The changing immune system in sepsis: Is individualized immuno-modulatory therapy the answer?

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• Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during early-stage sepsis in ICU patients.

  2013cited by this paper
• Genomic responses in mouse models poorly mimic human inflammatory diseases

  2013cited by this paper
• Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

  2013cited by this paper
• Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach.

  2013cited by this paper
• Recombinant human activated protein C as a therapy for severe sepsis: lessons learned?

  2013cited by this paper
• Surviving sepsis campaign : international guidelines for management of severe sepsis and septic shock

  2013cited by this paper
• A rapidly progressing lymphocyte exhaustion after severe sepsis

  2012cited by this paper
• A historical perspective on sepsis.

  2012cited by this paper
• The immune response to severe bacterial infections: consequences for therapy

  2012influential reference
• IL-7 in human health and disease.

  2012cited by this paper
• BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction

  2012cited by this paper
• Regulatory T cells: mechanisms of differentiation and function.

  2012cited by this paper
• Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival

  2012cited by this paper
• Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

  2012cited by this paper
• Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

  2012cited by this paper
• A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis

  2012influential reference
• Interleukin-15 biology and its therapeutic implications in cancer.

  2012cited by this paper
• IL-7 Restores Lymphocyte Functions in Septic Patients

  2012cited by this paper
• Effects of Recombinant Human Interleukin 7 on T-Cell Recovery and Thymic Output in HIV-Infected Patients Receiving Antiretroviral Therapy: Results of a Phase I/IIa Randomized, Placebo-Controlled, Multicenter Study

  2012cited by this paper
• Sepsis studies need new direction.

  2012cited by this paper
• Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis.

  2012cited by this paper
• An early circulating factor in severe sepsis modulates apoptosis of monocytes and lymphocytes

  2011cited by this paper
• The late phase of sepsis is characterized by an increased microbiological burden and death rate

  2011cited by this paper
• The search for effective therapy for sepsis: back to the drawing board?

  2011cited by this paper
• Mechanism of T cell exhaustion in a chronic environment.

  2011cited by this paper
• Binding of Superantigen Toxins into the CD28 Homodimer Interface Is Essential for Induction of Cytokine Genes That Mediate Lethal Shock

  2011cited by this paper
• Immunomodulatory therapy for sepsis: an update

  2011influential reference
• Clinical review: flow cytometry perspectives in the ICU - from diagnosis of infection to monitoring of injury-induced immune dysfunctions

  2011cited by this paper
• Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases

  2011cited by this paper
• Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome

  2011cited by this paper
• Prospects for TIM3-Targeted Antitumor Immunotherapy.

  2011cited by this paper
• The CD4-like molecule LAG-3, biology and therapeutic applications

  2011cited by this paper
• ICU-acquired immunosuppression and the risk for secondary fungal infections.

  2011cited by this paper
• Immunosuppression in patients who die of sepsis and multiple organ failure.

  2011cited by this paper
• Immunologic alterations and the pathogenesis of organ failure in the ICU.

  2011influential reference
• Peroxisome proliferator-activated receptor γ-induced T cell apoptosis reduces survival during polymicrobial sepsis.

  2011cited by this paper
• Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors.

  2011cited by this paper
• Cytomegalovirus reactivation and associated outcome of critically ill patients with severe sepsis

  2011cited by this paper
• Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients

  2011cited by this paper
• Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis

  2011cited by this paper
• Treatment with granulocyte–macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock

  2010cited by this paper
• An enigmatic tail of CD28 signaling.

  2010cited by this paper
• Cell Death

  2010cited by this paper
• Sepsis-Induced Apoptosis Leads to Active Suppression of Delayed-Type Hypersensitivity by CD8+ Regulatory T Cells through a TRAIL-Dependent Mechanism

  2010cited by this paper
• Immunotherapy for sepsis--a new approach against an ancient foe.

  2010cited by this paper
• Phase I Study of Recombinant Human Interleukin-7 Administration in Subjects with Refractory Malignancy

  2010cited by this paper
• Delayed administration of anti‐PD‐1 antibody reverses immune dysfunction and improves survival during sepsis

  2010cited by this paper
• Genome-wide transcription profiling of human sepsis: a systematic review

  2010cited by this paper
• Th17 and regulatory T cells in mediating and restraining inflammation.

