TEMPORAL CHANGES IN INNATE AND ADAPTIVE IMMUNITY DURING SEPSIS AS DETERMINED BY ELISPOT.

Background: The inability to evaluate host immunity in a rapid quantitative manner in patients with sepsis has severely hampered development of novel immune therapies. The enzyme-linked immunospot (ELISpot) assay is a functional bioassay that measures the number of cytokine-secreting cells and the relative amount of cytokine produced at the single-cell level. A key advantage of ELISpot is its excellent dynamic range enabling a more precise quantifiable assessment of host immunity.

Low-dose interleukin-2 reverses chronic migraine-related sensitizations through peripheral interleukin-10 and transforming growth factor beta-1 signaling.

Low-dose interleukin-2 (LD-IL-2) treatment has been shown to effectively reverse chronic migraine-related behaviors and the sensitization of trigeminal ganglion (TG) neurons through expansion and activation of peripheral regulatory T cells (Tregs) in mice. In this study, we investigated the molecular mechanisms underlying the effects of LD-IL-2 and Treg cells. LD-IL-2 treatment increases the production of cytokines interleukin-10 (IL-10) and transforming growth factor beta-1 (TGFβ1) in T cells, especially Treg cells, suggesting that they may mediate the therapeutic effect of LD-IL-2.

Viral Delivery of IL-7 Is a Potent Immunotherapy Stimulating Innate and Adaptive Immunity and Confers Survival in Sepsis Models.

Persistence of an immunosuppressive state plays a role in septic patient morbidity and late mortality. Both innate and adaptive pathways are impaired, pointing toward the need for immune interventions targeting both arms of the immune system. We developed a virotherapy using the nonpropagative modified vaccinia virus Ankara (MVA), which harbors the intrinsic capacity to stimulate innate immunity, to deliver IL-7, a potent activator of adaptive immunity.

Frontline Science: OX40 agonistic antibody reverses immune suppression and improves survival in sepsis.

A defining feature of protracted sepsis is development of immunosuppression that is thought to be a major driving force in the morbidity and mortality associated with the syndrome. The immunosuppression that occurs in sepsis is characterized by profound apoptosis-induced depletion of CD4 and CD8 T cells and severely impaired T cell function. OX40, a member of the TNF receptor superfamily, is a positive co-stimulatory molecule expressed on activated T cells.

A Peptide-Based Checkpoint Immunomodulator Alleviates Immune Dysfunction in Murine Polymicrobial Sepsis.

Sepsis-induced immunosuppression involves both innate and adaptive immunity and is associated with the increased expression of checkpoint inhibitors, such as programmed cell-death protein 1 (PD-1). The expression of PD-1 is associated with poor outcomes in septic patients, and in models of sepsis, blocking PD-1 or its ligands with antibodies increased survival and alleviated immune suppression. While inhibitory antibodies are effective, they can lead to immune-related adverse events (irAEs), in part due to continual blockade of the PD-1 pathway, resulting in hyperactivation of the immune response.

Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections.

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections.

Low-dose interleukin-2 reverses behavioral sensitization in multiple mouse models of headache disorders.

Headache disorders are highly prevalent and debilitating, with limited treatment options. Previous studies indicate that many proinflammatory immune cells contribute to headache pathophysiology. Given the well-recognized role of regulatory T (Treg) cells in maintaining immune homeostasis, we hypothesized that enhancing Treg function may be effective to treat multiple headache disorders.

Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial.

Background: A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common γ-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity.

Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia.

Patients with protracted sepsis develop impaired immunity, which predisposes them to acquiring secondary infections. One of the most common and lethal secondary infections is Pseudomonas aeruginosa pneumonia. Immunoadjuvant therapy is a promising approach to reverse sepsis-induced immunosuppression and improve morbidity and mortality from secondary infections.

Interleukin-7 and anti-programmed cell death 1 antibody have differing effects to reverse sepsis-induced immunosuppression.

Sepsis remains a major cause of morbidity and mortality in most intensive care units. Protracted sepsis can evolve into a state of profound immunosuppression characterized by secondary infections, frequently with opportunistic-type pathogens. Immunoadjuvant therapy is currently being evaluated as a novel treatment for patients with sepsis.

