A continuous infusion of a minor histocompatibility antigen-immunodominant peptide induces a delay of male skin graft rejection.

We previously reported that an inhibition of antigen-specific Interferon-gamma release and cytotoxicity occurs after a continuous infusion of an HY immunodominant peptide although this treatment is not able to cause a significant delay of male skin grafts rejection. In vivo administration of high doses of an HY peptide, through mini-osmotic pumps, in naïve female mice was used to study the effects on the male skin grafts rejection. A continuous infusion of 1mg of an HY peptide induces a significant delay of male skin graft rejection. In vitro HY-specific Interferon-gamma release was inhibited adding peptide-specific suppressor cells: the ability to inhibit Interferon-gamma release was evident when two HY peptides were present on the same dendritic cells indicating that the suppressor cells exert "linked-suppression". The phenotype of the suppressor cells is CD8(+)CD28(-) and these cells express more CD62 ligand and FOXP3 than controls. Suppressor cells were able to cause a significant delay of rejection of male skin grafts when injected in naive female mice. The inhibitory effects of these suppressor cells seem to be due to the impairment of antigen presentation; down-regulation of B7 molecules on dendritic cells occurred. Taken all together, our data demonstrate that a continuous infusion of an immunodominant HY peptide induces a T CD8 suppressor subset able to inhibit immune responses to male tissues and cells

Identification of plasma biomarkers for discrimination between tuberculosis infection/disease and pulmonary non tuberculosis disease

We used the Luminex Bead Array Multiplex Immunoassay to measure cytokines, chemokines and growth factors responses to the same antigens used for RD1-based Interferon \ue3 Release Assay (IGRA) test. Seventy-nine individuals, 27 active TB, 32 latent infection subsets, 20 individuals derivative purified protein (PPD) negative (subjects that do not have any indurative cutaneous reaction after 72 hrs of intradermal injection of PPD) and with other pulmonary disease were retrospectively studied. Forty-eight analytes were evaluated by Luminex Assay in plasma obtained from whole blood stimulated cells. The diagnostic accuracies of the markers detected were evaluated by ROC curve analysis and by the combination of multiple biomarkers to improve the potential to discriminate between infection/disease and non infection. Among 48 cytokines, 13 analytes, namely IL-3, IL-12-p40, LIF, IFN\u3b12, IL-2ra, IL-13, b-NGF, SCF, TNF-\u3b2, TRAIL, IL-2, IFN-\u3b3, IP-10, and MIG, were significantly higher in the active TB and LTBI groups, compared to NON-TB patients, while MIF was significantly lower in active TB patients compared to NON-TB and LTBI groups. The diagnostic accuracies of the markers detected in the culture supernatants evaluated by ROC curve analysis revealed that 11 analytes (IL2, IP10, IFN-\u3b3, IL13, MIG, SCF, b-NGF, IL12-p40, TRAIL, IL2 Ra, LIF) discriminated between NON-TB and LTBI groups, with AUC for all analytes 650.73, while 14 analytes (IL2, IP10, IFN-\u3b3, MIG, SCF, b-NGF, IL12-p40, TRAIL, IL2Ra, MIF, TNF-\u3b2, IL3, IFN-\u3b12, LIF) discriminated between NON-TB and active TB groups, with AUC 650.78, that is a moderate, value in terms of accuracy of a diagnostic test. Finally, the combinations of seven biomarkers resulted in the accurate prediction of 88.89% of active TB patients, 82.35% of subjects with latent infection and 90% of non-TB patients, respectively. Taken together, our data suggest that combinations of whole blood Mycobacterium tuberculosis (Mtb) antigen dependent cytokines production could be useful as biomarkers to determine tuberculosis disease states when compared to non TB cohort

Sustainable yield of the Colle Quartara carbonate aquifer in the Southern Lepini Mountains (Central Italy)

The present research is aimed to contribute to the groundwater resource sustainable management of a carbonate aquifer in a test area of the Lepini Mountains (Central Italy). This aquifer constitutes a major exploited groundwater body of central Apennines. At regional scale, the hydrogeological features of the Lepini hydrostructure are well known. The present study focuses on a portion of the Lepini Mountains where important tapping-works for drinking water supply are in activity (about 1.2 m3/s). New investigations were carried out including: meteo-climatic analysis, spring discharge and hydrometric time series processing, pumping test result interpretation. In addition, a detailed lithostratigraphical and structural survey of a portion of the Lepini hydrostructure at 1:10,000 scale was performed also examining the dense network of discontinuities affecting the carbonate aquifer. Extensional Plio-Pleistocene tectonic activity displaced the carbonate rock sequence under the Pontina Plain, where the carbonate aquifer is confined. The investigation results have allowed the reconstruction of the hydrogeological conceptual model of the studied portion of carbonate massif. Given the scale of the study and the results of the investigation, the carbonate aquifer can be treated as an equivalent porous medium, and the simplified numerical model of the aquifer was constructed with the code MODFLOW-2005. The numerical model, still now under continuous implementation, produced first results on the current withdrawal sustainability, allowing evaluation of possible alternative exploitation scenarios of the carbonate aquifer also considering the probably not significant flow exchanges with the Pontina Plain aquifer

