanus toxin-specific CD4+ T-cell responses were 6, 27, 33 and 39 (intradermal), or 9, 46, 54 and 63 (intramuscular). In conclusion, intradermal LIPO-4 immunization was well tolerated, required one-fifth of the intramuscular dose, and induced similar HIV-specific CD8+ T-cell responses. Moreover, the immunization route influenced which antigen-specific T-cells (CD4+ or CD8+) were induced. TRIAL REGISTRATION: ClinicalTrials.gov NCT00121121.

Establishment and characterization of continuous hematopoietic progenitors-derived pig normal mast cell lines.

Mast cells (MCs) are tissue resident, hematopoietic stem cells-derived elements, distributed throughout the body. They are the pivotal mediating cells of allergic reactions. In addition, in mice, MCs play a critical role in the defense against several pathogens, such as bacteria, parasites and viruses. Whereas the biology of rodent and human MCs has been extensively studied using in vitro derived populations, the role of MCs in pigs has not yet been evaluated, given the very low availability of pure porcine MCs populations. In the present report, we describe an original method to obtain continuous factor-dependent normal pig MCs (PMC) lines from fetal hematopoietic progenitors. These Stem Cell Factor (SCF) and Interleukin-3- (IL-3)-dependent PMC lines retain their capacity to growth after conventional freezing methods and exhibit most of the morphological and biochemical properties of normal, although immature, MCs, including metachromatic granules containing sulfated polysaccharides, the expression of c-kit and high-affinity IgE receptors (FcepsilonRI), and the ability to store histamine that is released upon cross-linking of FcepsilonRI. In vitro derived PMC lines might thus be valuable tools to further investigate the reactivity of these elements towards several parasites frequently encountered in pig, such as, but not limited to, Ascaris suum, Trichinella spiralis or Trichuris suis, or towards antigens derived from these pathogens.