The new normal: immunomodulatory agents against sepsis immune suppression.

Sepsis is the leading cause of death among critically ill patients in intensive care units, and treatment options are limited. Therapies developed against the proinflammatory stage have failed clinically; therefore, new approaches that target the host immune response in sepsis are necessary. Increasing evidence suggests that a major pathophysiological event in sepsis is immune suppression, often resulting in secondary fungal, bacterial, or viral infections.

Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis.

Introduction: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).

Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis.

Background: Secondary hospital-acquired fungal infections are common in critically-ill patients and mortality remains high despite antimicrobial therapy. Interleukin-7 (IL-7) is a potent immunotherapeutic agent that improves host immunity and has shown efficacy in bacterial and viral models of infection. This study examined the ability of IL-7, which is currently in multiple clinical trials (including hepatitis and human immunodeficiency virus), to improve survival in a clinically relevant 2-hit model of fungal sepsis.

Dose-dependent effect of anti-CTLA-4 on survival in sepsis.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T-cell activation and proliferation, which opposes the actions of CD28-mediated costimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition that shares many of the same mechanisms of immune suppression with cancer.

Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis.

The sepsis syndrome represents an improper immune response to infection and is associated with unacceptably high rates of mortality and morbidity. The interactions between T cells and the innate immune system while combating sepsis are poorly understood. In this report, we observed that treatment with the potent, antiapoptotic cytokine interleukin-7 (IL-7) accelerated neutrophil recruitment and improved bacterial clearance.

Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis.

There is increasing recognition that a major pathophysiologic event in sepsis is the progression to an immunosuppressive state in which the host is unable to eradicate invading pathogens. Although there are likely numerous causes for the immunosuppression, expression of negative costimulatory molecules on immune effector cells is a likely contributing factor. PD-1 is a recently described, negative costimulatory molecule that has potent effects to inhibit T cell activation, cytokine production, and cytotoxic functions.

Sepsis-induced apoptosis leads to active suppression of delayed-type hypersensitivity by CD8+ regulatory T cells through a TRAIL-dependent mechanism.

Patients who survive severe sepsis often display severely compromised immune function. One hallmark of such immune suppression in septic patients is an impaired delayed-type hypersensitivity (DTH) response, manifested by a loss of skin testing to recall Ags. Because sepsis induces significant apoptosis in lymphoid and myeloid cells, and apoptotic cells are themselves tolerogenic, we tested the hypothesis that suppression of DTH is mediated by tolerogenic properties of the apoptotic cells generated during sepsis.

IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis.

Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model.

IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis.

IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis.

Sepsis-induced human lymphocyte apoptosis and cytokine production in "humanized" mice.

Sepsis is the leading cause of death in critically ill patients in the United States with over 210,000 deaths annually. One stumbling block to an effective therapy of sepsis has been the lack of a clinically relevant animal model. There are important distinctions in the mouse versus human immune system regarding the host response to invading pathogens.

Differential lymphopenia-induced homeostatic proliferation for CD4+ and CD8+ T cells following septic injury.

Sepsis is a severe, life-threatening infection and a leading cause of death in hospitals. A hallmark of sepsis is the profound apoptosis-induced depletion of lymphocytes generating a lymphopenic environment. As lymphopenia can induce nonantigen-driven homeostatic proliferation (HP), we examined this process during sepsis.

Targeted delivery of siRNA to cell death proteins in sepsis.

Immune suppression is a major cause of morbidity and mortality in the patients with sepsis. Apoptotic loss of immune effector cells such as CD4 T and B cells is a key component in the loss of immune competence in sepsis. Inhibition of lymphocyte apoptosis has led to improved survival in animal models of sepsis.

Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages.

This study examined the fate of dendritic cells (DCs) and macrophages (M Phi) in vivo in a murine model of sepsis. Wild-type, knockout, and transgenic mice were used to examine the role of Bcl-2 family members on the regulation of splenic DCs and M Phi survival. Bim knockout (Bim) mice and mice overexpressing Bcl-2 in selected hematopoietic cells were used: (a) overexpression of Bcl-2 in all hematopoietic cells using a vav promoter (Vav-Bcl-2) and (b) overexpression of Bcl-2 in all Major histocompatibility complex (MHC) class I cells (H-2K-Bcl-2).