Mechanisms of T cell mediated kidney disease

Immune mediated glomerulonephritis (GN) is a major cause renal inflammation leading to terminal kidney failure. B cells and autoantibodies are well known to contribute to the progression of glomerular disease. The role of CD8+ T cells, however, remains to be clarified, partially because of lack of suitable disease models. To investigate this question, a transgenic murine model system was created by expressing a membrane-bound model antigen (OVA-HEL) under the control of the nephrin promoter specifically on glomerular podocytes (NOH mice). These cells would then be targets of adoptively transferred OVA- or HEL-specific lymphocytes. NOH mice could therefore be used as a model for antigen specific attacks of the cellular or humoral immune response. This approach has been used successfully in the past to elucidate mechanisms in other autoimmune diseases, e.g. Diabetes Type I and Autoimmune Encephalomyelitis. CD8+ OVA-specific T cells were activated exclusively in the renal draining lymph node in a DC dependent fashion, indicating cross-presentation of glomerular antigen whereas CD4+ OVA-specific T cells remained inactive after adoptive transfer. In contrast to the Diabetes models, even high numbers of OVA-specific CD8+ T cells alone only inflicted minor glomerular damage. Co-injection of OVA-activated OVAspecific CD4+ T helper cells induced influx of antigen specific T cells and inflammatory mononuclear cells and resulted in renal immunopathology. The infiltrate was predominantly periglomerular, similar to the histological changes seen in rapid progressive forms of glomerulonephritis. The infiltrate was dominated by myeloid dendritic cells (DC) expressing CD11c, CD11b and the costimulatory markers CD40 and CD86, proinflammatory DC of the Gr-1hiCX3CR1lo phenotype and also contained antigen-specific CD8+ and CD4+ T cells. DC activation and CD8+ T cell effector function strongly depended on the availability of CD4+ T cell help. Persisting infiltration led to podocyte dysfunction and glomerulosclerosis. CD8+ T cell priming in the kidney lymph node as well as inflammation within the kidney required the presence of DCs, as demonstrated by ablation of CD11c+ cells in NOH x CD11c-diphteria toxin receptor mice, which allow deletion of DCs upon injection of diphtheria toxin. Within infiltrates, proinflammatory cytokines and the chemokines CCL2, 3, 4 and 5 as well as their correlating receptors were detected on infiltrating leukocytes. These findings demonstrate that T cells specific for glomerular antigens can induce kidney immunopathology and structural damage reminiscent of rapid and crescentic types of glomerulonephritis

Role of IL-17 and Th17 Cells in Liver Diseases

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4+ T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease

Deciphering the Immune Microenvironment on A Single Archival Formalin-Fixed Paraffin-Embedded Tissue Section by An Immediately Implementable Multiplex Fluorescence Immunostaining Protocol

Technological breakthroughs have fundamentally changed our understanding on the complexity of the tumor microenvironment at the single-cell level. Characterizing the immune cell composition in relation to spatial distribution and histological changes may provide important diagnostic and therapeutic information. Immunostaining on formalin-fixed paraffin-embedded (FFPE) tissue samples represents a widespread and simple procedure, allowing the visualization of cellular distribution and processes, on preserved tissue structure. Recent advances in microscopy and molecular biology have made multiplexing accessible, yet technically challenging. We herein describe a novel, simple and cost-effective method for a reproducible and highly flexible multiplex immunostaining on archived FFPE tissue samples, which we optimized for solid organs (e.g., liver, intestine, lung, kidney) from mice and humans. Our protocol requires limited specific equipment and reagents, making multiplexing (>12 antibodies) immediately implementable to any histology laboratory routinely performing immunostaining. Using this method on single sections and combining it with automated whole-slide image analysis, we characterize the hepatic immune microenvironment in preclinical mouse models of liver fibrosis, steatohepatitis and hepatocellular carcinoma (HCC) and on human-patient samples with chronic liver diseases. The data provide useful insights into tissue organization and immune-parenchymal cell-to-cell interactions. It also highlights the profound macrophage heterogeneity in liver across premalignant conditions and HCC