Pivotal advance: alpha-galactosylceramide induces protection against lipopolysaccharide-induced shock.

alpha-galactosylceramide, a natural killer T cell ligand, and its synthetic homolog, KRN7000, consistently influence IFN-gamma and TNF-alpha release, both mediators of LPS-induced shock. To modify the course of endotoxin shock, we injected KRN7000 at different time points of experimental systemic Shwartzman reaction. Mice treated with KRN7000 survived when it was injected within 2 h before and after LPS challenge. Mice survival was associated with low levels of T helper 1 (Th1) cytokines, such as IFN-gamma and TNF-alpha. By contrast, protection from endotoxin shock was associated with an increase of T helper 2 (Th2) cytokines, like IL-4 and IL-10. A role of Th2 cytokines in counteracting LPS-induced shock was supported by experiments in which the protection against Shwartzman reaction by KRN7000 was abrogated by in vivo coadministration of anti-Th2 cytokines antibodies. In addition, cytofluorimetric analysis showed that surviving animals have higher percentages of NKT-IL-10-positive cells and lower percentages of NKT-IFN-gamma and macrophages/TNF-alpha-stained cells than nonprotected mice. Taken together, our data demonstrate that KRN7000 treatment given at times near LPS challenge is protective for endotoxin shock inhibiting IFN-gamma and TNF-alpha release. Moreover, KRN7000-mediated protection occurs through an increased production of IL-4 and IL-10, which are mainly secreted by NKT cells. Since IFN-gamma release by NKT requires a longer TCR stimulation than that required for Th2 cytokines production, we demonstrate that timing of KRN7000 in vivo exposure affect the pattern of cytokines expression protecting animals by endotoxin shoc

Surface faulting hazard in italy: Towards a first assessment based on the ithaca database

The Italian territory is characterized by a great number of capable faults (i.e., faults able to produce significant ruptures/deformations at or near the surface). However, the potential of tectonic surface rupture/deformation (Surface Faulting Hazard, SFH) is not properly considered in national seismic hazard maps and legislation. In this paper it is proposed an assessment of SFH in Italy based on the ITHACA database, where the shape and width along capable faults as well as maximum expected surface displacements are defined in function of the seismotectonic behaviour and the severity of maximum expected earthquake. The proposed assessment indicates where SFH is expected to be relevant. In this sense, it is an helpful tool for site selection of critical facilities but also for ordinary land planning. Of course, the evaluation of SFH at local scale in the setback areas requires a more detailed characterization through ad hoc seismotectonic and paleoseismic investigations

HLA-E-Restricted CD8+ T Lymphocytes Efficiently Control Mycobacterium tuberculosis and HIV-1 Co-Infection

RATIONALE: We have investigated the contribution of HLA-A2 and HLA-E-restricted CD8+ T cells in patients with Mycobacterium tuberculosis and HIV-1 co-infection. OBJECTIVE: HIV-1 downregulates HLA-A, -B and -C molecules in infected cells thus influencing recognition by HLA class I-restricted CD8+ T cells but not by HLA-E restricted CD8+ T cells due to the inability of the virus to downmodulate their expression. Therefore antigen-specific HLA-E-restricted CD8+ T cells could play a protective response in Mycobacterium tuberculosis and HIV-1 co-infection. METHODS: HLA-E- and HLA-A2-restricted Mycobacterium tuberculosis-specific CD8+ T cells were tested in vitro for cytotoxic and microbicidal activities and their frequencies and phenotypes evaluated ex vivo in patients with active tuberculosis and concomitant HIV-1 infection. MEASUREMENTS AND MAIN RESULTS: HIV-1 and Mycobacterium tuberculosis co-infection caused downmodulation of HLA-A2 expression in human monocyte-derived, macrophages associated with resistance to lysis by HLA-A2-restricted CD8+ T cells and failure to restrict the growth of intracellular Mycobacterium tuberculosis. Conversely, HLA-E surface expression and HLA-E-restricted cytolytic and microbicidal CD8 responses were not affected. HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells were expanded in the circulation of patients with Mycobacterium tuberculosis/HIV-1 co-infection, as measured by tetramer staining, but displayed a terminally-differentiated and exhausted phenotype which was rescued in vitro by anti-programmed death-1 monoclonal antibody. CONCLUSIONS: HLA-E-restricted and Mycobacterium tuberculosis-specific CD8+ T cells in patients with Mycobacterium tuberculosis/HIV-1 co-infection have an exhausted phenotype and fail to expand in vitro in response to antigen stimulation, which can be restored by blocking programmed death-1 pathway using the specific monoclonal antibody Nivolumab