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Biomaterial-Driven Immunomodulation: Cell Biology-Based Strategies to Mitigate Severe Inflammation and Sepsis.

ABSTRACT: 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.

SUBMITTER: Lasola JJM

PROVIDER: S-EPMC7418829 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Biomaterial-Driven Immunomodulation: Cell Biology-Based Strategies to Mitigate Severe Inflammation and Sepsis.

Lasola Jackline Joy Martín JJM Kamdem Henry H McDaniel Michael W MW Pearson Ryan M RM

Frontiers in immunology 20200804

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 ...[more]

PMID: 32849612

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Project description:OBJECTIVES:We tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis. DESIGN:Prospective cohort study. SETTING:Tertiary PICU. PATIENTS:Children with 100 separate admission episodes of severe sepsis were enrolled. INTERVENTIONS:Blood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2?×?2 contingency table using C-reactive protein and ferritin thresholds was developed. MEASUREMENTS AND MAIN RESULTS:A C-reactive protein of 4.08?mg/dL and a ferritin of 1,980?ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08?mg/dL and ferritin greater than or equal to 1,980?ng/mL category (6/13 [46.15%]) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08?mg/dL and ferritin less than 1,980?ng/mL or C-reactive protein less than 4.08?mg/dL and ferritin greater than or equal to 1,980?ng/mL categories (2/43 [4.65%]), and the "low-risk" C-reactive protein less than 4.08?mg/dL and ferritin less than 1,980?ng/mL category (0/44 [0%]) (odds ratio, 36.43 [95% CI, 6.16-215.21]). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 [95% CI, 1.34-14.96]) and macrophage activation syndrome (odds ratio, 24.20 [95% CI, 5.50-106.54]). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 [35%]; p < 0.05). CONCLUSIONS:A C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08?mg/dL and ferritin of 1,980?ng/mL appeared to be a desired response in children with severe sepsis.

Project description:BackgroundThe adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C.MethodsIn an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-).ResultsStimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p < 0.05). Leptin levels of supernatants of adipocyte culture decreased by 25% and 23% (p < 0.05) after incubation with TNF alpha after 6 and 24 hours. Incubation with DAA at 50 ng/ml DAA and 5 μg/ml doubled mRNA expression significantly at 24 hours (p < 0.05) but not at 6 hours. From day 1 to day 3 of sepsis, leptin levels increased in DAA+ compared to DAA- patients (p<0.10).ConclusionsLeptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.

Project description: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.

Dataset Information

Biomaterial-Driven Immunomodulation: Cell Biology-Based Strategies to Mitigate Severe Inflammation and Sepsis.

Publications

Biomaterial-Driven Immunomodulation: Cell Biology-Based Strategies to Mitigate Severe Inflammation and Sepsis.

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