  2010cited by this paper
• PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction

  2010cited by this paper
• IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis

  2010cited by this paper
• T‐cell exhaustion: characteristics, causes and conversion

  2010influential reference
• T-CELL ACTIVATION DIFFERENTIALLY MEDIATES THE HOST RESPONSE TO SEPSIS

  2010cited by this paper
• Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit*

  2009cited by this paper
• PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis

  2009cited by this paper
• Increased circulating regulatory T cells (CD4+CD25+CD127−) contribute to lymphocyte anergy in septic shock patients

  2009cited by this paper
• Molecular biology of inflammation and sepsis: A primer*

  2009influential reference
• The role of T regulatory cells in human sepsis.

  2009cited by this paper
• Animal models of sepsis: Why does preclinical efficacy fail to translate to the clinical setting?

  2009cited by this paper
• Sepsis‐induced human lymphocyte apoptosis and cytokine production in “humanized” mice

  2009cited by this paper
• Decrease of CD4-lymphocytes and apoptosis of CD14-monocytes are characteristic alterations in sepsis caused by ventilator-associated pneumonia: results from an observational study

  2009cited by this paper
• IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection.

  2009cited by this paper
• IL-15 Prevents Apoptosis, Reverses Innate and Adaptive Immune Dysfunction, and Improves Survival in Sepsis

  2009cited by this paper
• The sepsis seesaw: tilting toward immunosuppression

  2009cited by this paper
• Twelve immunotherapy drugs that could cure cancers.

  2008cited by this paper
• Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis

  2008cited by this paper
• Apoptosis in sepsis: mechanisms, clinical impact and potential therapeutic targets.

  2008cited by this paper
• Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets

  2008cited by this paper
• Role of Toll-like receptor responses for sepsis pathogenesis.

  2008cited by this paper
• Host-pathogen interactions in sepsis.

  2008cited by this paper
• Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock

  2008cited by this paper
• Increased mortality in long-term intensive care patients with active cytomegalovirus infection*

  2008cited by this paper
• Regulatory T cell populations in sepsis and trauma

  2008cited by this paper
• The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome.

  2008cited by this paper
• Immunoparalysis and adverse outcomes from critical illness.

  2008cited by this paper
• PD-1 and its ligands in tolerance and immunity.

  2008cited by this paper
• The Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008.

  2008cited by this paper
• Downregulation of CD40 Ligand Response in Monocytes from Sepsis Patients

  2008cited by this paper
• The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum

  2008cited by this paper
• Efficacy and safety of renal tubule cell therapy for acute renal failure.

  2008cited by this paper
• Principles of adoptive T cell cancer therapy.

  2007cited by this paper
• Evolving functions of endothelial cells in inflammation

  2007cited by this paper
• A randomized controlled trial of granulocyte colony-stimulating factor for the treatment of severe sepsis due to melioidosis in Thailand.

  2007cited by this paper
• Multiple triggers of cell death in sepsis: death receptor and mitochondrial‐mediated apoptosis

  2007cited by this paper
• Coupled plasma filtration adsorption.

  2007cited by this paper
• The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection

  2007cited by this paper
• MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis

  2007cited by this paper
• Surviving sepsis: bcl-2 overexpression modulates splenocyte transcriptional responses in vivo.

  2007cited by this paper
• Chronic Sepsis Mortality Characterized by an Individualized Inflammatory Response1

  2007cited by this paper
• Adoptive T cell therapy for cancer in the clinic.

  2007cited by this paper
• Involvement of the Programmed Death-1/Programmed Death-1 Ligand Pathway in CD4+CD25+ Regulatory T-Cell Activity to Suppress Alloimmune Responses

  2007cited by this paper
• The systemic inflammatory response syndrome.

  2006influential reference
• Mechanisms of Mortality in Early and Late Sepsis

  2006cited by this paper
• Regulation of immune responses by T cells.

  2006cited by this paper
• Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis.

  2006cited by this paper
• Safety and efficacy of affinity-purified, anti–tumor necrosis factor-&agr;, ovine fab for injection (CytoFab) in severe sepsis*

  2006cited by this paper
• Compartmentalization of the inflammatory response in sepsis and SIRS.

