Impaired CD4 + T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis

Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4 + T-cell responses remains unclear. In the present study, CD4 + T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro . CD4 + CD62L + T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4 + CD62L + T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the T H 1 or T H 2 lineage. Repressive histone methylation marks were also evident at promoter regions for the T H 1 cytokine IFN-Γ and the T H 2 transcription factor GATA-3 in naÏve CD4 + T cells from CLP mice. These results provide evidence that CD4 + T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71365/1/998_ftp.pd

Oral Bromelain Attenuates Inflammation in an Ovalbumin-induced Murine Model of Asthma

Bromelain, a widely used pineapple extract with cysteine protease activity, has been shown to have immunomodulatory effects in a variety of immune system models. The purpose of the present study was to determine the effects of orally administered bromelain in an ovalbumin (OVA)-induced murine model of acute allergic airway disease (AAD). To establish AAD, female C57BL/6J mice were sensitized with intraperitoneal (i.p.) OVA/alum and then challenged with OVA aerosols for 3 days. Mice were gavaged with either (phosphate buffered saline)PBS or 200 mg/kg bromelain in PBS, twice daily for four consecutive days, beginning 1 day prior to OVA aerosol challenge. Airway reactivity and methacholine sensitivity, bronchoalveolar lavage (BAL) cellular differential, Th2 cytokines IL-5 and IL-13, and lung histology were compared between treatment groups. Oral bromelain-treatment of AAD mice demonstrated therapeutic efficacy as evidenced by decreased methacholine sensitivity (P ≤ 0.01), reduction in BAL eosinophils (P ≤ 0.02) and IL-13 concentrations (P ≤ 0.04) as compared with PBS controls. In addition, oral bromelain significantly reduced BAL CD19+ B cells (P ≤ 0.0001) and CD8+ T cells (P ≤ 0.0001) in AAD mice when compared with controls. These results suggest that oral treatment with bromelain had a beneficial therapeutic effect in this murine model of asthma and bromelain may also be effective in human conditions

JCL Implementation on a Human Spaceflight Program

No abstract availabl

Epigenetic regulation of IL‐12‐dependent T cell proliferation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141412/1/jlb0601-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141412/2/jlb0601.pd

Efficacy of a trivalent influenza vaccine against seasonal strains and against 2009 pandemic H1N1: a randomized, placebo-controlled trial

Background: Before pandemic H1N1 vaccines were available, the potential benefit of existing seasonal trivalent inactivated influenza vaccines (IIV3s) against influenza due to the 2009 pandemic H1N1 influenza strain was investigated, with conflicting results. This study assessed the efficacy of seasonal IIV3s against influenza due to 2008 and 2009 seasonal influenza strains and against the 2009 pandemic H1N1 strain. Methods: This observer-blind, randomized, placebo-controlled study enrolled adults aged 18–64 years during 2008 and 2009 in Australia and New Zealand. Participants were randomized 2:1 to receive IIV3 or placebo. The primary objective was to demonstrate the efficacy of IIV3 against laboratory-confirmed influenza. Participants reporting an influenza-like illness during the period from 14 days after vaccination until 30 November of each study year were tested for influenza by real-time reverse transcription polymerase chain reaction. Results: Over a study period of 2 years, 15,044 participants were enrolled (mean age ± standard deviation: 35.5 ± 14.7 years; 54.4% female). Vaccine efficacy of the 2008 and 2009 IIV3s against influenza due to any strain was 42% (95% confidence interval [CI]: 30%, 52%), whereas vaccine efficacy against influenza due to the vaccine-matched strains was 60% (95% CI: 44%, 72%). Vaccine efficacy of the 2009 IIV3 against influenza due to the 2009 pandemic H1N1 strain was 38% (95% CI: 19%, 53%). No vaccine-related deaths or serious adverse events were reported. Solicited local and systemic adverse events were more frequent in IIV3 recipients than placebo recipients (local: IIV3 74.6% vs placebo 20.4%, p < 0.001; systemic: IIV3 46.6% vs placebo 39.1%, p < 0.001). Conclusions: The 2008 and 2009 IIV3s were efficacious against influenza due to seasonal influenza strains and the 2009 IIV3 demonstrated moderate efficacy against influenza due to the 2009 pandemic H1N1 strain

GN and C Subsystem Concept for Safe Precision Landing of the Proposed Lunar MARE Robotic Science Mission

The Lunar MARE (Moon Age and Regolith Explorer) Discovery Mission concept targets delivery of a science payload to the lunar surface for sample collection and dating. The mission science is within a 100-meter radius region of smooth lunar maria terrain near Aristarchus crater. The location has several small, sharp craters and rocks that present landing hazards to the spacecraft. For successful delivery of the science payload to the surface, the vehicle Guidance, Navigation and Control (GN&C) subsystem requires safe and precise landing capability, so design infuses the NASA Autonomous precision Landing and Hazard Avoidance Technology (ALHAT) and a gimbaled, throttleable LOX/LCH4 main engine. The ALHAT system implemented for Lunar MARE is a specialization of prototype technologies in work within NASA for the past two decades, including a passive optical Terrain Relative Navigation (TRN) sensor, a Navigation Doppler Lidar (NDL) velocity and range sensor, and a Lidar-based Hazard Detection (HD) sensor. The landing descent profile is from a retrograde orbit over lighted terrain with landing near lunar dawn. The GN&C subsystem with ALHAT capabilities will deliver the science payload to the lunar surface within a 20-meter landing ellipse of the target location and at a site having greater than 99% safety probability, which minimizes risk to safe landing and delivery of the MARE science payload to the intended terrain region

Dysregulated Cytokine Expression by CD4+ T cells from Post-Septic Mice Modulates both Th1 and Th2-Mediated Granulomatous Lung Inflammation

Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative) and TH2-(Schistosoma mansoni egg antigen) driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of TH2 cytokines in TH1 inflammation, and increased production of TH1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression