Survivin as potential mediator to support autoreactive cell survival in myasthenia gravis: A human and animal model study

The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders

Class I Histone Deacetylase Inhibitor Entinostat Suppresses Regulatory T Cells and Enhances Immunotherapies in Renal and Prostate Cancer Models

Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been reported to have antitumor activity in different malignancies and immunomodulatory effects. Herein, we report the Tregs-targeting and immune-promoting effect of a class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell carcinoma (RENCA) model or a survivinbased vaccine therapy (SurVaxM) in a castration resistant prostate cancer (CR Myc-CaP) model. Methods and Results: RENCA or CR Myc-CaP tumors were implanted orthotopically or subcutaneously, respectively. Inoculated mice were randomized into four treatment groups: vehicle, entinostat, cytokine or vaccine, and combination. Tregs in the blood were assessed by FACS analysis. Real time quantitative PCR and Western blot analysis of isolated T cell subpopulations from spleen were performed to determine Foxp3 gene and protein expression. The suppressive function of Tregs was tested by T cell proliferation assay. Low dose (5 mg/kg) entinostat reduced Foxp3 levels in Tregs and this was associated with enhanced tumor growth inhibition in combination with either IL-2 or a SurVaxM vaccine. Entinostat downregulated Foxp3 expression transcriptionally and blocked Tregs suppressive function without affecting T effector cells (Teffs). In vitro low dose entinostat (0.5 mM) induced STAT3 acetylation and a specific inhibitor of STAT3 partially rescued entinostat-induced down-regulation of Foxp3, suggesting that STAT3 signaling is involved in Foxp3 down-regulation b

Biotic Processes Regulating the Carbon Balance of Desert Ecosystems - Final Report

Our results from the 10-year elevated atmospheric CO{sub 2} concentration study at the Nevada Desert FACE (Free-air CO{sub 2} Enrichment) Facility (NDFF) indicate that the Mojave Desert is a dynamic ecosystem with the capacity to respond quickly to environmental changes. The Mojave Desert ecosystem is accumulating carbon (C), and over the 10-year experiment, C accumulation was significantly greater under elevated [CO{sub 2}] than under ambient, despite great fluctuations in C inputs from year to year and even apparent reversals in which [CO{sub 2}] treatment had greater C accumulations

The presence of survivin on B cells from myasthenia gravis patients and the potential of an antibody to a modified survivin peptide to alleviate weakness in an animal model

Myasthenia gravis (MG) is an autoimmune disease in which Abs target neuromuscular junction proteins, in particular the acetylcholine receptor. We previously identified the antiapoptotic protein survivin in the autoreactive B cells and plasma cells of MG patients. To further define the role of survivin in MG, we have assessed PBMCs from 29 patients with MG and 15 controls. We confirmed the increased expression of survivin in CD20+ lymphocytes from MG patients compared with controls. Furthermore, the CD20+ population of cells from MG patients contained a higher percentage of extracellular survivin compared with controls. The analysis of CD4+ cells showed an increased percentage of intracellular survivin in MG patients compared with controls, whereas the extracellular survivin CD4+ percentage was unaffected. In an experimental mouse model of MG, we assessed the therapeutic potential of an Ab raised to a modified survivin peptide but cross-reactive to survivin. Ab treatment reduced disease severity, lowered acetylcholine receptor-specific Abs, and decreased CD19+ survivin+ splenocytes. The ability to target survivin through Ab recognition of autoreactive cells offers the potential for a highly specific therapeutic agent for MG

Final Technical Report: Effects of Changing Water and Nitrogen Inputs on a Mojave Desert Ecosystem

In order to anticipate the effects of global change on ecosystem function, it is essential that predictive relationships be established linking ecosystem function to global change scenarios. The Mojave Desert is of considerable interest with respect to global change. It contains the driest habitats in North America, and thus most closely approximates the world’s great arid deserts. In order to examine the effects of climate and land use changes, in 2001 we established a long-term manipulative global change experiment, called the Mojave Global Change Facility. Manipulations in this study include the potential effects of (1) increased summer rainfall (75 mm over three discrete 25 mm events), (2) increased nitrogen deposition (10 and 40 kg ha-1), and (3) the disturbance of biological N-fixing crusts . Questions addressed under this grant shared the common hypothesis that plant and ecosystem performance will positively respond to the augmentation of the most limiting resources to plant growth in the Mojave Desert, e.g., water and nitrogen. Specific hypotheses include (1) increased summer rainfall will significantly increase plant production through an alleviation of moisture stress in the dry summer months, (2) N-deposition will increase plant production in this N-limited system, particularly in wet years or in concert with added summer rain, and (3) biological crust disturbance will gradually decrease bio-available N, with concomitant long-term reductions in photosynthesis and ANPP. Individual plant and ecosystem responses to global change may be regulated by biogeochemical processes and natural weather variability, and changes in plant and ecosystem processes may occur rapidly, may occur only after a time lag, or may not occur at all. During the first PER grant period, we observed changes in plant and ecosystem processes that would fall under each of these time-response intervals: plant and ecosystem processes responded rapidly to added summer rain, whereas most processes responded slowly or in a lag fashion to N-deposition and with no significant response to crust disturbance. Therefore, the primary objectives of this renewal grant were to: (1) continue ongoing measurements of soil and plant parameters that assess primary treatment responses; (2) address the potential heterogeneity of soil properties and (3) initiate a new suite of measurements that will provide data necessary for scaling/modeling of whole-plot to ecosystem-level responses. Our experimental approach included soil plant-water interactions using TDR, neutron probe, and miniaturized soil matric potential and moisture sensors, plant ecophysiological and productivity responses to water and nitrogen treatments and remote sensing methodologies deployed on a radio control platform. We report here the most significant findings of our study

Survivin as a Potential Mediator to Support Autoreactive Cell Survival in Myasthenia Gravis: A Human and Animal Model Study

<div><p>The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.</p></div