  2006cited by this paper
• Human CD4+CD25+ Regulatory T Lymphocytes Inhibit Lipopolysaccharide-Induced Monocyte Survival through a Fas/Fas Ligand-Dependent Mechanism1

  2006cited by this paper
• Cell death signalling pathways in the pathogenesis and therapy of haematologic malignancies: overview of therapeutic approaches.

  2006influential reference
• IL-7 Administration to Humans Leads to Expansion of CD8+ and CD4+ Cells but a Relative Decrease of CD4+ T-Regulatory Cells

  2006cited by this paper

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• High expression of IRF4 mediated by m6A modification promotes immunosuppression in the late phase of sepsis

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• Inflammatory parameters in the prediction of sepsis-induced acute kidney injury: a case-control study

  2025cites this paper
• From Molecular Mechanisms of the Pathogenesis of Sepsis to the Novel Healing Biomolecules: Recent Progressions in Dealing With Sepsis

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• Assessing Monoclonal and Polyclonal Antibodies in Sepsis and Septic Shock: A Systematic Review of Efficacy and Safety

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• Hemoperfusion with Seraph-100 in septic patients removes pathogens and improves clinical outcomes

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• Resolvin D2 restores monocyte anisocytosis and mediates a shift toward classical monocytes ex vivo in blood samples from patients after major burns

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• Critical Care Pharmacology of Antiretroviral Therapy in Adults

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• The Role and Research Progress of CD8+ T Cells in Sepsis

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• Dynamic changes of natural killer cell immunophenotypes and receptors according to the mortality in the intra-abdominal murine sepsis model

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• The effect of cortisol on equine monocyte–derived dendritic cell phenotype and cytokine production

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• FOXO1-mediated autophagy regulation by miR-223 in sepsis-induced immunosuppression

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• Soluble Neuropilin-1 Is Elevated in Sepsis and Correlates with Organ Dysfunction and Long-Term Mortality in Critical Illness

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• Prognostic Significance of NLR and PLR in COVID-19: A Multi-Cohort Validation Study

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• Elevated Midkine Serum Levels Are Associated with Long-Term Survival in Critically Ill Patients

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• Whole blood transcriptomics identifies subclasses of pediatric septic shock

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• Neutrophil Extracellular Traps Are Induced by Coronavirus 2019 Disease-Positive Patient Plasma and Persist Longitudinally: A Possible Link to Endothelial Dysfunction as Measured by Syndecan-1

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• Comparison of whole blood cytokine immunoassays for rapid, functional immune phenotyping in critically ill patients with sepsis

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• Impact of Sepsis on the Oncologic Outcomes of Advanced Epithelial Ovarian Cancer Patients: A Multicenter Observational Study

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• O-GlcNAcylation Modification in Immune Cells: Potential Therapeutic Implications of Sepsis

  2023cites this paper
• α-Aminobutyric Acid Constrains Macrophage-Associated Inflammatory Diseases through Metabolic Reprogramming and Epigenetic Modification

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• Advances in Rodent Experimental Models of Sepsis

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• Vitamin D receptor (VDR) on the cell membrane of mouse macrophages participates in the formation of lipopolysaccharide tolerance: mVDR is related to the effect of artesunate to reverse LPS tolerance

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• Relationship Between the Expression of PD-1 and CTLA-4 on T Lymphocytes and the Severity and Prognosis of Sepsis

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• The leaky gut and the gut microbiome in sepsis – targets in research and treatment

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  2023cites this paper
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  2023cites this paper
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• Inflammation and Cell Death of the Innate and Adaptive Immune System during Sepsis

  2021cites this paper
• Immune Modulation in Critically Ill Septic Patients

  2021cites this paper
• Sepsis and Septic Shock; Current Treatment Dilemma and Role of Stem Cell Therapy in Pediatrics

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• Epigenomic and transcriptomic differences between low-grade and acute inflammation in LPS-induced murine immune cells

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• Use of ticagrelor and the risks of pneumonia and pneumonia-specific death in patients with non-acute coronary syndrome conditions: a population-based cohort study

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• Effects of IL-7 on sepsis: a systematic review

  2021cites this paper
• Methotrexate Ameliorates Systemic Inflammation and Septic Associated-Lung Damage in a Cecal Ligation and Puncture Septic Rat Model