Role of IL-17 and Th17 Cells in Liver Diseases

Unbalanced Th1/Th2 T-cell responses in the liver are a characteristic of hepatic inflammation and subsequent liver fibrosis. The recently discovered Th17 cells, a subtype of CD4 + T-helper cells mainly producing IL-17 and IL-22, have initially been linked to host defense against infections and to autoimmunity. Their preferred differentiation upon TGFβ and IL-6, two cytokines abundantly present in injured liver, makes a contribution of Th17 cells to hepatic inflammation very likely. Indeed, initial studies in humans revealed activated Th17 cells and Th17-related cytokines in various liver diseases. However, functional experiments in mouse models are not fully conclusive at present, and the pathogenic contribution of Th17 cells to liver inflammation might vary upon the disease etiology, for example, between infectious and autoimmune disorders. Understanding the chemokines and chemokine receptors promoting hepatic Th17 cell recruitment (possibly CCR6 or CCR4) might reveal new therapeutic targets interfering with Th17 migration or differentiation in liver disease

Разработка системы контроля параметров газоподачи в процессе добычи нефтепродуктов

Данная работа посвящена разработке системы контроля параметров газоподачи при добыче нефтепродуктов. Основным контролируемым параметром при реализации процесса нефтедобычи является значение гидростатического давления в системе газоподачи. Цель исследования: разработка системы контроля параметров газоподачи при добыче нефтепродуктов. Изучен процесс добычи нефтепродуктов газлифтовым способом. Проведены эксперименты по определению зависимости контролируемых параметров газоподачи при добыче нефтепродуктов. Объектом исследования является система управления процессом нефтедобычи. Область применения: нефтегазодобывающие месторождения с высоким газовым фактором.This research project is devoted to the development of a control system for gas delivery parameters for the extraction of petroleum products. The main controlled parameter in the implementation of the oil production process is the value of the hydrostatic pressure in the gas supply system. The purpose of the study was to develop a system for monitoring gas delivery parameters for the extraction of petroleum products. The process of oil products extraction by gas-lift method has been studied. Experiments have been carried out to determine the dependence of the controlled parameters of gas delivery in the extraction of petroleum products. The object of the study is the oil production management system. Scope: oil and gas fields with a high gas factor

Relaxation processes of point defects in vitreous silica from femtosecond to nanoseconds

We studied ultrafast relaxation of localized excited states at Ge-related oxygen deficient centers in silica using femtosecond transient-absorption spectroscopy. The relaxation dynamics exhibits a biexponential decay, which we ascribe to the departure from the Frank-Condon region of the first excited singlet state in 240 fs, followed by cooling in ∼10 ps. At later times, a nonexponential relaxation spanning up to 40 ns occurs, which is fitted with an inhomogeneous distribution of nonradiative relaxation rates, following a chi-square distribution with one degree of freedom. This reveals several analogies with phenomena such as neutron reactions, quantum dot blinking, or intramolecular vibrational redistribution. © 2008 American Institute of Physics.Peer Reviewe

Pleural effusions are associated with adverse outcomes after cardiac surgery: a propensity-matched analysis

Background: Pleural effusions commonly occur in patients recovering from cardiac surgery; however, the impact on outcomes is not well characterized. The purpose of this study is to characterize the clinical outcomes of cardiac surgery patients with pleural effusion. Methods: All patients undergoing cardiac surgery between 2006 and 2019 at a tertiary care university hospital were included in this observational, cross-sectional analysis using propensity matching. Results: Of 11,037 patients that underwent cardiac surgery during the study period, 6461 (58.5%) had no pleural effusion (Group 0), 3322 (30.1%) had pleural effusion only (Group 1), and 1254 (11.4%) required at least one secondary drainage procedure after the index operation (Group 2). After propensity matching, the mortality of patients who underwent secondary drainage procedures was 6.1% higher than in Group 1 (p < 0.001). Intensive care unit (ICU) stay was longer for those with pleural effusions (18 [IQR 9-32] days in Group 2, 10 [IQR 6-17] days for Group 1, and 7 [IQR 4-11] days for Group 0, p < 0.001). Patients with pleural effusions had a higher incidence of hemodialysis (246 [20.0%] in Group 2, 137 [11.1%] in Group 1, 98 [7.98%] in Group 0), and a longer ventilation time in the ICU (57 [IQR 21.0-224.0] hours in Group 2, 25.0 [IQR 14.0-58.0] hours in Group 1, 16.0 [IQR 10.0-29.0] hours in Group 0). Conclusion: Pleural effusions, especially those that require a secondary drainage procedure during recovery, are associated with significantly worse outcomes including increased mortality, longer length of stay, and higher complication rates. These insights may be of great interest to scientists, clinicians, and industry leaders alike to foster research into innovative methods for preventing and treating pleural effusions with the aim of improving outcomes for patients recovering from cardiac surgery