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Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

ABSTRACT: INTRODUCTION: Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis. METHODS: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (? 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6-8 weeks) and aged (20-22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured. RESULTS: The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased detection of gram-negative bacteria at days 14-16 and 28-32 after sepsis (P < 0.05). CONCLUSIONS: Persistent inflammation and T cell exhaustion may be associated with decreased survival in elderly patients and mice after sepsis.

SUBMITTER: Inoue S

PROVIDER: S-EPMC4230031 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

Inoue Shigeaki S Suzuki Kodai K Komori Yukako Y Morishita Yukiko Y Suzuki-Utsunomiya Kyoko K Hozumi Katsuto K Inokuchi Sadaki S Sato Takehito T

Critical care (London, England) 20140624 3

<h4>Introduction</h4>Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis.<h4>Methods</h4>Fifty-five patients with severe sepsis and 30 healthy donors were prospectively e ...[more]

PMID: 24962182

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Project description:Inflammation is an essential component of a wide variety of disease processes and oftentimes can increase the deleterious effects of a disease. Finding ways to modulate this essential immune process is the basis for many therapeutics under development and is a burgeoning area of research for both basic and translational immunology. In addition to developing therapeutics for cellular and molecular targets, the use of biomaterials to modify innate and adaptive immune responses is an area that has recently sparked significant interest. In particular, immunomodulatory activity can be engineered into biomaterials to elicit heightened or dampened immune responses for use in vaccines, immune tolerance, or anti-inflammatory applications. Importantly, the inherent physicochemical properties of the biomaterials play a significant role in determining the observed effects. Properties including composition, molecular weight, size, surface charge, and others affect interactions with immune cells (i.e., nano-bio interactions) and allow for differential biological responses such as activation or inhibition of inflammatory signaling pathways, surface molecule expression, and antigen presentation to be encoded. Numerous opportunities to open new avenues of research to understand the ways in which immune cells interact with and integrate information from their environment may provide critical solutions needed to treat a variety of disorders and diseases where immune dysregulation is a key inciting event. However, to elicit predictable immune responses there is a great need for a thorough understanding of how the biomaterial properties can be tuned to harness a designed immunological outcome. This review aims to systematically describe the biological effects of nanoparticle properties-separate from additional small molecule or biologic delivery-on modulating innate immune cell responses in the context of severe inflammation and sepsis. We propose that nanoparticles represent a potential polypharmacological strategy to simultaneously modify multiple aspects of dysregulated immune responses where single target therapies have fallen short for these applications. This review intends to serve as a resource for immunology labs and other associated fields that would like to apply the growing field of rationally designed biomaterials into their work.

Project description:We recently proffered that a new syndrome persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has replaced late multiple-organ failure as a predominant phenotype of chronic critical illness. Our goal was to validate this by determining whether severely injured trauma patients with complicated outcomes have evidence of PICS at the genomic level.We performed a secondary analysis of the Inflammation and Host Response to Injury database of adults with severe blunt trauma. Patients were classified into complicated, intermediate, and uncomplicated clinical trajectories. Existing genomic microarray data were compared between cohorts using Ingenuity Pathways Analysis. Epidemiologic data and outcomes were also analyzed between cohorts on admission, Day 7, and Day 14.Complicated patients were older, were sicker, and required increased ventilator days compared with the intermediate/uncomplicated patients. They also had persistent leukocytosis as well as low lymphocyte and albumin levels compared with uncomplicated patients. Total white blood cell leukocyte analysis in complicated patients showed that overall genome-wide expression patterns and those patterns on Days 7 and 14 were more aberrant from control subjects than were patterns from uncomplicated patients. Complicated patients also had significant down-regulation of adaptive immunity and up-regulation of inflammatory genes on Days 7 and 14 (vs. magnitude in fold change compared with control and in magnitude compared with uncomplicated patients). On Day 7, complicated patients had significant changes in functional pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients and controls. Subset analysis of monocyte, neutrophil, and T-cells supported these findings.Genomic analysis of patients with complicated clinical outcomes exhibit persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion. Overall, the data support the hypothesis that patients with complicated clinical outcomes are exhibiting PICS.Epidemiologic study, level III.

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Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

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Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

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