  2021cites this paper
• Novel Therapeutics for the Treatment of Burn Infection

  2020cites this paper
• Silencing of long non-coding RNA MALAT1 suppresses inflammation in septic mice: role of microRNA-23a in the down-regulation of MCEMP1 expression

  2020cites this paper
• Defective Granuloma Formation in Elderly Infected Patients

  2020cites this paper
• Alterations in Peripheral Lymphocyte Subsets in Early Stage of Novel Coronavirus Pneumonia

  2020cites this paper
• CTRP4 acts as an anti‐inflammatory factor in macrophages and protects against endotoxic shock

  2020cites this paper
• Clinical Trial Assessment of Intermittent and Continuous Infusion Dose of N-Acetylcysteine on Redox Status of the Body in Patients with Sepsis Admitted to the ICU

  2020cites this paper
• TREML4 receptor regulates inflammation and innate immune cell death during polymicrobial sepsis

  2020cites this paper
• TLR4-Independent Effects of LPS Identified Using Longitudinal Serum Proteomics.

  2020cites this paper
• miR-10a in Peripheral Blood Mononuclear Cells Is a Biomarker for Sepsis and Has Anti-Inflammatory Function

  2020cites this paper
• Deciphering heterogeneity of septic shock patients using immune functional assays: a proof of concept study

  2020cites this paper
• The unleashing of the immune system in COVID-19 and sepsis: the calm before the storm?

  2020cites this paper
• Scald Injury-Induced T Cell Dysfunction Can Be Mitigated by Gr1+ Cell Depletion and Blockage of CD47/CD172a Signaling

  2020cites this paper
• Early suppression of peripheral mononuclear blood cells in sepsis in response to stimulation with cytomegalovirus, OKT3, and pokeweed mitogen.

  2019cites this paper
• Platelet-Lymphocyte Ratio After Granulocyte Colony Stimulating Factor Administration: An Early Prognostic Marker in Septic Shock Patients with Chemotherapy-Induced Febrile Neutropenia.

  2019cites this paper
• Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

  2019cites this paper
• Pro-inflammatory agents released by pathogens, dying host cells, and neutrophils act synergistically to destroy host tissues: a working hypothesis

  2019cites this paper
• Silence of long noncoding RNA NEAT1 exerts suppressive effects on immunity during sepsis by promoting microRNA‐125‐dependent MCEMP1 downregulation

  2019cites this paper
• Loss of monocyte metabolic plasticity in endotoxin tolerance: A model for understanding sepsis‐induced immune paralysis?

  2019cites this paper
• Failures of intensive treatment of multiple organ failure: pathophysiology and the need for personalization

  2019cites this paper
• Dialyzable Leukocyte Extract (Transferon™) Administration in Sepsis: Experience from a Single Referral Pediatric Intensive Care Unit

  2019cites this paper
• The Diverse Function of PD-1/PD-L Pathway Beyond Cancer

  2019cites this paper
• Identification of suitable controls for miRNA quantification in T-cells and whole blood cells in sepsis

  2019cites this paper
• Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells

  2019cites this paper
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  2019cites this paper
• Ketamine Improves Sepsis-induced Immunosuppression by Attenuating Intracellular Calcium Elevation in Rat Peripheral Mononuclear Cells

  2018cites this paper
• Influence of autophagy on acute kidney injury in a murine cecal ligation and puncture sepsis model

  2018cites this paper
• Flow cytometric analysis of total lymphocyte apoptosis, a potential prognostic assay for sepsis

  2018cites this paper
• Using of TLR2 and TLR4 as Biomarker of Sepsis Severity Detection

  2018cites this paper
• Multidrug resistant bacteria in critically ill patients: a step further antibiotic therapy

  2018cites this paper
• Role of interleukin-3 as a prognostic marker in septic patients

  2018cites this paper
• Effects of the timing of administration of IgM- and IgA-enriched intravenous polyclonal immunoglobulins on the outcome of septic shock patients

  2018influential citation
• Sex and bacterial infectious diseases

  2018cites this paper
• TNFR1 Signaling Contributes to T Cell Anergy During Staphylococcus aureus Sepsis

  2018cites this paper
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• Intérêt de la recherche d’une hypophosphorémie au cours du sepsis

  2017cites this paper
• Interleukin-1 receptor-associated kinase 3 downregulation in peripheral blood mononuclear cells attenuates immunosuppression in sepsis.

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